Study of Durvalumab With Tremelimumab Versus SoC as 1st Line Therapy in Metastatic Non Small-Cell Lung Cancer (NSCLC) (NEPTUNE).
Sponsor
AstraZeneca (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02542293
Collaborator
(none)
953
212
2
85.9
4.5
0.1
Study Details
Study Description
Brief Summary
This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of durvalumab + tremelimumab combination therapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type advanced or metastatic NSCLC.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Patients will be randomized in a 1:1 to receive treatment with durvalumab + tremelimumab combination therapy or SoC therapy. The primary objective of this study is to assess the efficacy of combination treatment compared with SoC in terms of Overall Survival (OS) in patients.
Study Design
Study Type:
Interventional
Actual Enrollment
:
953 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC)
Actual Study Start Date
:
Nov 3, 2015
Actual Primary Completion Date
:
Sep 21, 2020
Anticipated Study Completion Date
:
Dec 30, 2022
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Combination Therapy Durvalumab (PD-L1 monoclonal antibody) + Tremelimumab (monoclonal antibody directed against CTLA-4) |
Biological: Durvalumab +Tremelimumab
|
| Active Comparator: Standard of Care Standard of Care chemotherapy treatment |
Drug: Paclitaxel + carboplatin
Chemotherapy Agents
Other Names:
Drug: Gemcitabine + cisplatin
Chemotherapy Agents
Other Names:
Drug: Gemcitabine + carboplatin
Chemotherapy Agents
Other Names:
Drug: Pemetrexed + cisplatin
Chemotherapy Agent
Other Names:
Drug: Pemetrexed + carboplatin
Chemotherapy Agent
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Overall Survival (OS); Global Cohort: Blood Tumor Mutational Burden (bTMB) ≥20 Mutations Per Megabase (Mut/Mb) Analysis Set [From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months).]
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
- OS; China Cohort: China Programmed Cell Death Ligand 1 (PD-L1) Negative NSCLC Analysis Set [From baseline (Day 1, Week 0) until death due to any cause, assessed up to the China cohort DCO date (a maximum of approximately 44 months).]
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Secondary Outcome Measures
- OS; Global Cohort: bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, PD-L1-Negative NSCLC, bTMB <20 Mut/Mb, bTMB Non-Evaluable Population, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets [From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months).]
OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at time of analysis was censored based on last recorded date on which participant was known to be alive. bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb and bTMB <20 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥16 mut/Mb, ≥12 mut/Mb and <20 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). bTMB non-evaluable analysis set included the subset of participants in FAS whose bTMB status at baseline could not be determined by the GuardantOMNI CDx assay or whose sample was not available. tTMB analysis sets are defined same as the bTMB analysis sets.
- OS; Global and China Cohorts: FAS, PD-L1 Tumor Cell (TC) ≥25%, and PD-L1 TC ≥50% Analysis Sets [From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global or China cohort DCO dates, as applicable (a maximum of approximately 44 months) for each cohort.]
The OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on last recorded date on which participant was known to be alive. Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.
- Progression-Free Survival (PFS); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).]
The PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- PFS; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.]
PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective PD or death regardless of whether participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). PD-L1-negative analysis set included subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: FAS included all randomized participants prior to end of global recruitment. China Cohort: China FAS included all randomized participants in China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included subset of participants in FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.
- Objective Response Rate (ORR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).]
The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) prior to PD. bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- ORR; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.]
The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay.
- Duration of Response (DoR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).]
DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- DoR; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.]
DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.
- Alive and Progression-Free at 12 Months (APF12); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets [Tumour scans performed at baseline then every 6 weeks up to 12 months.]
The APF12 was defined as the percentage of participants who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- APF12; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets [Tumour scans performed at baseline then every 6 weeks up to 12 months.]
The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.
- Time From Randomization to Second Progression or Death (PFS2); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months).]
The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- PFS2; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets [Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort.]
The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.
- OS at Months 12, 18 and 24; Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets [Months 12, 18 and 24]
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay.
- OS at Months 12, 18 and 24; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets [Months 12, 18 and 24]
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses.
- Serum Concentrations of Durvalumab [Pre-dose and within 1 hour after end of infusion at Week 0 and 12; pre-dose on Week 24 and at follow-up Month 3]
Blood samples were collected to determine the serum concentration of durvalumab.
- Serum Concentrations of Tremelimumab [Pre-dose and within 1 hour after end of infusion at Week 0 and 12, and at follow-up Month 3]
Blood samples were collected to determine the serum concentration of tremelimumab.
- Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab [At Weeks 0, 12, and 24; 3 and 6 months after last dose of study treatment.]
Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive.
- Number of Participants With ADA Response to Tremelimumab [At Weeks 0 and 12; 3 and 6 months after last dose of study treatment.]
Blood samples were measured for the presence of ADAs and ADA-nAb for tremelimumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 130 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
For inclusion in the study, patients should fulfill the following criteria:
-
Aged at least 18 years
-
Documented evidence of Stage IV NSCLC
-
No activating EGFR mutation or ALK rearrangement
-
No prior chemotherapy or any other systemic therapy for recurrent/metastatic NSCLC
-
World Health Organization (WHO) Performance Status of 0 or 1
-
No Prior exposure to Immune Mediated Therapy (IMT), including, but not limited to, other antiCTLA4, antiPD1, anti PDL1,or antiPDL2 antibodies, excluding therapeutic anticancer vaccines
Exclusion Criteria:
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
-
Mixed small cell lung cancer and NSCLC histology, sarcomatoid variant
-
Brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases) and off steroids for at least 14 days prior to start of study treatment.
-
Active or prior documented autoimmune or inflammatory disorders (e.g., Crohn's disease, ulcerative colitis)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Anaheim | California | United States | 92801 |
| 2 | Research Site | San Diego | California | United States | 92123 |
| 3 | Research Site | Santa Rosa | California | United States | 95403 |
| 4 | Research Site | Louisville | Kentucky | United States | 40202 |
| 5 | Research Site | Florham Park | New Jersey | United States | 07932 |
| 6 | Research Site | Albuquerque | New Mexico | United States | 87102 |
| 7 | Research Site | East Setauket | New York | United States | 11733 |
| 8 | Research Site | Fresh Meadows | New York | United States | 11366 |
| 9 | Research Site | Poughkeepsie | New York | United States | 12601 |
| 10 | Research Site | Stony Brook | New York | United States | 11794 |
| 11 | Research Site | Canton | Ohio | United States | 44710 |
| 12 | Research Site | Columbus | Ohio | United States | 43219 |
| 13 | Research Site | Zanesville | Ohio | United States | 43701 |
| 14 | Research Site | Pittsburgh | Pennsylvania | United States | 15212 |
| 15 | Research Site | Houston | Texas | United States | 77090 |
| 16 | Research Site | Berazategui | Argentina | B1884BBF | |
| 17 | Research Site | Buenos Aires | Argentina | C1025ABI | |
| 18 | Research Site | Caba | Argentina | C1426ANZ | |
| 19 | Research Site | Córdoba | Argentina | 5000 | |
| 20 | Research Site | La Rioja | Argentina | 5300 | |
| 21 | Research Site | Rosario | Argentina | S2000KZE | |
| 22 | Research Site | San Salvador de Jujuy | Argentina | 4600 | |
| 23 | Research Site | Santa Rosa | Argentina | 6300 | |
| 24 | Research Site | Barretos | Brazil | 14784-400 | |
| 25 | Research Site | Belo Horizonte | Brazil | 30110-022 | |
| 26 | Research Site | Belo Horizonte | Brazil | 30380-472 | |
| 27 | Research Site | Fortaleza | Brazil | 60336-045 | |
| 28 | Research Site | Ijui | Brazil | 98700-000 | |
| 29 | Research Site | Itajai | Brazil | 88310-110 | |
| 30 | Research Site | Porto Alegre | Brazil | 90035-003 | |
| 31 | Research Site | Porto Alegre | Brazil | 90160-093 | |
| 32 | Research Site | Porto Alegre | Brazil | 91350-200 | |
| 33 | Research Site | Sao Paulo | Brazil | 01221-020 | |
| 34 | Research Site | Sao Paulo | Brazil | 01246-000 | |
| 35 | Research Site | Sao Paulo | Brazil | 01323 900 | |
| 36 | Research Site | São José do Rio Preto | Brazil | 15090-000 | |
| 37 | Research Site | São Paulo | Brazil | 03102-002 | |
| 38 | Research Site | Plovdiv | Bulgaria | 4004 | |
| 39 | Research Site | Shumen | Bulgaria | 9700 | |
| 40 | Research Site | Sofia | Bulgaria | 1303 | |
| 41 | Research Site | Sofia | Bulgaria | 1330 | |
| 42 | Research Site | Sofia | Bulgaria | 1431 | |
| 43 | Research Site | Sofia | Bulgaria | 1784 | |
| 44 | Research Site | Varna | Bulgaria | 9010 | |
| 45 | Research Site | Vratza | Bulgaria | 3000 | |
| 46 | Research Site | Santiago | Chile | 7500713 | |
| 47 | Research Site | Santiago | Chile | 7500921 | |
| 48 | Research Site | Santiago | Chile | 7520349 | |
| 49 | Research Site | Santiago | Chile | 8380456 | |
| 50 | Research Site | Santiago | Chile | 8420383 | |
| 51 | Research Site | Temuco | Chile | 4810297 | |
| 52 | Research Site | Viña del Mar | Chile | 2520612 | |
| 53 | Research Site | Beijing | China | 100142 | |
| 54 | Research Site | Changchun | China | 130000 | |
| 55 | Research Site | Chongqing | China | 400030 | |
| 56 | Research Site | Guangzhou | China | 510100 | |
| 57 | Research Site | Hangzhou | China | 310022 | |
| 58 | Research Site | Shanghai | China | 200030 | |
| 59 | Research Site | Shanghai | China | 200032 | |
| 60 | Research Site | Urumqi | China | 830000 | |
| 61 | Research Site | Wuhan | China | 430022 | |
| 62 | Research Site | Wuhan | China | 430030 | |
| 63 | Research Site | Odense C | Denmark | 5000 | |
| 64 | Research Site | Oulu | Finland | FI-90029 | |
| 65 | Research Site | Tampere | Finland | FI-33521 | |
| 66 | Research Site | Athens | Greece | 115 22 | |
| 67 | Research Site | Athens | Greece | 11527 | |
| 68 | Research Site | Athens | Greece | 14564 | |
| 69 | Research Site | Heraklion | Greece | 711 11 | |
| 70 | Research Site | Holargos, Athens | Greece | 155 62 | |
| 71 | Research Site | Ioannina | Greece | 45000 | |
| 72 | Research Site | Hong Kong | Hong Kong | ||
| 73 | Research Site | King's Park | Hong Kong | 150001 | |
| 74 | Research Site | Shatin | Hong Kong | 00000 | |
| 75 | Research Site | Ahmedabad | India | 380016 | |
| 76 | Research Site | Bangalore | India | 560068 | |
| 77 | Research Site | Bangalore | India | 560076 | |
| 78 | Research Site | Chennai | India | 600035 | |
| 79 | Research Site | Gurgaon | India | 122001 | |
| 80 | Research Site | Karamsad | India | 388325 | |
| 81 | Research Site | New Delhi | India | 110 085 | |
| 82 | Research Site | Beer Sheva | Israel | 8410101 | |
| 83 | Research Site | Jerusalem | Israel | 91031 | |
| 84 | Research Site | Kfar Saba | Israel | 95847 | |
| 85 | Research Site | Nahariya | Israel | 22100 | |
| 86 | Research Site | Petah Tikva | Israel | 49100 | |
| 87 | Research Site | Ramat Gan | Israel | 5265601 | |
| 88 | Research Site | Bunkyo-ku | Japan | 160-0023 | |
| 89 | Research Site | Fukushima-shi | Japan | 960-1295 | |
| 90 | Research Site | Habikino-shi | Japan | 583-8588 | |
| 91 | Research Site | Hirosaki-shi | Japan | 036-8545 | |
| 92 | Research Site | Iizuka-shi | Japan | 820-8505 | |
| 93 | Research Site | Iwakuni-shi | Japan | 740-8510 | |
| 94 | Research Site | Kanazawa | Japan | 920-8641 | |
| 95 | Research Site | Kishiwada-shi | Japan | 596-8501 | |
| 96 | Research Site | Kobe-shi | Japan | 650-0047 | |
| 97 | Research Site | Kurume-shi | Japan | 830-0011 | |
| 98 | Research Site | Kyoto-shi | Japan | 607-8062 | |
| 99 | Research Site | Mitaka-shi | Japan | 181-8611 | |
| 100 | Research Site | Nagaoka-shi | Japan | 940-2085 | |
| 101 | Research Site | Nagoya-shi | Japan | 460-0001 | |
| 102 | Research Site | Nagoya-shi | Japan | 466-8560 | |
| 103 | Research Site | Niigata-shi | Japan | 951-8566 | |
| 104 | Research Site | Okayama-shi | Japan | 700-8607 | |
| 105 | Research Site | Osaka-shi | Japan | 541-8567 | |
| 106 | Research Site | Saga-shi | Japan | 840-8571 | |
| 107 | Research Site | Sagamihara-shi | Japan | 252-0375 | |
| 108 | Research Site | Sakai-shi | Japan | 591-8555 | |
| 109 | Research Site | Sendai-shi | Japan | 980-0873 | |
| 110 | Research Site | Tokushima-shi | Japan | 770-8503 | |
| 111 | Research Site | Ube-shi | Japan | 755-0241 | |
| 112 | Research Site | Wakayama-shi | Japan | 641-8510 | |
| 113 | Research Site | Yokohama-shi | Japan | 236-0004 | |
| 114 | Research Site | Yokohama-shi | Japan | 241-8515 | |
| 115 | Research Site | Daegu | Korea, Republic of | 41404 | |
| 116 | Research Site | Hwasun-gun | Korea, Republic of | 58128 | |
| 117 | Research Site | Seoul | Korea, Republic of | 05030 | |
| 118 | Research Site | Seoul | Korea, Republic of | 06273 | |
| 119 | Research Site | Seoul | Korea, Republic of | 08308 | |
| 120 | Research Site | Kuala Lumpur | Malaysia | 59100 | |
| 121 | Research Site | Kuantan | Malaysia | 25100 | |
| 122 | Research Site | Kuching | Malaysia | 93586 | |
| 123 | Research Site | Acapulco | Mexico | 39670 | |
| 124 | Research Site | Aguascalientes | Mexico | 20020 | |
| 125 | Research Site | Mexico | Mexico | 14080 | |
| 126 | Research Site | Monterrey | Mexico | 64710 | |
| 127 | Research Site | Mérida | Mexico | 97134 | |
| 128 | Research Site | México | Mexico | 06100 | |
| 129 | Research Site | Arequipa | Peru | AREQUIPA01 | |
| 130 | Research Site | Bellavista | Peru | CALLAO 2 | |
| 131 | Research Site | Lima | Peru | 15033 | |
| 132 | Research Site | Lima | Peru | 41 | |
| 133 | Research Site | Lima | Peru | L27 | |
| 134 | Research Site | Lima | Peru | LIMA 34 | |
| 135 | Research Site | Lima | Peru | LIMA 41 | |
| 136 | Research Site | Baguio City | Philippines | 2600 | |
| 137 | Research Site | Cebu | Philippines | 6000 | |
| 138 | Research Site | Las Pinas City | Philippines | PH-1704 | |
| 139 | Research Site | Manila | Philippines | 1000 | |
| 140 | Research Site | Manila | Philippines | 1003 | |
| 141 | Research Site | Pasay City | Philippines | ||
| 142 | Research Site | Quezon City | Philippines | 1112 | |
| 143 | Research Site | Bydgoszcz | Poland | 85-796 | |
| 144 | Research Site | Kielce | Poland | 25-734 | |
| 145 | Research Site | Kraków | Poland | 31-202 | |
| 146 | Research Site | Mrozy | Poland | 05-320 | |
| 147 | Research Site | Olsztyn | Poland | 10-357 | |
| 148 | Research Site | Poznan | Poland | 60-569 | |
| 149 | Research Site | Poznań | Poland | 60-569 | |
| 150 | Research Site | Warszawa | Poland | 01-138 | |
| 151 | Research Site | Warszawa | Poland | 02-781 | |
| 152 | Research Site | Wodzisław Śląski | Poland | 44-300 | |
| 153 | Research Site | Łódź | Poland | 93-513 | |
| 154 | Research Site | Amadora | Portugal | 2720-276 | |
| 155 | Research Site | Lisboa | Portugal | 1500-650 | |
| 156 | Research Site | Porto | Portugal | 4099-001 | |
| 157 | Research Site | Porto | Portugal | 4100-180 | |
| 158 | Research Site | Porto | Portugal | 4200-319 | |
| 159 | Research Site | Doha | Qatar | P.O. Box 3050 | |
| 160 | Research Site | Suceava | Romania | 720237 | |
| 161 | Research Site | Moscow | Russian Federation | 105229 | |
| 162 | Research Site | Moscow | Russian Federation | 115280 | |
| 163 | Research Site | Moscow | Russian Federation | 125367 | |
| 164 | Research Site | Omsk | Russian Federation | 644013 | |
| 165 | Research Site | Saint Petersburg | Russian Federation | 197022 | |
| 166 | Research Site | Saint Petersburg | Russian Federation | 197342 | |
| 167 | Research Site | Saint-Petersburg | Russian Federation | 194291 | |
| 168 | Research Site | Saint-Petersburg | Russian Federation | 197183 | |
| 169 | Research Site | St. Petersburg | Russian Federation | 197758 | |
| 170 | Research Site | Dammam | Saudi Arabia | 31444 | |
| 171 | Research Site | Riyadh | Saudi Arabia | 11426 | |
| 172 | Research Site | Riyadh | Saudi Arabia | 12372 | |
| 173 | Research Site | Singapore | Singapore | 119228 | |
| 174 | Research Site | Singapore | Singapore | 217562 | |
| 175 | Research Site | Singapore | Singapore | 258499 | |
| 176 | Research Site | Singapore | Singapore | 308433 | |
| 177 | Research Site | Eskilstuna | Sweden | 63188 | |
| 178 | Research Site | Linköping | Sweden | 581 85 | |
| 179 | Research Site | Stockholm | Sweden | 171 64 | |
| 180 | Research Site | Uppsala | Sweden | 751 85 | |
| 181 | Research Site | Adana | Turkey | 01120 | |
| 182 | Research Site | Ankara | Turkey | 06200 | |
| 183 | Research Site | Ankara | Turkey | 06230 | |
| 184 | Research Site | Ankara | Turkey | 06280 | |
| 185 | Research Site | Ankara | Turkey | 6500 | |
| 186 | Research Site | Istanbul | Turkey | 31755 | |
| 187 | Research Site | Istanbul | Turkey | 34030 | |
| 188 | Research Site | Istanbul | Turkey | 34349 | |
| 189 | Research Site | Izmir | Turkey | 35100 | |
| 190 | Research Site | Chernivtsі | Ukraine | 58013 | |
| 191 | Research Site | Dnipro | Ukraine | 49102 | |
| 192 | Research Site | Ivano-Frankivsk | Ukraine | 76018 | |
| 193 | Research Site | Kapitanivka Village | Ukraine | 08111 | |
| 194 | Research Site | Kharkiv Region | Ukraine | 61070 | |
| 195 | Research Site | Kirovohrad | Ukraine | 25006 | |
| 196 | Research Site | Kyiv | Ukraine | 03115 | |
| 197 | Research Site | Kyiv | Ukraine | 04107 | |
| 198 | Research Site | Lviv | Ukraine | 79031 | |
| 199 | Research Site | Lyutizh | Ukraine | 07352 | |
| 200 | Research Site | Odesa | Ukraine | 65055 | |
| 201 | Research Site | Sumy | Ukraine | 40022 | |
| 202 | Research Site | Uzhhorod | Ukraine | 88000 | |
| 203 | Research Site | Vinnytsia | Ukraine | 21029 | |
| 204 | Research Site | Guildford | United Kingdom | ||
| 205 | Research Site | London | United Kingdom | EC1M 6BQ | |
| 206 | Research Site | London | United Kingdom | NW1 2PG | |
| 207 | Research Site | London | United Kingdom | W6 8RF | |
| 208 | Research Site | Manchester | United Kingdom | M20 4BX | |
| 209 | Research Site | Nottingham | United Kingdom | NG5 1PB | |
| 210 | Research Site | Taunton | United Kingdom | TA1 5DA | |
| 211 | Research Site | Wirral | United Kingdom | CH63 4JY | |
| 212 | Research Site | Wolverhampton | United Kingdom | WV10 0QP |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Principal Investigator: Gilberto de Castro, Faculdade de Medicina da Universidade de São Paulo
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02542293
Other Study ID Numbers:
- D419AC00003
First Posted:
Sep 7, 2015
Last Update Posted:
May 24, 2022
Last Verified:
Apr 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | A total of 192 centers across 29 countries in North America, Latin America, Asia, Europe and Gulf countries randomized adults with epidermal growth factor receptor and anaplastic lymphoma kinase wild-type advanced or metastatic non-small-cell lung cancer (NSCLC) in this study. First participant was enrolled on 03 November 2015 and final data cut-off (DCO) date was 24 June 2019 for Global cohort and 21 September 2020 for China cohort. SoC = standard of care |
|---|---|
| Pre-assignment Detail | 823 participants in Global cohort and 160 participants in China cohort were randomized in 1:1 ratio to receive durvalumab + tremelimumab or SoC chemotherapy. China cohort comprised participants from mainland China (30 from Global cohort and 130 randomized after end of Global cohort recruitment). Thus, 953 unique participants were randomized in the study overall. Participants included in both cohorts for Started, Completed and Reasons for Not Completed are not double-counted for participant flow. |
| Arm/Group Title | All Participants: Durvalumab + Tremelimumab | All Participants: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 milligram per kilogram (mg/kg) and tremelimumab 1 mg/kg intravenous (IV) infusion every 4 weeks (Q4W) in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective disease progression (PD), initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/square meter (m^2) and carboplatin area under the plasma concentration curve (AUC) 5 or 6 mg*minute per milliliter (mg*min/mL). Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Period Title: Overall Study | ||
| STARTED | 474 | 479 |
| Randomized in Global Cohort | 410 | 413 |
| Received Treatment in Global Cohort | 410 | 399 |
| Randomized in China Cohort | 78 | 82 |
| Received Treatment in China Cohort | 77 | 78 |
| Included in Both Cohorts (Global and China) | 14 | 16 |
| Ongoing in Study at DCO for Final Analysis in Global Cohort | 75 | 67 |
| Ongoing in Study at DCO for Final Analysis in China Cohort | 27 | 18 |
| COMPLETED | 99 | 83 |
| NOT COMPLETED | 375 | 396 |
Baseline Characteristics
| Arm/Group Title | All Participants: Durvalumab + Tremelimumab | All Participants: SoC Chemotherapy | Total |
|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Total of all reporting groups |
| Overall Participants | 474 | 479 | 953 |
| Age, Customized (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
278
58.6%
|
244
50.9%
|
522
54.8%
|
| >=65 years |
196
41.4%
|
235
49.1%
|
431
45.2%
|
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
233
49.2%
|
203
42.4%
|
436
45.8%
|
| >=65 years |
177
37.3%
|
210
43.8%
|
387
40.6%
|
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
53
11.2%
|
51
10.6%
|
104
10.9%
|
| >=65 years |
25
5.3%
|
31
6.5%
|
56
5.9%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
127
26.8%
|
129
26.9%
|
256
26.9%
|
| Male |
347
73.2%
|
350
73.1%
|
697
73.1%
|
| Female |
113
23.8%
|
108
22.5%
|
221
23.2%
|
| Male |
297
62.7%
|
305
63.7%
|
602
63.2%
|
| Female |
18
3.8%
|
25
5.2%
|
43
4.5%
|
| Male |
60
12.7%
|
57
11.9%
|
117
12.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| White |
307
64.8%
|
289
60.3%
|
596
62.5%
|
| Black or African American |
3
0.6%
|
7
1.5%
|
10
1%
|
| Asian |
150
31.6%
|
165
34.4%
|
315
33.1%
|
| American Indian or Alaska Native |
10
2.1%
|
12
2.5%
|
22
2.3%
|
| Other |
3
0.6%
|
4
0.8%
|
7
0.7%
|
| Missing |
1
0.2%
|
2
0.4%
|
3
0.3%
|
| White |
307
64.8%
|
289
60.3%
|
596
62.5%
|
| Black or African American |
3
0.6%
|
7
1.5%
|
10
1%
|
| Asian |
86
18.1%
|
99
20.7%
|
185
19.4%
|
| American Indian or Alaska Native |
10
2.1%
|
12
2.5%
|
22
2.3%
|
| Other |
3
0.6%
|
4
0.8%
|
7
0.7%
|
| Missing |
1
0.2%
|
2
0.4%
|
3
0.3%
|
| White |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| Asian |
78
16.5%
|
82
17.1%
|
160
16.8%
|
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Other |
0
0%
|
0
0%
|
0
0%
|
| Missing |
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Hispanic or Latino |
50
10.5%
|
48
10%
|
98
10.3%
|
| Not Hispanic or Latino |
423
89.2%
|
429
89.6%
|
852
89.4%
|
| Missing |
1
0.2%
|
2
0.4%
|
3
0.3%
|
| Hispanic or Latino |
50
10.5%
|
48
10%
|
98
10.3%
|
| Not Hispanic or Latino |
359
75.7%
|
363
75.8%
|
722
75.8%
|
| Missing |
1
0.2%
|
2
0.4%
|
3
0.3%
|
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
78
16.5%
|
82
17.1%
|
160
16.8%
|
| Missing |
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| Title | Overall Survival (OS); Global Cohort: Blood Tumor Mutational Burden (bTMB) ≥20 Mutations Per Megabase (Mut/Mb) Analysis Set |
|---|---|
| Description | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| Time Frame | From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The bTMB ≥20 mut/Mb analysis set included the subset of participants in the FAS whose blood TMB status was ≥20 mut/Mb at baseline as defined by the GuardantOMNI CDx assay. Only participants randomized in Global cohort were analyzed as bTMB and tissue tumor mutational burden (tTMB) testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 69 | 60 |
| Median (95% Confidence Interval) [months] |
11.7
|
9.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | Global: Durvalumab + Tremelimumab versus (Vs) Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0808 |
| Comments | The 2-sided p-value was calculated using an unstratified log-rank test. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.71 | |
| Confidence Interval |
(2-Sided) 95% 0.485 to 1.045 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and confidence interval (CI) were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
| Title | OS; China Cohort: China Programmed Cell Death Ligand 1 (PD-L1) Negative NSCLC Analysis Set |
|---|---|
| Description | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| Time Frame | From baseline (Day 1, Week 0) until death due to any cause, assessed up to the China cohort DCO date (a maximum of approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The China PD-L1-negative population analysis set included the subset of participants in the China FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Only participants randomized in China cohort were analyzed. |
| Arm/Group Title | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 26 | 29 |
| Median (95% Confidence Interval) [months] |
15.0
|
11.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.60 | |
| Confidence Interval |
(2-Sided) 95% 0.322 to 1.109 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
| Title | OS; Global Cohort: bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, PD-L1-Negative NSCLC, bTMB <20 Mut/Mb, bTMB Non-Evaluable Population, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets |
|---|---|
| Description | OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at time of analysis was censored based on last recorded date on which participant was known to be alive. bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb and bTMB <20 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥16 mut/Mb, ≥12 mut/Mb and <20 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). bTMB non-evaluable analysis set included the subset of participants in FAS whose bTMB status at baseline could not be determined by the GuardantOMNI CDx assay or whose sample was not available. tTMB analysis sets are defined same as the bTMB analysis sets. |
| Time Frame | From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global cohort DCO date (a maximum of approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb, PD-L1-Negative NSCLC, bTMB <20 mut/Mb, bTMB non-evaluable population, tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb, and tTMB ≥8 mut/Mb analysis sets are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 |
| bTMB ≥16 mut/Mb analysis set |
12.1
|
11.9
|
| bTMB ≥12 mut/Mb analysis set |
10.9
|
10.3
|
| PD-L1 negative analysis set |
11.1
|
12.5
|
| bTMB <20 mut/Mb analysis set |
9.9
|
11.5
|
| bTMB non-evaluable analysis set |
9.3
|
10.4
|
| tTMB ≥14 mut/Mb analysis set |
17.5
|
10.6
|
| tTMB ≥12 mut/Mb analysis set |
11.1
|
13.9
|
| tTMB ≥10 mut/Mb analysis set |
11.1
|
10.6
|
| tTMB ≥8 mut/Mb analysis set |
11.0
|
10.2
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥16 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.87 | |
| Confidence Interval |
(2-Sided) 95% 0.629 to 1.201 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.94 | |
| Confidence Interval |
(2-Sided) 95% 0.726 to 1.213 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 negative analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.07 | |
| Confidence Interval |
(2-Sided) 95% 0.786 to 1.464 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB <20 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.04 | |
| Confidence Interval |
(2-Sided) 95% 0.835 to 1.302 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB non-evaluable analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.01 | |
| Confidence Interval |
(2-Sided) 95% 0.758 to 1.353 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥14 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.57 | |
| Confidence Interval |
(2-Sided) 95% 0.309 to 1.008 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.87 | |
| Confidence Interval |
(2-Sided) 95% 0.560 to 1.350 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥10 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.88 | |
| Confidence Interval |
(2-Sided) 95% 0.614 to 1.251 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 9
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥8 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.78 | |
| Confidence Interval |
(2-Sided) 95% 0.564 to 1.080 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
| Title | OS; Global and China Cohorts: FAS, PD-L1 Tumor Cell (TC) ≥25%, and PD-L1 TC ≥50% Analysis Sets |
|---|---|
| Description | The OS was defined as time from date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis was censored based on last recorded date on which participant was known to be alive. Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay. |
| Time Frame | From baseline (Day 1, Week 0) until death due to any cause, assessed up to the Global or China cohort DCO dates, as applicable (a maximum of approximately 44 months) for each cohort. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% analysis sets are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| FAS |
10.9
|
12.1
|
20.0
|
14.1
|
| PD-L1 TC ≥25% analysis set |
12.2
|
10.4
|
36.6
|
15.8
|
| PD-L1 TC ≥50% analysis set |
14.1
|
10.5
|
36.6
|
15.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.02 | |
| Confidence Interval |
(2-Sided) 95% 0.871 to 1.186 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (≥25% Vs <25%), smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.70 | |
| Confidence Interval |
(2-Sided) 95% 0.480 to 1.018 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (>= 25% Vs < 25 and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥25% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.84 | |
| Confidence Interval |
(2-Sided) 95% 0.654 to 1.078 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥ 25% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.56 | |
| Confidence Interval |
(2-Sided) 95% 0.289 to 1.065 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 95% 0.587 to 1.081 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer OS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.47 | |
| Confidence Interval |
(2-Sided) 95% 0.222 to 0.955 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
| Title | Progression-Free Survival (PFS); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets |
|---|---|
| Description | The PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] using Investigator assessments) was defined as the time from the date of randomization until the date of objective PD or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb, tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb, and tTMB ≥8 mut/Mb analysis sets are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 |
| bTMB ≥20 mut/Mb analysis set |
4.2
|
5.1
|
| bTMB ≥16 mut/Mb analysis set |
4.2
|
5.5
|
| bTMB ≥12 mut/Mb analysis set |
3.9
|
5.1
|
| tTMB ≥14 mut/Mb analysis set |
8.7
|
5.8
|
| tTMB ≥12 mut/Mb analysis set |
5.2
|
5.8
|
| tTMB ≥10 mut/Mb analysis set |
4.3
|
5.1
|
| tTMB ≥8 mut/Mb analysis set |
4.4
|
5.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥20 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.77 | |
| Confidence Interval |
(2-Sided) 95% 0.514 to 1.146 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI interval were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥16 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.86 | |
| Confidence Interval |
(2-Sided) 95% 0.623 to 1.189 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI interval were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.92 | |
| Confidence Interval |
(2-Sided) 95% 0.714 to 1.193 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI interval were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥14 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.46 | |
| Confidence Interval |
(2-Sided) 95% 0.258 to 0.818 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 95% 0.524 to 1.228 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥10 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.83 | |
| Confidence Interval |
(2-Sided) 95% 0.585 to 1.177 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥8 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.74 | |
| Confidence Interval |
(2-Sided) 95% 0.534 to 1.017 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
| Title | PFS; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets |
|---|---|
| Description | PFS (per RECIST 1.1 using Investigator assessments) was defined as time from date of randomization until date of objective PD or death regardless of whether participant withdrew from randomized therapy or received another anticancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). PD-L1-negative analysis set included subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: FAS included all randomized participants prior to end of global recruitment. China Cohort: China FAS included all randomized participants in China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included subset of participants in FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% analysis sets are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| PD-L1-negative NSCLC analysis set |
4.1
|
5.6
|
5.1
|
6.0
|
| FAS |
4.0
|
5.6
|
4.2
|
6.0
|
| PD-L1 TC ≥25% analysis set |
4.2
|
5.4
|
6.8
|
5.7
|
| PD-L1 TC ≥50% analysis set |
4.6
|
5.4
|
6.8
|
5.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.11 | |
| Confidence Interval |
(2-Sided) 95% 0.810 to 1.517 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.13 | |
| Confidence Interval |
(2-Sided) 95% 0.592 to 2.141 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI interval were calculated using an stratified Cox proportional hazards model, adjusting histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.08 | |
| Confidence Interval |
(2-Sided) 95% 0.924 to 1.253 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (≥25% Vs <25%), smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.95 | |
| Confidence Interval |
(2-Sided) 95% 0.655 to 1.362 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (≥ 25% Vs < 25%) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥25% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.80 | |
| Confidence Interval |
(2-Sided) 95% 0.621 to 1.024 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥ 25% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.389 to 1.317 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.74 | |
| Confidence Interval |
(2-Sided) 95% 0.542 to 1.010 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer PFS than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.65 | |
| Confidence Interval |
(2-Sided) 95% 0.335 to 1.251 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
| Title | Objective Response Rate (ORR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, bTMB ≥12 Mut/Mb, tTMB ≥14 Mut/Mb, tTMB ≥12 Mut/Mb, tTMB ≥10 Mut/Mb, and tTMB ≥8 Mut/Mb Analysis Sets |
|---|---|
| Description | The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) prior to PD. bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb and tTMB ≥8 mut/Mb analysis sets included the subset of participants in FAS whose tTMB status was ≥14 mut/Mb, ≥12 mut/Mb, ≥10 mut/Mb and ≥8 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, bTMB ≥12 mut/Mb, tTMB ≥14 mut/Mb, tTMB ≥12 mut/Mb, tTMB ≥10 mut/Mb, and tTMB ≥8 mut/Mb analysis sets with measurable disease are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 |
| bTMB ≥20 mut/Mb analysis set |
27.5
5.8%
|
43.3
9%
|
| bTMB ≥16 mut/Mb analysis set |
31.2
6.6%
|
46.1
9.6%
|
| bTMB ≥12 mut/Mb analysis set |
28.7
6.1%
|
42.0
8.8%
|
| tTMB ≥14 mut/Mb analysis set |
61.3
12.9%
|
44.7
9.3%
|
| tTMB ≥12 mut/Mb analysis set |
42.6
9%
|
41.8
8.7%
|
| tTMB ≥10 mut/Mb analysis set |
37.7
8%
|
42.5
8.9%
|
| tTMB ≥8 mut/Mb analysis set |
36.7
7.7%
|
41.2
8.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥20 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.50 | |
| Confidence Interval |
(2-Sided) 95% 0.236 to 1.030 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥16 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.53 | |
| Confidence Interval |
(2-Sided) 95% 0.288 to 0.968 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.55 | |
| Confidence Interval |
(2-Sided) 95% 0.336 to 0.908 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥14 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.96 | |
| Confidence Interval |
(2-Sided) 95% 0.752 to 5.234 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.03 | |
| Confidence Interval |
(2-Sided) 95% 0.482 to 2.214 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥10 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.82 | |
| Confidence Interval |
(2-Sided) 95% 0.430 to 1.548 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | tTMB ≥8 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.83 | |
| Confidence Interval |
(2-Sided) 95% 0.456 to 1.486 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | ORR; Global and China Cohorts: PD-L1-Negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% Analysis Sets |
|---|---|
| Description | The ORR (per RECIST 1.1 using Investigator assessments) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD. PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. PD-L1 TC ≥25% and PD-L1 TC ≥50% analysis sets included the subset of participants in the FAS whose PD-L1 status was TC ≥25% and TC ≥50% membrane expression in tumoral tissue, respectively at baseline as defined by the Ventana SP263 PD-L1 Assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC, FAS, PD-L1 TC ≥25%, and PD-L1 TC ≥50% analysis sets with measurable disease are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| PD-L1-negative NSCLC analysis set |
23.1
4.9%
|
38.8
8.1%
|
23.1
2.4%
|
41.4
NaN
|
| FAS |
25.9
5.5%
|
41.7
8.7%
|
35.9
3.8%
|
39.0
NaN
|
| PD-L1 TC ≥25% analysis set |
35.2
7.4%
|
43.9
9.2%
|
54.8
5.8%
|
40.6
NaN
|
| PD-L1 TC ≥50% analysis set |
37.4
7.9%
|
44.0
9.2%
|
60.0
6.3%
|
46.4
NaN
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.47 | |
| Confidence Interval |
(2-Sided) 95% 0.245 to 0.869 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.42 | |
| Confidence Interval |
(2-Sided) 95% 0.124 to 1.337 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.48 | |
| Confidence Interval |
(2-Sided) 95% 0.356 to 0.647 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression adjusting for PD-L1 status (≥25% Vs <25%), smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.87 | |
| Confidence Interval |
(2-Sided) 95% 0.450 to 1.660 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for PD-L1 status (>= 25% Vs < 25%), smoking status (never smoker Va ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥25% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.69 | |
| Confidence Interval |
(2-Sided) 95% 0.443 to 1.079 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥ 25% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.78 | |
| Confidence Interval |
(2-Sided) 95% 0.658 to 4.919 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for PD-L1 status (>= 25% Vs < 25%), smoking status (never smoker Va ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 7
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 0.76 | |
| Confidence Interval |
(2-Sided) 95% 0.449 to 1.291 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
Statistical Analysis 8
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1 TC ≥50% analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy An odds ratio >1 favors Durvalumab + Tremelimumab combination therapy over SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.73 | |
| Confidence Interval |
(2-Sided) 95% 0.585 to 5.270 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The analysis was performed using logistic regression, adjusting for PD-L1 status (>= 25% Vs < 25%), smoking status (never smoker Va ever smoker) and histology (squamous Vs non-squamous), with 95% CI calculated by profile likelihood. | |
| Title | Duration of Response (DoR); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets |
|---|---|
| Description | DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, and bTMB ≥12 mut/Mb analysis sets are reported in this outcome measure. Only participants with objective response and randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 106 | 172 |
| bTMB ≥20 mut/Mb analysis set |
11.6
|
4.2
|
| bTMB ≥16 mut/Mb analysis set |
10.6
|
4.3
|
| bTMB ≥12 mut/Mb analysis set |
11.5
|
4.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥20 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.25 | |
| Confidence Interval |
(2-Sided) 95% 0.113 to 0.532 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥16 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.36 | |
| Confidence Interval |
(2-Sided) 95% 0.196 to 0.639 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.38 | |
| Confidence Interval |
(2-Sided) 95% 0.233 to 0.611 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
| Title | DoR; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets |
|---|---|
| Description | DoR (per RECIST 1.1 using Investigator assessments) was defined as the time from the date of first documented response (CR or PR) until the first date of documented progression or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC and FAS analysis sets are reported in this outcome measure. Only participants with objective response were included in this analysis. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 106 | 172 | 28 | 32 |
| PD-L1-negative NSCLC analysis set |
10.2
|
4.9
|
10.5
|
6.1
|
| FAS |
11.1
|
4.9
|
12.9
|
6.1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.41 | |
| Confidence Interval |
(2-Sided) 95% 0.199 to 0.787 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.79 | |
| Confidence Interval |
(2-Sided) 95% 0.183 to 2.860 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.44 | |
| Confidence Interval |
(2-Sided) 95% 0.324 to 0.588 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab combination therapy to be associated with a longer DoR than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.39 | |
| Confidence Interval |
(2-Sided) 95% 0.193 to 0.761 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (>= 25% Vs < 25%) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
| Title | Alive and Progression-Free at 12 Months (APF12); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets |
|---|---|
| Description | The APF12 was defined as the percentage of participants who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Tumour scans performed at baseline then every 6 weeks up to 12 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, and bTMB ≥12 mut/Mb analysis sets are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 143 | 138 |
| bTMB ≥20 mut/Mb analysis set |
25.6
5.4%
|
7.0
1.5%
|
| bTMB ≥16 mut/Mb analysis set |
22.0
4.6%
|
12.3
2.6%
|
| bTMB ≥12 mut/Mb analysis set |
21.6
4.6%
|
13.8
2.9%
|
| Title | APF12; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets |
|---|---|
| Description | The APF12 was defined as the percentage of patients who were alive and progression free at 12 months from randomization (ie, PFS rate at 12 months). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Time Frame | Tumour scans performed at baseline then every 6 weeks up to 12 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC and FAS analysis sets are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| PD-L1-negative NSCLC analysis set |
18.2
3.8%
|
12.1
2.5%
|
15.6
1.6%
|
11.3
NaN
|
| FAS |
20.2
4.3%
|
14.9
3.1%
|
23.9
2.5%
|
16.6
NaN
|
| Title | Time From Randomization to Second Progression or Death (PFS2); Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets |
|---|---|
| Description | The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global cohort DCO date (approximately 44 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, and bTMB ≥12 mut/Mb analysis sets are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 143 | 138 |
| bTMB ≥20 mut/Mb analysis set |
10.6
|
8.6
|
| bTMB ≥16 mut/Mb analysis set |
10.9
|
10.5
|
| bTMB ≥12 mut/Mb analysis set |
9.9
|
9.0
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥20 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.494 to 1.058 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥16 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.84 | |
| Confidence Interval |
(2-Sided) 95% 0.607 to 1.151 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | bTMB ≥12 mut/Mb analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.89 | |
| Confidence Interval |
(2-Sided) 95% 0.689 to 1.146 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using an unstratified Cox proportional hazards model, with ties handled by the Efron approach. | |
| Title | PFS2; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets |
|---|---|
| Description | The PFS2 was defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary variable PFS, or death (ie, date of PFS2 event or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Time Frame | Tumour scans performed at baseline and every 6 weeks up to 48 weeks relative to date of randomization, then every 8 weeks thereafter until confirmed PD/death. Up to Global or China cohort DCO dates, as applicable (approximately 44 months) for each cohort. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC and FAS analysis sets are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| PD-L1-negative NSCLC analysis set |
9.1
|
12.4
|
13.8
|
10.3
|
| FAS |
9.4
|
10.4
|
15.5
|
12.9
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.02 | |
| Confidence Interval |
(2-Sided) 95% 0.748 to 1.388 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | PD-L1-negative analysis set: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.67 | |
| Confidence Interval |
(2-Sided) 95% 0.360 to 1.219 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Global: Durvalumab + Tremelimumab, Global: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: Global: Durvalumab + Tremelimumab Vs Global: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.98 | |
| Confidence Interval |
(2-Sided) 95% 0.845 to 1.147 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for PD-L1 status (>= 25% Vs < 25%), smoking status (never smoker Vs ever smoker) and histology (squamous Vs non-squamous), with ties handled by Efron approach. | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | China: Durvalumab + Tremelimumab, China: SoC Chemotherapy |
|---|---|---|
| Comments | FAS: China: Durvalumab + Tremelimumab Vs China: SoC Chemotherapy A HR <1 favors Durvalumab + Tremelimumab to be associated with a longer time to second progression than SoC. | |
| Type of Statistical Test | Other | |
| Comments | The study was not designed or powered to show statistical significance for efficacy endpoints in the China cohort, so all statistical analyses for the China cohort were considered exploratory. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.71 | |
| Confidence Interval |
(2-Sided) 95% 0.492 to 1.030 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were calculated using a stratified Cox proportional hazards model, adjusting for histology (squamous Vs non-squamous), with ties handled by the Efron approach. | |
| Title | OS at Months 12, 18 and 24; Global Cohort: bTMB ≥20 Mut/Mb, bTMB ≥16 Mut/Mb, and bTMB ≥12 Mut/Mb Analysis Sets |
|---|---|
| Description | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb and bTMB ≥12 mut/Mb analysis sets included the subset of participants in FAS whose bTMB status was ≥20 mut/Mb, ≥16 mut/Mb and ≥12 mut/Mb, respectively at baseline as defined by the GuardantOMNI CDx assay. |
| Time Frame | Months 12, 18 and 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in bTMB ≥20 mut/Mb, bTMB ≥16 mut/Mb, and bTMB ≥12 mut/Mb analysis sets are reported in this outcome measure. Only participants randomized in Global cohort were analyzed as bTMB and tTMB testing was not performed in China cohort. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 143 | 138 |
| Month 12: bTMB ≥20 mut/Mb analysis set |
49.3
10.4%
|
40.8
8.5%
|
| Month 12: bTMB ≥16 mut/Mb analysis set |
50.5
10.7%
|
48.9
10.2%
|
| Month 12: bTMB ≥12 mut/Mb analysis set |
46.9
9.9%
|
44.6
9.3%
|
| Month 18: bTMB ≥20 mut/Mb analysis set |
36.2
7.6%
|
20.4
4.3%
|
| Month 18: bTMB ≥16 mut/Mb analysis set |
35.5
7.5%
|
28.5
5.9%
|
| Month 18: bTMB ≥12 mut/Mb analysis set |
29.4
6.2%
|
27.8
5.8%
|
| Month 24: bTMB ≥20 mut/Mb analysis set |
26.1
5.5%
|
13.6
2.8%
|
| Month 24: bTMB ≥16 mut/Mb analysis set |
24.0
5.1%
|
18.2
3.8%
|
| Month 24: bTMB ≥12 mut/Mb analysis set |
21.3
4.5%
|
19.0
4%
|
| Title | OS at Months 12, 18 and 24; Global and China Cohorts: PD-L1-Negative NSCLC and FAS Analysis Sets |
|---|---|
| Description | The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). PD-L1-negative analysis set included the subset of participants in FAS whose PD-L1 status was PD-L1-negative at baseline as defined by the Ventana SP263 PD-L1 Assay (ie, <1% PD-L1-membrane expression in tumoral tissue). Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Time Frame | Months 12, 18 and 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants included in PD-L1-negative NSCLC and FAS analysis sets are reported in this outcome measure. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy |
|---|---|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). |
| Measure Participants | 410 | 413 | 78 | 82 |
| Month 12: PD-L1-negative NSCLC analysis set |
47.8
10.1%
|
52.8
11%
|
68.0
7.1%
|
46.4
NaN
|
| Month 12: FAS |
47.7
10.1%
|
50.0
10.4%
|
72.8
7.6%
|
53.1
NaN
|
| Month 18: PD-L1-negative NSCLC analysis set |
34.1
7.2%
|
34.5
7.2%
|
44.0
4.6%
|
39.3
NaN
|
| Month 18: FAS |
34.8
7.3%
|
34.6
7.2%
|
54.6
5.7%
|
41.8
NaN
|
| Month 24: PD-L1-negative NSCLC analysis set |
22.1
4.7%
|
22.3
4.7%
|
36.0
3.8%
|
17.9
NaN
|
| Month 24: FAS |
25.7
5.4%
|
23.4
4.9%
|
44.2
4.6%
|
30.4
NaN
|
| Title | Serum Concentrations of Durvalumab |
|---|---|
| Description | Blood samples were collected to determine the serum concentration of durvalumab. |
| Time Frame | Pre-dose and within 1 hour after end of infusion at Week 0 and 12; pre-dose on Week 24 and at follow-up Month 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | China: Durvalumab + Tremelimumab |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. |
| Measure Participants | 410 | 78 |
| Week 0: Pre-infusion |
NA
(NA)
|
NA
(NA)
|
| Week 0: End of infusion |
418.6
(74.8)
|
392.7
(48.9)
|
| Week 12: Pre-infusion |
77.5
(138.1)
|
72.4
(55.0)
|
| Week 12: End of infusion |
434.3
(105.6)
|
448.9
(40.0)
|
| Week 24: Pre-infusion |
108.8
(95.7)
|
85.6
(93.9)
|
| Follow-up Month 3 |
8.8
(253.9)
|
5.4
(351.7)
|
| Title | Serum Concentrations of Tremelimumab |
|---|---|
| Description | Blood samples were collected to determine the serum concentration of tremelimumab. |
| Time Frame | Pre-dose and within 1 hour after end of infusion at Week 0 and 12, and at follow-up Month 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | China: Durvalumab + Tremelimumab |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. |
| Measure Participants | 410 | 78 |
| Week 0: Pre-infusion |
NA
(NA)
|
NA
(NA)
|
| Week 0: End of infusion |
20.3
(38.7)
|
18.4
(43.3)
|
| Week 12: Pre-infusion |
3.4
(99.6)
|
3.3
(64.6)
|
| Week 12: End of infusion |
20.8
(67.4)
|
23.2
(43.4)
|
| Follow-up Month 3 |
NA
(NA)
|
NA
(NA)
|
| Title | Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab |
|---|---|
| Description | Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for durvalumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive. |
| Time Frame | At Weeks 0, 12, and 24; 3 and 6 months after last dose of study treatment. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. The denominator for calculation of percentage for all categories is the number of ADA evaluable participants. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | China: Durvalumab + Tremelimumab |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. |
| Measure Participants | 266 | 61 |
| ADA positive at any visit (ADA prevalence) |
26
5.5%
|
1
0.2%
|
| Treatment-emergent ADA positive (ADA incidence) |
12
2.5%
|
1
0.2%
|
| Treatment-boosted ADA |
0
0%
|
0
0%
|
| Treatment-induced ADA (positive post-baseline only) |
12
2.5%
|
1
0.2%
|
| ADA positive post-baseline and positive at baseline |
1
0.2%
|
0
0%
|
| Persistent positive |
11
2.3%
|
1
0.2%
|
| Transient positive |
2
0.4%
|
0
0%
|
| nAb positive at any visit |
3
0.6%
|
0
0%
|
| ADA positive at baseline and not detected post-baseline |
13
2.7%
|
0
0%
|
| Title | Number of Participants With ADA Response to Tremelimumab |
|---|---|
| Description | Blood samples were measured for the presence of ADAs and ADA-nAb for tremelimumab using validated assays. ADA prevalence is defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as the sum of treatment-induced ADA and treatment-boosted ADA. ADA incidence is the percentage of participants who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to >=4 fold during the study period. Persistently positive is defined as having at least 2 post baseline ADA positive measurements with at least 16 weeks (112 days) between the first and last positive measurements, or an ADA positive result at the last available assessment. Transiently positive is defined as having at least 1 post baseline ADA positive measurement and not fulfilling the conditions for persistently positive. |
| Time Frame | At Weeks 0 and 12; 3 and 6 months after last dose of study treatment. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global Cohort: The FAS included all randomized participants prior to the end of global recruitment. Any participants recruited in China, after global recruitment had ended, were not included in the FAS. China Cohort: The China FAS included all randomized participants in the China cohort and were used for all China only efficacy analyses. The denominator for calculation of percentage for all categories is the number of ADA evaluable participants. |
| Arm/Group Title | Global: Durvalumab + Tremelimumab | China: Durvalumab + Tremelimumab |
|---|---|---|
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. |
| Measure Participants | 265 | 61 |
| ADA positive at any visit (ADA prevalence) |
49
10.3%
|
2
0.4%
|
| Treatment-emergent ADA positive (ADA incidence) |
37
7.8%
|
1
0.2%
|
| Treatment-boosted ADA |
1
0.2%
|
0
0%
|
| Treatment-induced ADA (positive post-baseline only) |
36
7.6%
|
1
0.2%
|
| ADA positive post-baseline and positive at baseline |
4
0.8%
|
1
0.2%
|
| Persistent positive |
29
6.1%
|
0
0%
|
| Transient positive |
11
2.3%
|
2
0.4%
|
| nAb positive at any visit |
33
7%
|
0
0%
|
| ADA positive at baseline and not detected post-baseline |
9
1.9%
|
0
0%
|
Adverse Events
| Time Frame | Assessed until final analysis DCO for each cohort (24 June 2019 for Global Cohort and 21 September 2020 for China Cohort); maximum timeframe of approximately 44 months for each cohort. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Global Cohort: The safety analysis set included all participants recruited prior to end of the global recruitment who received at least 1 dose of study treatment. China Cohort: The China safety analysis set included all participants recruited in the China cohort who received at least 1 dose of study treatment. All-Cause Mortality: Data from participants included in Global and China FAS was summarized separately. 30 participants in China cohort were also included in Global cohort. | |||||||
| Arm/Group Title | Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy | ||||
| Arm/Group Description | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | Participants received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV infusion Q4W in combination for up to 4 doses/cycles. Participants then continued to receive durvalumab 20 mg/kg Q4W, starting on Week 16 until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. | Participants received 1 of the following IV infusion treatment combinations on Day 1 of each 21-day cycle for 4 to 6 cycles or until objective PD, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or specific treatment discontinuation criteria were met. Paclitaxel 200 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Gemcitabine 1000 or 1250 mg/m^2 and cisplatin 75 or 80 mg/m^2. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Gemcitabine 1000 or 1250 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL. Additional dose of gemcitabine 1000 or 1250 mg/m^2 on Day 8 of each cycle (For squamous participants only). Pemetrexed 500 mg/m^2 and cisplatin 75 mg/m^2 (For non-squamous participants only; pemetrexed maintenance dose was permitted). Pemetrexed 500 mg/m^2 and carboplatin AUC 5 or 6 mg*min/mL (For non-squamous participants only; pemetrexed maintenance dose was permitted). | ||||
All Cause Mortality |
||||||||
| Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 328/410 (80%) | 329/413 (79.7%) | 50/78 (64.1%) | 62/82 (75.6%) | ||||
Serious Adverse Events |
||||||||
| Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 193/410 (47.1%) | 112/399 (28.1%) | 32/77 (41.6%) | 22/78 (28.2%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Agranulocytosis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Anaemia | 0/410 (0%) | 0 | 11/399 (2.8%) | 12 | 0/77 (0%) | 0 | 2/78 (2.6%) | 2 |
| Bone marrow failure | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 3/78 (3.8%) | 3 |
| Febrile neutropenia | 0/410 (0%) | 0 | 5/399 (1.3%) | 5 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Haematotoxicity | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Leukocytosis | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Neutropenia | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pancytopenia | 0/410 (0%) | 0 | 4/399 (1%) | 5 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Thrombocytopenia | 1/410 (0.2%) | 1 | 3/399 (0.8%) | 6 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Cardiac disorders | ||||||||
| Acute coronary syndrome | 3/410 (0.7%) | 3 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Acute myocardial infarction | 4/410 (1%) | 4 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Angina unstable | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Atrial fibrillation | 3/410 (0.7%) | 3 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Atrial flutter | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Atrial thrombosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardiac arrest | 1/410 (0.2%) | 1 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardiac failure | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardiac failure acute | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardiac failure congestive | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardiac tamponade | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Coronary artery disease | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Myocardial infarction | 1/410 (0.2%) | 1 | 3/399 (0.8%) | 3 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pericardial effusion | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Tachycardia | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Ventricular fibrillation | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Arrhythmia | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cardio-respiratory arrest | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||
| Hypoacusis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Vertigo | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Endocrine disorders | ||||||||
| Hyperthyroidism | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Hypophysitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypopituitarism | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Eye disorders | ||||||||
| Diplopia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Optic neuropathy | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Abdominal pain upper | 0/410 (0%) | 0 | 1/399 (0.3%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Ascites | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Autoimmune pancreatitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Colitis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Constipation | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Diarrhoea | 9/410 (2.2%) | 9 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Dysphagia | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Enterocolitis | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastric ulcer | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastric ulcer haemorrhage | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastric ulcer perforation | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastritis | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Immune-mediated enterocolitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Immune-mediated pancreatitis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Intestinal obstruction | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Large intestine perforation | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Lower gastrointestinal haemorrhage | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Mouth ulceration | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Nausea | 3/410 (0.7%) | 4 | 3/399 (0.8%) | 3 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Pancreatitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Stomatitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Upper gastrointestinal haemorrhage | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Vomiting | 3/410 (0.7%) | 4 | 4/399 (1%) | 4 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Gastrointestinal haemorrhage | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Intestinal ischaemia | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| General disorders | ||||||||
| Asthenia | 2/410 (0.5%) | 2 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Chest pain | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Death | 5/410 (1.2%) | 5 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Fatigue | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gait disturbance | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| General physical health deterioration | 2/410 (0.5%) | 2 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Multiple organ dysfunction syndrome | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Non-cardiac chest pain | 1/410 (0.2%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pain | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pyrexia | 12/410 (2.9%) | 12 | 1/399 (0.3%) | 1 | 3/77 (3.9%) | 3 | 0/78 (0%) | 0 |
| Sudden death | 2/410 (0.5%) | 2 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Vascular stent occlusion | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hepatobiliary disorders | ||||||||
| Autoimmune hepatitis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Bile duct stenosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cholangitis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cholecystitis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cholecystitis acute | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cholelithiasis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Drug-induced liver injury | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Hepatitis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hepatitis toxic | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hepatotoxicity | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Immune-mediated hepatitis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Jaundice | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Immune system disorders | ||||||||
| Anaphylactic shock | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypersensitivity | 1/410 (0.2%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Anaphylactic reaction | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Infections and infestations | ||||||||
| Bronchitis | 2/410 (0.5%) | 2 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Candida infection | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cellulitis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Dengue fever | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Device related infection | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Gastroenteritis | 1/410 (0.2%) | 3 | 1/399 (0.3%) | 1 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Herpes zoster | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Infection | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Infectious pleural effusion | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Influenza | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Labyrinthitis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Lower respiratory tract infection | 7/410 (1.7%) | 7 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Lung infection | 4/410 (1%) | 5 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Neutropenic sepsis | 0/410 (0%) | 0 | 6/399 (1.5%) | 6 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Oral fungal infection | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Orchitis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pleural infection | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Pneumocystis jirovecii pneumonia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pneumonia | 27/410 (6.6%) | 33 | 13/399 (3.3%) | 15 | 3/77 (3.9%) | 3 | 5/78 (6.4%) | 6 |
| Pneumonia mycoplasmal | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Post procedural infection | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Rectal abscess | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Respiratory tract infection | 0/410 (0%) | 0 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Sepsis | 4/410 (1%) | 4 | 4/399 (1%) | 4 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Septic shock | 4/410 (1%) | 4 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Soft tissue infection | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Upper respiratory tract infection | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Urinary tract infection | 1/410 (0.2%) | 1 | 3/399 (0.8%) | 3 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Urosepsis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||
| Accident | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Fall | 0/410 (0%) | 0 | 3/399 (0.8%) | 3 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Femur fracture | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Humerus fracture | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Procedural pain | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Snake bite | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Head injury | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Spinal compression fracture | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Investigations | ||||||||
| Alanine aminotransferase increased | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Amylase increased | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Aspartate aminotransferase increased | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Blood calcium increased | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Blood corticotrophin decreased | 1/410 (0.2%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 2 | 0/78 (0%) | 0 |
| Blood creatinine increased | 0/410 (0%) | 0 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Lipase increased | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Liver function test increased | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Neutrophil count decreased | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 2/78 (2.6%) | 8 |
| Platelet count decreased | 0/410 (0%) | 0 | 3/399 (0.8%) | 3 | 0/77 (0%) | 0 | 2/78 (2.6%) | 2 |
| White blood cell count decreased | 0/410 (0%) | 0 | 1/399 (0.3%) | 3 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||
| Cachexia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Decreased appetite | 3/410 (0.7%) | 3 | 1/399 (0.3%) | 1 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Dehydration | 1/410 (0.2%) | 2 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Diabetic ketoacidosis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Electrolyte imbalance | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Fluid overload | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypercalcaemia | 3/410 (0.7%) | 3 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hyperglycaemia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypokalaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Hyponatraemia | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 1/78 (1.3%) | 1 |
| Malnutrition | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Metabolic acidosis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Tumour lysis syndrome | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Type 2 diabetes mellitus | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Type 1 diabetes mellitus | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Back pain | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 2 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Intervertebral disc protrusion | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Musculoskeletal chest pain | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Myalgia | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Myositis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pain in extremity | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Paraneoplastic arthritis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Polymyositis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Spinal pain | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Acute myeloid leukaemia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Basal cell carcinoma | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Invasive ductal breast carcinoma | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Metastases to central nervous system | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Ovarian cancer | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Tumour invasion | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Prostate cancer | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Nervous system disorders | ||||||||
| Brain oedema | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Carotid artery disease | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Carotid artery stenosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cerebral haemorrhage | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Cerebrovascular accident | 2/410 (0.5%) | 2 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Dizziness | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Embolic stroke | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Encephalopathy | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Ischaemic stroke | 4/410 (1%) | 4 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Lateral medullary syndrome | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Neuropathy peripheral | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Peripheral motor neuropathy | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Peripheral sensory neuropathy | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Polyneuropathy | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Seizure | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Spinal cord compression | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Syncope | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cerebral infarction | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Psychiatric disorders | ||||||||
| Acute psychosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| Acute kidney injury | 4/410 (1%) | 4 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hydronephrosis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Renal colic | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Renal failure | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Renal impairment | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 1/78 (1.3%) | 1 |
| Ureterolithiasis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Urethral pain | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Urinary retention | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Dysuria | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Acute respiratory failure | 3/410 (0.7%) | 3 | 1/399 (0.3%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Asthma | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Atelectasis | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Bronchospasm | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Chronic obstructive pulmonary disease | 2/410 (0.5%) | 2 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Cough | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Dyspnoea | 5/410 (1.2%) | 5 | 2/399 (0.5%) | 3 | 3/77 (3.9%) | 3 | 1/78 (1.3%) | 2 |
| Haemoptysis | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 2/77 (2.6%) | 2 | 0/78 (0%) | 0 |
| Hypoxia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Interstitial lung disease | 3/410 (0.7%) | 3 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Organising pneumonia | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pleural effusion | 5/410 (1.2%) | 5 | 1/399 (0.3%) | 2 | 4/77 (5.2%) | 4 | 2/78 (2.6%) | 3 |
| Pleurisy | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pneumonitis | 16/410 (3.9%) | 17 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pneumothorax | 3/410 (0.7%) | 4 | 1/399 (0.3%) | 1 | 1/77 (1.3%) | 2 | 1/78 (1.3%) | 1 |
| Pneumothorax spontaneous | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pulmonary embolism | 5/410 (1.2%) | 5 | 4/399 (1%) | 4 | 0/77 (0%) | 0 | 2/78 (2.6%) | 2 |
| Pulmonary haemorrhage | 3/410 (0.7%) | 5 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Pulmonary oedema | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Respiratory failure | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 2/77 (2.6%) | 2 | 0/78 (0%) | 0 |
| Respiratory distress | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||
| Rash | 0/410 (0%) | 0 | 2/399 (0.5%) | 2 | 2/77 (2.6%) | 3 | 0/78 (0%) | 0 |
| Rash maculo-papular | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Skin toxicity | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Urticaria | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Vascular disorders | ||||||||
| Deep vein thrombosis | 1/410 (0.2%) | 1 | 2/399 (0.5%) | 2 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Embolism | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Embolism arterial | 0/410 (0%) | 0 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Haematoma | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypertension | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Hypotension | 1/410 (0.2%) | 1 | 1/399 (0.3%) | 1 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Superior vena cava stenosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Superior vena cava syndrome | 2/410 (0.5%) | 2 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Venous thrombosis | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 0/78 (0%) | 0 |
| Hypovolaemic shock | 1/410 (0.2%) | 1 | 0/399 (0%) | 0 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||
| Global: Durvalumab + Tremelimumab | Global: SoC Chemotherapy | China: Durvalumab + Tremelimumab | China: SoC Chemotherapy | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 310/410 (75.6%) | 349/399 (87.5%) | 73/77 (94.8%) | 77/78 (98.7%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 59/410 (14.4%) | 66 | 146/399 (36.6%) | 201 | 25/77 (32.5%) | 35 | 53/78 (67.9%) | 74 |
| Leukopenia | 2/410 (0.5%) | 3 | 38/399 (9.5%) | 55 | 1/77 (1.3%) | 1 | 13/78 (16.7%) | 21 |
| Neutropenia | 3/410 (0.7%) | 5 | 71/399 (17.8%) | 113 | 2/77 (2.6%) | 3 | 10/78 (12.8%) | 15 |
| Thrombocytopenia | 4/410 (1%) | 6 | 50/399 (12.5%) | 73 | 0/77 (0%) | 0 | 8/78 (10.3%) | 11 |
| Endocrine disorders | ||||||||
| Hyperthyroidism | 34/410 (8.3%) | 35 | 0/399 (0%) | 0 | 9/77 (11.7%) | 10 | 0/78 (0%) | 0 |
| Hypothyroidism | 51/410 (12.4%) | 58 | 2/399 (0.5%) | 2 | 5/77 (6.5%) | 12 | 0/78 (0%) | 0 |
| Gastrointestinal disorders | ||||||||
| Abdominal discomfort | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 5/78 (6.4%) | 6 |
| Abdominal distension | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 7 | 2/78 (2.6%) | 4 |
| Abdominal pain | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 6 | 2/78 (2.6%) | 3 |
| Abdominal pain upper | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 6 | 1/78 (1.3%) | 1 |
| Constipation | 59/410 (14.4%) | 64 | 84/399 (21.1%) | 90 | 10/77 (13%) | 13 | 9/78 (11.5%) | 12 |
| Diarrhoea | 72/410 (17.6%) | 96 | 40/399 (10%) | 53 | 5/77 (6.5%) | 7 | 6/78 (7.7%) | 7 |
| Nausea | 57/410 (13.9%) | 74 | 128/399 (32.1%) | 244 | 10/77 (13%) | 13 | 33/78 (42.3%) | 108 |
| Stomatitis | 9/410 (2.2%) | 10 | 27/399 (6.8%) | 40 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Vomiting | 29/410 (7.1%) | 41 | 57/399 (14.3%) | 80 | 8/77 (10.4%) | 10 | 19/78 (24.4%) | 34 |
| General disorders | ||||||||
| Asthenia | 50/410 (12.2%) | 72 | 52/399 (13%) | 59 | 9/77 (11.7%) | 9 | 12/78 (15.4%) | 16 |
| Fatigue | 56/410 (13.7%) | 76 | 73/399 (18.3%) | 95 | 1/77 (1.3%) | 1 | 6/78 (7.7%) | 9 |
| Malaise | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 4/77 (5.2%) | 4 | 7/78 (9%) | 13 |
| Non-cardiac chest pain | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 8/77 (10.4%) | 9 | 5/78 (6.4%) | 5 |
| Oedema peripheral | 29/410 (7.1%) | 30 | 16/399 (4%) | 23 | 6/77 (7.8%) | 7 | 3/78 (3.8%) | 3 |
| Pyrexia | 40/410 (9.8%) | 51 | 32/399 (8%) | 35 | 12/77 (15.6%) | 21 | 9/78 (11.5%) | 10 |
| Hepatobiliary disorders | ||||||||
| Hepatic function abnormal | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 1/77 (1.3%) | 1 | 5/78 (6.4%) | 6 |
| Infections and infestations | ||||||||
| Pneumonia | 14/410 (3.4%) | 14 | 20/399 (5%) | 22 | 8/77 (10.4%) | 9 | 0/78 (0%) | 0 |
| Upper respiratory tract infection | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 7 | 2/78 (2.6%) | 2 |
| Investigations | ||||||||
| Alanine aminotransferase increased | 33/410 (8%) | 39 | 34/399 (8.5%) | 48 | 22/77 (28.6%) | 27 | 22/78 (28.2%) | 49 |
| Amylase increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 21/77 (27.3%) | 34 | 7/78 (9%) | 7 |
| Aspartate aminotransferase increased | 27/410 (6.6%) | 35 | 28/399 (7%) | 41 | 25/77 (32.5%) | 39 | 20/78 (25.6%) | 38 |
| Bilirubin conjugated increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 4/77 (5.2%) | 10 | 1/78 (1.3%) | 2 |
| Blood alkaline phosphatase increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 8/77 (10.4%) | 12 | 2/78 (2.6%) | 3 |
| Blood bilirubin increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 9 | 4/78 (5.1%) | 6 |
| Blood creatinine increased | 8/410 (2%) | 18 | 28/399 (7%) | 36 | 0/77 (0%) | 0 | 9/78 (11.5%) | 12 |
| Blood lactate dehydrogenase increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 8/77 (10.4%) | 12 | 5/78 (6.4%) | 5 |
| Blood pressure increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 3/77 (3.9%) | 8 | 7/78 (9%) | 8 |
| Blood thyroid stimulating hormone decreased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 4/77 (5.2%) | 8 | 0/78 (0%) | 0 |
| Gamma-glutamyltransferase increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 19/77 (24.7%) | 33 | 10/78 (12.8%) | 15 |
| Haemoglobin decreased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 3/77 (3.9%) | 3 | 6/78 (7.7%) | 9 |
| Lipase increased | 21/410 (5.1%) | 30 | 7/399 (1.8%) | 8 | 15/77 (19.5%) | 26 | 2/78 (2.6%) | 2 |
| Neutrophil count decreased | 4/410 (1%) | 10 | 29/399 (7.3%) | 68 | 4/77 (5.2%) | 8 | 35/78 (44.9%) | 94 |
| Platelet count decreased | 2/410 (0.5%) | 2 | 30/399 (7.5%) | 51 | 3/77 (3.9%) | 6 | 15/78 (19.2%) | 30 |
| Weight decreased | 45/410 (11%) | 46 | 16/399 (4%) | 16 | 16/77 (20.8%) | 16 | 4/78 (5.1%) | 4 |
| Weight increased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 8/77 (10.4%) | 10 | 2/78 (2.6%) | 2 |
| White blood cell count decreased | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 2/77 (2.6%) | 9 | 35/78 (44.9%) | 126 |
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 69/410 (16.8%) | 79 | 72/399 (18%) | 88 | 14/77 (18.2%) | 14 | 22/78 (28.2%) | 37 |
| Hyperglycaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 11/77 (14.3%) | 16 | 7/78 (9%) | 10 |
| Hypertriglyceridaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 4/77 (5.2%) | 5 | 4/78 (5.1%) | 5 |
| Hyperuricaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 5/77 (6.5%) | 8 | 4/78 (5.1%) | 5 |
| Hypoalbuminaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 23/77 (29.9%) | 31 | 15/78 (19.2%) | 17 |
| Hypocalcaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 7 | 3/78 (3.8%) | 3 |
| Hypochloraemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 7/77 (9.1%) | 13 | 7/78 (9%) | 8 |
| Hypokalaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 13/77 (16.9%) | 19 | 8/78 (10.3%) | 13 |
| Hypomagnesaemia | 6/410 (1.5%) | 6 | 20/399 (5%) | 24 | 5/77 (6.5%) | 10 | 3/78 (3.8%) | 3 |
| Hyponatraemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 19/77 (24.7%) | 38 | 15/78 (19.2%) | 20 |
| Hypophosphataemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 7/77 (9.1%) | 14 | 1/78 (1.3%) | 1 |
| Hypoproteinaemia | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 16/77 (20.8%) | 19 | 6/78 (7.7%) | 6 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 28/410 (6.8%) | 32 | 27/399 (6.8%) | 53 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Back pain | 29/410 (7.1%) | 29 | 15/399 (3.8%) | 15 | 7/77 (9.1%) | 7 | 7/78 (9%) | 16 |
| Nervous system disorders | ||||||||
| Dizziness | 20/410 (4.9%) | 21 | 21/399 (5.3%) | 21 | 4/77 (5.2%) | 4 | 5/78 (6.4%) | 6 |
| Headache | 24/410 (5.9%) | 30 | 24/399 (6%) | 25 | 5/77 (6.5%) | 8 | 2/78 (2.6%) | 2 |
| Peripheral sensory neuropathy | 2/410 (0.5%) | 2 | 23/399 (5.8%) | 28 | 0/77 (0%) | 0 | 0/78 (0%) | 0 |
| Psychiatric disorders | ||||||||
| Insomnia | 22/410 (5.4%) | 23 | 17/399 (4.3%) | 18 | 5/77 (6.5%) | 7 | 7/78 (9%) | 9 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 46/410 (11.2%) | 57 | 19/399 (4.8%) | 22 | 11/77 (14.3%) | 12 | 4/78 (5.1%) | 4 |
| Dyspnoea | 30/410 (7.3%) | 33 | 16/399 (4%) | 17 | 3/77 (3.9%) | 3 | 6/78 (7.7%) | 6 |
| Haemoptysis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 10/77 (13%) | 19 | 2/78 (2.6%) | 2 |
| Productive cough | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 6/77 (7.8%) | 6 | 0/78 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||
| Alopecia | 3/410 (0.7%) | 3 | 50/399 (12.5%) | 50 | 0/77 (0%) | 0 | 6/78 (7.7%) | 6 |
| Pruritus | 51/410 (12.4%) | 62 | 11/399 (2.8%) | 25 | 5/77 (6.5%) | 5 | 3/78 (3.8%) | 4 |
| Rash | 58/410 (14.1%) | 78 | 22/399 (5.5%) | 25 | 12/77 (15.6%) | 16 | 5/78 (6.4%) | 6 |
| Vascular disorders | ||||||||
| Hypertension | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 7/77 (9.1%) | 10 | 2/78 (2.6%) | 2 |
| Phlebitis | 0/410 (0%) | 0 | 0/399 (0%) | 0 | 4/77 (5.2%) | 5 | 5/78 (6.4%) | 18 |
Limitations/Caveats
Analysis of the China cohort was performed to evaluate the consistency of efficacy and safety in Chinese participants with the global cohort in order to meet China health regulatory requirements and was not powered for a formal assessment of statistical significance.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Global Clinical Lead |
|---|---|
| Organization | AstraZeneca |
| Phone | 1-877-240-9479 |
| information.center@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02542293
Other Study ID Numbers:
- D419AC00003
First Posted:
Sep 7, 2015
Last Update Posted:
May 24, 2022
Last Verified:
Apr 1, 2022