Study of Durvalumab + Tremelimumab With Chemotherapy or Durvalumab With Chemotherapy or Chemotherapy Alone for Patients With Lung Cancer (POSEIDON).
Sponsor
AstraZeneca (Industry)
Overall Status
Recruiting
CT.gov ID
NCT03164616
Collaborator
(none)
1,193
182
3
95.9
6.6
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 + Standard of care (SoC) chemotherapy or durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as first line treatment in patients with metastatic non small-cell lung cancer (NSCLC) with tumors that lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Adult patients with a histologically or cytologically documented metastatic NSCLC, with tumors that lack activating EGFR mutations and ALK fusions, are eligible for enrollment. Patients will be randomized in a 1:1:1 ratio to receive treatment with durvalumab + tremelimumab combination therapy + SoC chemotherapy, durvalumab monotherapy + SoC chemotherapy, or SoC chemotherapy alone. Tumor evaluation scans will be performed until objective disease progression as efficacy assessment. All patients will be followed for survival until the end of the study. An independent data monitoring committee (IDMC) composed of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule.
Study Design
Study Type:
Interventional
Anticipated Enrollment
:
1193 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Multi-Center, Open-Label, Comparative Global Study to Determine the Efficacy of Durvalumab or Durvalumab and Tremelimumab in Combination With Platinum-Based Chemotherapy for First-Line Treatment in Patients With Metastatic Non Small-Cell Lung Cancer (NSCLC) (POSEIDON)
Actual Study Start Date
:
Jun 1, 2017
Actual Primary Completion Date
:
Mar 12, 2021
Anticipated Study Completion Date
:
May 28, 2025
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Arm 1 durvalumab + tremelimumab combination therapy + SoC chemotherapy |
Drug: Durvalumab
IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until disease progression or other discontinuation criteria
Drug: Tremelimumab
IV infusions every 3 weeks for 12 weeks (4 cycles). An additional dose of tremelimumab will be administered in the week 16.
Drug: Abraxane + carboplatin
Standard of care chemotherapy (squamous and non-squamous patients): Abraxane 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Carboplatin Area under the plasma drug concentration-time curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + cisplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + carboplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Pemetrexed + carboplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
Drug: Pemetrexed + cisplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
|
| Experimental: Treatment Arm 2 durvalumab monotherapy + SoC chemotherapy |
Drug: Durvalumab
IV infusions every 3 weeks for 12 weeks (4 cycles) and every 4 weeks thereafter until disease progression or other discontinuation criteria
Drug: Abraxane + carboplatin
Standard of care chemotherapy (squamous and non-squamous patients): Abraxane 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Carboplatin Area under the plasma drug concentration-time curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + cisplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + carboplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Pemetrexed + carboplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
Drug: Pemetrexed + cisplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
|
| Active Comparator: Treatment Arm 3 SoC chemotherapy alone |
Drug: Abraxane + carboplatin
Standard of care chemotherapy (squamous and non-squamous patients): Abraxane 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Carboplatin Area under the plasma drug concentration-time curve (AUC) 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + cisplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Gemcitabine + carboplatin
Standard of care chemotherapy (squamous patients only): Gemcitabine 1000 or 1250 mg/m2 via IV infusion on Days 1 and 8 of each 21-day cycle + carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3).
Drug: Pemetrexed + carboplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and carboplatin AUC 5 or 6 via IV infusion on Day 1 of each 21-day cycle for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
Drug: Pemetrexed + cisplatin
Standard of care chemotherapy (non-squamous patients only): Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 via IV infusion on Day 1 of each 21-day cycle, for 4 to 6 cycles (ie, 4 cycles for Treatment Arms 1 and 2 and 4 to 6 cycles for Treatment Arm 3); then continue pemetrexed 500 mg/m2 maintenance [i.e., q4w for Treatment Arms 1 and 2. For Treatment Arm 3, Pemetrexed maintenance therapy can be given either q3w or q4w (dependent on Investigator decision and local standards)] until objective disease progression.
|
Outcome Measures
Primary Outcome Measures
- Progression-Free Survival (PFS); D + SoC Compared With SoC Alone [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months).]
PFS (per RECIST version 1.1 [RECIST 1.1] using Blinded Independent Central Review [BICR] assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. The final analysis of PFS in the global cohort was pre-specified after approximately 497 BICR PFS events occurred across the D + SoC and SoC alone treatment arms (75% maturity).
- Overall Survival (OS); D + SoC Compared With SoC Alone [From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months).]
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The final analysis of OS in the global cohort was pre-specified after approximately 532 OS events occurred across the D + SoC and SoC alone treatment arms (80% maturity).
Secondary Outcome Measures
- PFS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months.]
PFS (per RECIST 1.1 using BICR assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique.
- OS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC [From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months).]
OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
- Objective Response Rate (ORR) [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months).]
ORR (per RECIST 1.1 using BICR assessments) was defined as the percentage of patients with at least one visit response of complete response (CR) or partial response (PR). Results are presented for the pre-specified ORR analysis using unconfirmed responses based on BICR.
- Best Objective Response (BoR) [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months).]
The BoR was calculated based on the overall visit responses from each RECIST 1.1 assessment. BOR was defined as the best response a patient had following randomization, but prior to starting any subsequent cancer therapy and up to and including RECIST 1.1 progression or the last evaluable assessment in the absence of RECIST 1.1 progression, as determined by BICR. Categorization of BoR was based on RECIST using the following 'response' categories: CR and PR and the following 'non-response' categories: stable disease (SD) ≥6 weeks, progression (ie, PD) and not evaluable (NE). Results are presented for number (%) of patients in each specified category.
- Duration of Response (DoR) [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months).]
DoR (per RECIST 1.1 using BICR assessments) was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. The end of response coincided with the date of progression or death from any cause used for the RECIST 1.1 PFS endpoint. The time of the initial response was defined as the latest of the dates contributing towards the first visit of PR or CR. Results are presented for the pre-specified DoR analysis using unconfirmed responses based on BICR.
- Time From Randomization to Second Progression (PFS2) [Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months).]
PFS2 was defined as the time from the date of randomization to the earliest of the progression event (subsequent to that used for the primary variable PFS) or death. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could involve any of: objective radiological imaging, symptomatic progression or death.
- Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations [Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021.]
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
- PK of Tremelimumab; Peak and Trough Serum Concentrations [Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021.]
To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively.
- Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab [Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, durvalumab).]
Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against durvalumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples.
- Number of Patients With ADA Response to Tremelimumab [Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, tremelimumab).]
Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against tremelimumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples.
- Time to Deterioration of Global Health Status / Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) [At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months).]
The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
- Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) [At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months).]
The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration.
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.
-
Histologically or cytologically documented Stage IV NSCLC.
-
Confirmed tumor PD-L1 status prior to randomization.
-
Patients must have tumors that lack activating EGFR mutations and ALK fusions.
-
No prior chemotherapy or any other systemic therapy for metastatic NSCLC.
-
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
-
No prior exposure to immunemediated therapy, 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.
-
Active or prior documented autoimmune or inflammatory disorders.
-
Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids.
-
Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Phoenix | Arizona | United States | 85054 |
| 2 | Research Site | Bakersfield | California | United States | 93309 |
| 3 | Research Site | Santa Monica | California | United States | 90404 |
| 4 | Research Site | Fort Myers | Florida | United States | 33901 |
| 5 | Research Site | Jacksonville | Florida | United States | 32224 |
| 6 | Research Site | Saint Petersburg | Florida | United States | 33705 |
| 7 | Research Site | West Palm Beach | Florida | United States | 33401 |
| 8 | Research Site | Louisville | Kentucky | United States | 40202 |
| 9 | Research Site | Kansas City | Missouri | United States | 64132 |
| 10 | Research Site | Canton | Ohio | United States | 44710 |
| 11 | Research Site | Pittsburgh | Pennsylvania | United States | 15212 |
| 12 | Research Site | Chattanooga | Tennessee | United States | 37404 |
| 13 | Research Site | Nashville | Tennessee | United States | 37203 |
| 14 | Research Site | Fort Worth | Texas | United States | 76104 |
| 15 | Research Site | Houston | Texas | United States | 77090 |
| 16 | Research Site | Richmond | Virginia | United States | 23298 |
| 17 | Research Site | Barretos | Brazil | 14784-400 | |
| 18 | Research Site | Belo Horizonte | Brazil | 30380-472 | |
| 19 | Research Site | Curitiba | Brazil | 81520-060 | |
| 20 | Research Site | Porto Alegre | Brazil | 90035-003 | |
| 21 | Research Site | Porto Alegre | Brazil | 90610-000 | |
| 22 | Research Site | Porto Alegre | Brazil | 91350-200 | |
| 23 | Research Site | Ribeirao Preto | Brazil | 14015-140 | |
| 24 | Research Site | Rio de Janeiro | Brazil | 20231-050 | |
| 25 | Research Site | Santo Andre | Brazil | 09080-110 | |
| 26 | Research Site | Santo André | Brazil | 09060-650 | |
| 27 | Research Site | Sao Paulo | Brazil | 01209-000 | |
| 28 | Research Site | Sao Paulo | Brazil | 01246-000 | |
| 29 | Research Site | São José do Rio Preto | Brazil | 15090-000 | |
| 30 | Research Site | São Paulo | Brazil | 03102-002 | |
| 31 | Research Site | Plovdiv | Bulgaria | 4000 | |
| 32 | Research Site | Plovdiv | Bulgaria | 4004 | |
| 33 | Research Site | Sofia | Bulgaria | 1330 | |
| 34 | Research Site | Sofia | Bulgaria | 1431 | |
| 35 | Research Site | Sofia | Bulgaria | 1618 | |
| 36 | Research Site | Sofia | Bulgaria | 1784 | |
| 37 | Research Site | Varna | Bulgaria | 9010 | |
| 38 | Research Site | Beijing | China | 100021 | |
| 39 | Research Site | Beijing | China | 100053 | |
| 40 | Research Site | Beijing | China | 100142 | |
| 41 | Research Site | Changchun | China | 130012 | |
| 42 | Research Site | Changsha | China | 410013 | |
| 43 | Research Site | Fuzhou | China | 350014 | |
| 44 | Research Site | Guangzhou | China | 510080 | |
| 45 | Research Site | Hangzhou | China | 310022 | |
| 46 | Research Site | Harbin | China | 150081 | |
| 47 | Research Site | He Fei | China | 230022 | |
| 48 | Research Site | Hefei | China | 230001 | |
| 49 | Research Site | Hefei | China | 230601 | |
| 50 | Research Site | Jinan | China | 2501117 | |
| 51 | Research Site | Kunming | China | 650118 | |
| 52 | Research Site | Kunming | China | CN-650034 | |
| 53 | Research Site | Linyi | China | 276000 | |
| 54 | Research Site | Liuzhou | China | 545006 | |
| 55 | Research Site | Nanjing | China | 210009 | |
| 56 | Research Site | Qingdao | China | 110016 | |
| 57 | Research Site | Shanghai | China | 200030 | |
| 58 | Research Site | Shanghai | China | 200032 | |
| 59 | Research Site | Shanghai | China | 200080 | |
| 60 | Research Site | Shanghai | China | 200433 | |
| 61 | Research Site | Shantou | China | 515041 | |
| 62 | Research Site | Wenzhou | China | 325015 | |
| 63 | Research Site | Wuhan | China | 430022 | |
| 64 | Research Site | Wuhan | China | 430079 | |
| 65 | Research Site | Xi'an | China | 710000 | |
| 66 | Research Site | Xining | China | 810001 | |
| 67 | Research Site | Yangzhou | China | 225001 | |
| 68 | Research Site | Zhanjiang | China | 524001 | |
| 69 | Research Site | Zhengzhou | China | 450008 | |
| 70 | Research Site | Zhengzhou | China | 450052 | |
| 71 | Research Site | Berlin | Germany | 13125 | |
| 72 | Research Site | Essen | Germany | 45122 | |
| 73 | Research Site | Freiburg | Germany | 79106 | |
| 74 | Research Site | Gauting | Germany | 82131 | |
| 75 | Research Site | Hamburg | Germany | 20251 | |
| 76 | Research Site | Hamburg | Germany | 21075 | |
| 77 | Research Site | Heidelberg | Germany | 69126 | |
| 78 | Research Site | Immenhausen | Germany | 34376 | |
| 79 | Research Site | Mainz | Germany | 55131 | |
| 80 | Research Site | Oldenburg | Germany | 26121 | |
| 81 | Research Site | Würzburg | Germany | 97067 | |
| 82 | Research Site | Shatin | Hong Kong | 00000 | |
| 83 | Research Site | Budapest | Hungary | 1083 | |
| 84 | Research Site | Budapest | Hungary | 1121 | |
| 85 | Research Site | Kecskemét | Hungary | 6000 | |
| 86 | Research Site | Miskolc | Hungary | 3529 | |
| 87 | Research Site | Törökbálint | Hungary | 2045 | |
| 88 | Research Site | Bunkyo-ku | Japan | 113-8603 | |
| 89 | Research Site | Chuo-ku | Japan | 104-0045 | |
| 90 | Research Site | Fukuoka-shi | Japan | 812-8582 | |
| 91 | Research Site | Hiroshima-shi | Japan | 730-0011 | |
| 92 | Research Site | Iwakuni-shi | Japan | 740-8510 | |
| 93 | Research Site | Kanazawa | Japan | 920-8641 | |
| 94 | Research Site | Kashiwa | Japan | 227-8577 | |
| 95 | Research Site | Koto-ku | Japan | 135-8550 | |
| 96 | Research Site | Kurume-shi | Japan | 830-0011 | |
| 97 | Research Site | Matsuyama-shi | Japan | 790-0007 | |
| 98 | Research Site | Okayama-shi | Japan | 700-8558 | |
| 99 | Research Site | Okayama-shi | Japan | 700-8607 | |
| 100 | Research Site | Osakasayama | Japan | 589-8511 | |
| 101 | Research Site | Sapporo-shi | Japan | 003-0804 | |
| 102 | Research Site | Sunto-gun | Japan | 411-8777 | |
| 103 | Research Site | Toyoake-shi | Japan | 470-1101 | |
| 104 | Research Site | Ube-shi | Japan | 755-0241 | |
| 105 | Research Site | Yokohama-shi | Japan | 236-0004 | |
| 106 | Research Site | Yokohama-shi | Japan | 241-8515 | |
| 107 | Research Site | Busan | Korea, Republic of | 47392 | |
| 108 | Research Site | Chungcheongbuk-do | Korea, Republic of | 28644 | |
| 109 | Research Site | Daegu | Korea, Republic of | 42415 | |
| 110 | Research Site | Incheon | Korea, Republic of | 21565 | |
| 111 | Research Site | Seongnam-si | Korea, Republic of | 13620 | |
| 112 | Research Site | Seoul | Korea, Republic of | 05505 | |
| 113 | Research Site | Seoul | Korea, Republic of | 06591 | |
| 114 | Research Site | Seoul | Korea, Republic of | 120-752 | |
| 115 | Research Site | Seoul | Korea, Republic of | 135-710 | |
| 116 | Research Site | Ulsan | Korea, Republic of | 44033 | |
| 117 | Research Site | Aguascalientes | Mexico | 20230 | |
| 118 | Research Site | Cuautitlan Izcalli | Mexico | 54769 | |
| 119 | Research Site | Guadalajara | Mexico | 44280 | |
| 120 | Research Site | Mexico City | Mexico | 0 3100 | |
| 121 | Research Site | Mexico | Mexico | 14080 | |
| 122 | Research Site | Monterrey | Mexico | 64060 | |
| 123 | Research Site | Monterrey | Mexico | 64460 | |
| 124 | Research Site | México | Mexico | 04739 | |
| 125 | Research Site | Tuxtla | Mexico | 29030 | |
| 126 | Research Site | Arequipa | Peru | AREQUIPA01 | |
| 127 | Research Site | Lima | Peru | L27 | |
| 128 | Research Site | Lima | Peru | LIMA 29 | |
| 129 | Research Site | Lima | Peru | LIMA 34 | |
| 130 | Research Site | Lima | Peru | LIMA 41 | |
| 131 | Research Site | San Isidro | Peru | 27 | |
| 132 | Research Site | Olsztyn | Poland | 10-357 | |
| 133 | Research Site | Tomaszów Mazowiecki | Poland | 97-200 | |
| 134 | Research Site | Warszawa | Poland | 02-781 | |
| 135 | Research Site | Wodzisław Śląski | Poland | 44-300 | |
| 136 | Research Site | Moscow | Russian Federation | 105229 | |
| 137 | Research Site | Moscow | Russian Federation | 115280 | |
| 138 | Research Site | Moscow | Russian Federation | 115478 | |
| 139 | Research Site | Moscow | Russian Federation | 125367 | |
| 140 | Research Site | Omsk | Russian Federation | 644013 | |
| 141 | Research Site | Saint Petersburg | Russian Federation | 195271 | |
| 142 | Research Site | Saint-Petersburg | Russian Federation | 194291 | |
| 143 | Research Site | St. Petersburg | Russian Federation | 197758 | |
| 144 | Research Site | Durban | South Africa | 4091 | |
| 145 | Research Site | Johannesburg | South Africa | 0001 | |
| 146 | Research Site | Kraaifontein | South Africa | 7570 | |
| 147 | Research Site | Parktown | South Africa | 2193 | |
| 148 | Research Site | Pretoria | South Africa | 0001 | |
| 149 | Research Site | Rondebosch | South Africa | 7700 | |
| 150 | Research Site | Vereeniging | South Africa | 1930 | |
| 151 | Research Site | Changhua City | Taiwan | 50006 | |
| 152 | Research Site | Kaohsiung City | Taiwan | 83301 | |
| 153 | Research Site | Kaohsiung | Taiwan | 82445 | |
| 154 | Research Site | Taichung | Taiwan | 40447 | |
| 155 | Research Site | Taichung | Taiwan | 40705 | |
| 156 | Research Site | Tainan | Taiwan | 70403 | |
| 157 | Research Site | Taipei | Taiwan | 10002 | |
| 158 | Research Site | Taipei | Taiwan | 112 | |
| 159 | Research Site | Taipei | Taiwan | 235 | |
| 160 | Research Site | Tao-Yuan | Taiwan | 333 | |
| 161 | Research Site | Bangkok | Thailand | 10210 | |
| 162 | Research Site | Bangkok | Thailand | 10330 | |
| 163 | Research Site | Bangkok | Thailand | 10400 | |
| 164 | Research Site | Muang | Thailand | 50200 | |
| 165 | Research Site | Songkhla | Thailand | 90110 | |
| 166 | Research Site | Dnipro | Ukraine | 49102 | |
| 167 | Research Site | Ivano-Frankivsk | Ukraine | 76018 | |
| 168 | Research Site | Kirovohrad | Ukraine | 25006 | |
| 169 | Research Site | Kyiv | Ukraine | 03022 | |
| 170 | Research Site | Kyiv | Ukraine | 03115 | |
| 171 | Research Site | Lviv | Ukraine | 79031 | |
| 172 | Research Site | Odesa | Ukraine | 65055 | |
| 173 | Research Site | Sumy | Ukraine | 40022 | |
| 174 | Research Site | Vinnytsia | Ukraine | 21029 | |
| 175 | Research Site | Zaporizhzhia | Ukraine | 69040 | |
| 176 | Research Site | Leicester | United Kingdom | LE1 5WW | |
| 177 | Research Site | London | United Kingdom | EC1M 6BQ | |
| 178 | Research Site | London | United Kingdom | NW1 2PG | |
| 179 | Research Site | London | United Kingdom | W6 8RF | |
| 180 | Research Site | Manchester | United Kingdom | M20 4BX | |
| 181 | Research Site | Hanoi | Vietnam | 100000 | |
| 182 | Research Site | Ho Chi Minh | Vietnam | 700000 |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Study Director: Xiaojin Shi, M.D., MSc, One MedImmune Way, Gaithersburg, Maryland 20878, United States
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT03164616
Other Study ID Numbers:
- D419MC00004
First Posted:
May 23, 2017
Last Update Posted:
Aug 18, 2022
Last Verified:
Aug 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Study was conducted in 142 study centers across 18 countries in North and Latin America, Europe, Asia Pacific and Africa. First patient randomized: 27 June 2017. Results are presented for the global cohort at final analysis data cut-offs (DCOs) of 24 July 2019 (Response Evaluation Criteria in Solid Tumors [RECIST]-based endpoints) and 12 March 2021 (all other data). Once global enrollment was complete, enrollment was started in mainland China. Results for the China cohort will be reported later. |
|---|---|
| Pre-assignment Detail | Patients were randomized in a stratified manner as per programmed cell death ligand 1 (PD-L1) tumor expression status (PD-L1 tumor cells [TC] ≥50% versus [vs] <50%), disease stage (IVA vs IVB), and histology (non-squamous vs squamous) in a 1:1:1 ratio to receive treatment with tremelimumab + durvalumab combination therapy + standard of care (SoC) chemotherapy (also referred to as T+ D + SoC), durvalumab monotherapy + SoC chemotherapy (also referred to as D + SoC), or SoC chemotherapy alone. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 milligrams (mg) + durvalumab 1500 mg combination therapy + SoC chemotherapy via intravenous (IV) infusion every 3 weeks (Q3W) for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion every 4 weeks (Q4W) from Week 12 until progressive disease (PD), unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Period Title: Overall Study | |||
| STARTED | 338 | 338 | 337 |
| Received Treatment | 331 | 335 | 331 |
| COMPLETED | 80 | 65 | 40 |
| NOT COMPLETED | 258 | 273 | 297 |
Baseline Characteristics
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone | Total |
|---|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. | Total of all reporting groups |
| Overall Participants | 338 | 338 | 337 | 1013 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
62.6
(9.43)
|
63.5
(9.10)
|
63.1
(9.87)
|
63.1
(9.47)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
69
20.4%
|
85
25.1%
|
89
26.4%
|
243
24%
|
| Male |
269
79.6%
|
253
74.9%
|
248
73.6%
|
770
76%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| White |
205
60.7%
|
182
53.8%
|
179
53.1%
|
566
55.9%
|
| Black or African American |
8
2.4%
|
4
1.2%
|
8
2.4%
|
20
2%
|
| Asian |
99
29.3%
|
123
36.4%
|
128
38%
|
350
34.6%
|
| Native Hawaiian or other Pacific Islander |
2
0.6%
|
0
0%
|
0
0%
|
2
0.2%
|
| American Indian or Alaska Native |
12
3.6%
|
17
5%
|
9
2.7%
|
38
3.8%
|
| Other |
12
3.6%
|
12
3.6%
|
13
3.9%
|
37
3.7%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| Hispanic or Latino |
51
15.1%
|
54
16%
|
55
16.3%
|
160
15.8%
|
| Not Hispanic or Latino |
287
84.9%
|
284
84%
|
282
83.7%
|
853
84.2%
|
| Age (Count of Participants) | ||||
| ≥18 to <50 |
29
8.6%
|
27
8%
|
30
8.9%
|
86
8.5%
|
| ≥50 to <65 |
162
47.9%
|
142
42%
|
146
43.3%
|
450
44.4%
|
| ≥65 to <75 |
112
33.1%
|
130
38.5%
|
121
35.9%
|
363
35.8%
|
| ≥75 |
35
10.4%
|
39
11.5%
|
40
11.9%
|
114
11.3%
|
Outcome Measures
| Title | Progression-Free Survival (PFS); D + SoC Compared With SoC Alone |
|---|---|
| Description | PFS (per RECIST version 1.1 [RECIST 1.1] using Blinded Independent Central Review [BICR] assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. The final analysis of PFS in the global cohort was pre-specified after approximately 497 BICR PFS events occurred across the D + SoC and SoC alone treatment arms (75% maturity). |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. Analysis of PFS was assessed as a primary outcome measure for comparison of the D + SoC vs SoC alone treatment arms only. The alternative treatment arm comparisons were assessed as a secondary outcome measure. |
| Arm/Group Title | D + SoC | SoC Alone |
|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 338 | 337 |
| Median (95% Confidence Interval) [months] |
5.5
|
4.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | D + SoC vs SoC alone. A hazard ratio (HR) <1 favors D + SoC to be associated with a longer PFS than SoC alone. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00093 |
| Comments | Analysis was performed using a stratified log-rank test adjusting for PD-L1 tumor expression (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using the Breslow approach for handling ties. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.74 | |
| Confidence Interval |
(2-Sided) 95% 0.620 to 0.885 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and confidence interval (CI) were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
| Title | Overall Survival (OS); D + SoC Compared With SoC Alone |
|---|---|
| Description | OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. The final analysis of OS in the global cohort was pre-specified after approximately 532 OS events occurred across the D + SoC and SoC alone treatment arms (80% maturity). |
| Time Frame | From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. Analysis of OS was assessed as a primary outcome measure for comparison of the D + SoC vs SoC alone treatment arms only. The alternative treatment arm comparisons were assessed as a secondary outcome measure. |
| Arm/Group Title | D + SoC | SoC Alone |
|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 338 | 337 |
| Median (95% Confidence Interval) [months] |
13.3
|
11.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | D + SoC vs SoC alone. An HR <1 favors D + SoC to be associated with a longer OS than SoC alone. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.07581 |
| Comments | Analysis was performed using a stratified log-rank test adjusting for PD-L1 tumor expression (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using the Breslow approach for handling ties. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.86 | |
| Confidence Interval |
(2-Sided) 95% 0.724 to 1.016 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
| Title | PFS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC |
|---|---|
| Description | PFS (per RECIST 1.1 using BICR assessments) was defined as time from date of randomization until date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to progression. Median PFS was calculated using the Kaplan-Meier technique. |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 338 | 338 | 337 |
| Median (95% Confidence Interval) [months] |
6.2
|
5.5
|
4.8
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | T + D + SoC vs SoC alone. An HR <1 favors T + D + SoC to be associated with a longer PFS than SoC alone. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00031 |
| Comments | Analysis was performed using a stratified log-rank test adjusting for PD-L1 tumor expression (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using the Breslow approach for handling ties. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.72 | |
| Confidence Interval |
(2-Sided) 95% 0.600 to 0.860 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
| Title | OS; T + D + SoC Compared With SoC Alone and T + D + SoC Compared With D + SoC |
|---|---|
| Description | OS was defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Median OS was calculated using the Kaplan-Meier technique. |
| Time Frame | From baseline until death due to any cause. Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 338 | 338 | 337 |
| Median (95% Confidence Interval) [months] |
14.0
|
13.3
|
11.7
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | T + D + SoC vs SoC alone. An HR <1 favors T + D + SoC to be associated with a longer OS than SoC alone. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.00304 |
| Comments | Analysis was performed using a stratified log-rank test adjusting for PD-L1 tumor expression (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using the Breslow approach for handling ties. | |
| Method | Log Rank | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.77 | |
| Confidence Interval |
(2-Sided) 95% 0.650 to 0.916 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
| Title | Objective Response Rate (ORR) |
|---|---|
| Description | ORR (per RECIST 1.1 using BICR assessments) was defined as the percentage of patients with at least one visit response of complete response (CR) or partial response (PR). Results are presented for the pre-specified ORR analysis using unconfirmed responses based on BICR. |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. The denominator was a subset of the FAS who had measurable disease at baseline. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 335 | 330 | 332 |
| Number [percentage of patients] |
46.3
|
48.5
|
33.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | SoC Alone, SoC Alone |
|---|---|---|
| Comments | D + SoC vs SoC alone. An odds ratio >1 favors D + SoC compared to SoC alone. Analysis was performed using logistic regression adjusting for PD-L1 tumor expression (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB), with the CI calculated using a profile likelihood approach. | |
| 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 | 1.90 | |
| Confidence Interval |
(2-Sided) 95% 1.382 to 2.619 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | T + D + SoC vs SoC alone. An odds ratio >1 favors T + D + SoC compared to SoC alone. Analysis was performed using logistic regression adjusting for PD-L1 tumor expression (TC ≥50% vs TC <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB), with the CI calculated using a profile likelihood approach. | |
| 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 | 1.72 | |
| Confidence Interval |
(2-Sided) 95% 1.260 to 2.367 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Best Objective Response (BoR) |
|---|---|
| Description | The BoR was calculated based on the overall visit responses from each RECIST 1.1 assessment. BOR was defined as the best response a patient had following randomization, but prior to starting any subsequent cancer therapy and up to and including RECIST 1.1 progression or the last evaluable assessment in the absence of RECIST 1.1 progression, as determined by BICR. Categorization of BoR was based on RECIST using the following 'response' categories: CR and PR and the following 'non-response' categories: stable disease (SD) ≥6 weeks, progression (ie, PD) and not evaluable (NE). Results are presented for number (%) of patients in each specified category. |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. The denominator was a subset of the FAS who had measurable disease at baseline. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 335 | 330 | 332 |
| CR |
2
0.6%
|
3
0.9%
|
0
0%
|
| PR |
153
45.3%
|
157
46.4%
|
111
32.9%
|
| SD ≥6 weeks |
120
35.5%
|
107
31.7%
|
150
44.5%
|
| PD |
48
14.2%
|
60
17.8%
|
61
18.1%
|
| NE |
12
3.6%
|
3
0.9%
|
10
3%
|
| Title | Duration of Response (DoR) |
|---|---|
| Description | DoR (per RECIST 1.1 using BICR assessments) was defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. The end of response coincided with the date of progression or death from any cause used for the RECIST 1.1 PFS endpoint. The time of the initial response was defined as the latest of the dates contributing towards the first visit of PR or CR. Results are presented for the pre-specified DoR analysis using unconfirmed responses based on BICR. |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. Only patients with an objective response were included in the analysis. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 155 | 160 | 111 |
| Median (Inter-Quartile Range) [months] |
7.4
|
6.0
|
4.2
|
| Title | Time From Randomization to Second Progression (PFS2) |
|---|---|
| Description | PFS2 was defined as the time from the date of randomization to the earliest of the progression event (subsequent to that used for the primary variable PFS) or death. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could involve any of: objective radiological imaging, symptomatic progression or death. |
| Time Frame | Tumor scans performed at baseline, Week 6, Week 12 and then every 8 weeks relative to date of randomization until radiological progression. Assessed until global cohort DCO of 24 July 2019 (maximum of approximately 25 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 338 | 338 | 337 |
| Median (95% Confidence Interval) [months] |
10.4
|
10.2
|
9.4
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | SoC Alone, SoC Alone |
|---|---|---|
| Comments | D + SoC vs SoC alone. An HR <1 favors D + SoC to be associated with a longer PFS2 than SoC alone. | |
| 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 | 0.79 | |
| Confidence Interval |
(2-Sided) 95% 0.666 to 0.928 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | D + SoC, SoC Alone |
|---|---|---|
| Comments | T + D + SoC vs SoC alone. An HR <1 favors T + D + SoC to be associated with a longer PFS2 than SoC alone. | |
| 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 | 0.75 | |
| Confidence Interval |
(2-Sided) 95% 0.632 to 0.883 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The HR and CI were estimated from a stratified Cox proportional hazards model adjusting for PD-L1 (TC ≥50% vs <50%), histology (squamous vs non-squamous) and disease stage (IVA vs IVB) and using Efron method to control for ties. | |
| Title | Pharmacokinetics (PK) of Durvalumab; Peak and Trough Serum Concentrations |
|---|---|
| Description | To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of durvalumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively. |
| Time Frame | Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The PK analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol for whom any post-dose PK data were available and without any protocol deviations that would significantly affect the PK analyses. PK for durvalumab was performed for the T + D + SoC and D + SoC treatment arms only. |
| Arm/Group Title | T + D + SoC | D + SoC |
|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 327 | 330 |
| Week 0 |
418.80
(164.20)
|
505.01
(48.76)
|
| Week 3 |
82.08
(84.38)
|
91.53
(100.58)
|
| Week 12 |
195.62
(58.65)
|
212.11
(60.37)
|
| Follow-up (3 months) |
13.42
(166.36)
|
16.06
(249.88)
|
| Title | PK of Tremelimumab; Peak and Trough Serum Concentrations |
|---|---|
| Description | To evaluate PK, blood samples were collected at pre-specified timepoints and peak and trough serum concentrations of tremelimumab were determined. Peak concentration on Week 0 is the post-infusion concentration of Week 0 (collected within 10 minutes of the end of infusion). Trough concentrations on Weeks 3 and 12 are the pre-infusion concentrations of Weeks 3 and 12, respectively. |
| Time Frame | Samples were collected post-dose on Day 1 (Week 0), pre-dose on Weeks 3 and 12 and at follow-up (3 months after the last valid dose). Assessed at the global cohort DCO of 12 March 2021. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The PK analysis set included all patients who received at least 1 dose of durvalumab or tremelimumab per the protocol for whom any post-dose PK data were available and without any protocol deviations that would significantly affect the PK analyses. PK for tremelimumab was performed for the T + D + SoC treatment arm only. |
| Arm/Group Title | T + D + SoC |
|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 327 |
| Week 0 |
23.17
(65.62)
|
| Week 3 |
4.16
(80.83)
|
| Week 12 |
7.82
(75.68)
|
| Follow-up (3 months) |
0.86
(87.65)
|
| Title | Number of Patients With Anti-Drug Antibody (ADA) Response to Durvalumab |
|---|---|
| Description | Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against durvalumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of neutralizing antibody (nAb) was tested for all ADA positive samples. |
| Time Frame | Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, durvalumab). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The ADA evaluable patients included those in the safety analysis set with non-missing baseline ADA sample and at least 1 post-baseline ADA sample. ADA for durvalumab was performed for the T + D + SoC and D + SoC treatment arms only. The denominator was durvalumab ADA evaluable patients. |
| Arm/Group Title | T + D + SoC | D + SoC |
|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 286 | 285 |
| ADA positive at any visit (ADA prevalence) |
42
12.4%
|
33
9.8%
|
| Treatment-emergent ADA positive (ADA incidence) |
29
8.6%
|
19
5.6%
|
| Treatment-boosted ADA |
2
0.6%
|
1
0.3%
|
| Treatment-induced ADA (ADA positive post-baseline only) |
27
8%
|
18
5.3%
|
| ADA positive at baseline only |
8
2.4%
|
13
3.8%
|
| ADA positive post-baseline and positive at baseline |
7
2.1%
|
2
0.6%
|
| Persistently positive |
8
2.4%
|
7
2.1%
|
| Transiently positive |
26
7.7%
|
13
3.8%
|
| nAb positive at any visit |
3
0.9%
|
3
0.9%
|
| Title | Number of Patients With ADA Response to Tremelimumab |
|---|---|
| Description | Blood samples were collected at pre-specified timepoints and number of patients who developed detectable ADAs against tremelimumab was determined. ADA prevalence is defined as percentage of patients with positive ADA result at any time, baseline or post-baseline. Treatment-emergent ADA is defined as either treatment-induced ADA or treatment-boosted ADA. ADA incidence is percentage of patients who were treatment-emergent ADA-positive. Treatment-boosted ADA is defined as baseline positive ADA titer that was boosted by ≥4-fold during the study period. Persistently positive is defined as having ≥2 post-baseline ADA positive measurements with ≥16 weeks (112 days) between the first and last positive, or an ADA positive result at the last available assessment. Transiently positive is defined as having ≥1 post-baseline ADA positive measurement and not fulfilling the conditions for persistently positive. Presence of nAb was tested for all ADA positive samples. |
| Time Frame | Samples were collected on Day 1 (Week 0), Week 12 and at 3 months after the last dose of study treatment (ie, tremelimumab). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The ADA evaluable patients included those in the safety analysis set with non-missing baseline ADA sample and at least 1 post-baseline ADA sample. ADA for tremelimumab was performed for the T + D + SoC treatment arm only. The denominator was tremelimumab ADA evaluable patients. |
| Arm/Group Title | T + D + SoC |
|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 278 |
| ADA positive at any visit (ADA prevalence) |
44
13%
|
| Treatment-emergent ADA positive (ADA incidence) |
38
11.2%
|
| Treatment-boosted ADA |
3
0.9%
|
| Treatment-induced ADA (ADA positive post-baseline only) |
35
10.4%
|
| ADA positive at baseline only |
4
1.2%
|
| ADA positive post-baseline and positive at baseline |
5
1.5%
|
| Persistently positive |
22
6.5%
|
| Transiently positive |
18
5.3%
|
| nAb positive at any visit |
31
9.2%
|
| Title | Time to Deterioration of Global Health Status / Health-Related Quality of Life (HRQoL) and Patient Reported Outcome (PRO) Symptoms, Assessed Using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) |
|---|---|
| Description | The EORTC QLQ-Core 30 version 3 (QLQ-C30 v3) was included for assessing HRQoL. It assesses HRQoL/health status through 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), and a global health and QoL scale. 6 single-item symptom measures are also included: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. Scores from 0 to 100 were derived for each of the 15 domains, with higher scores representing greater functioning, greater HRQoL, or greater level of symptoms. Time to deterioration was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration. |
| Time Frame | At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. For QLQ-C30 function scales and global health status/HRQoL, only patients with baseline scores ≥10 (and with data available) were included in the analysis. For QLQ-C30 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 325 | 326 | 321 |
| QLQ-C30 Global Health Status / HRQoL |
8.3
|
7.8
|
5.6
|
| QLQ-C30 Physical Functioning |
7.7
|
8.3
|
5.3
|
| QLQ-C30 Role Functioning |
6.6
|
7.4
|
4.8
|
| QLQ-C30 Cognitive Functioning |
7.6
|
7.4
|
5.8
|
| QLQ-C30 Emotional Functioning |
8.5
|
9.5
|
7.5
|
| QLQ-C30 Social Functioning |
6.4
|
7.1
|
5.7
|
| QLQ-C30 Fatigue |
3.7
|
3.8
|
2.8
|
| QLQ-C30 Pain |
8.9
|
6.5
|
5.7
|
| QLQ-C30 Nausea / Vomiting |
7.8
|
5.6
|
5.6
|
| QLQ-C30 Dyspnea |
7.9
|
6.9
|
6.7
|
| QLQ-C30 Insomnia |
8.3
|
7.4
|
5.8
|
| QLQ-C30 Appetite Loss |
7.2
|
7.2
|
7.0
|
| QLQ-C30 Constipation |
9.2
|
8.7
|
6.1
|
| QLQ-C30 Diarrhea |
11.0
|
9.8
|
10.8
|
| Title | Time to Deterioration of PRO Symptoms, Assessed Using EORTC QLQ-Lung Cancer Module 13 (QLQ-LC13) |
|---|---|
| Description | The EORTC QLQ-LC13 is a disease-specific 13-item self-administered questionnaire for lung cancer, to be used in conjunction with the EORTC QLQ-C30. It comprises both multi-item and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, dyspnea, and pain) and treatment-related symptoms from conventional chemotherapy and radiotherapy (ie, hair loss, neuropathy, sore mouth, and dysphagia). Scores from 0 to 100 were derived for each symptom item, with higher scores representing greater level of symptoms. Time to deterioration was defined as time from randomization until the date of first clinically meaningful deterioration that was confirmed at a subsequent visit or death (by any cause) in the absence of a clinically meaningful deterioration. |
| Time Frame | At baseline, Weeks 3, 6, 9, 12, 16 and 20, then Q4W until PD, on Day 28 and 2 months post-PD, then every 8 weeks until second progression/death (whichever came first). Assessed until global cohort DCO of 12 March 2021 (maximum of approximately 45 months). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Global cohort: The FAS included all randomized patients. For QLQ-LC13 symptom scales/items, only patients with baseline scores ≤90 (and with data available) were included in the analysis. |
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone |
|---|---|---|---|
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. |
| Measure Participants | 325 | 326 | 321 |
| QLQ-LC13 Cough |
9.7
|
11.0
|
8.8
|
| QLQ-LC13 Hemoptysis |
17.8
|
14.0
|
11.4
|
| QLQ-LC13 Dyspnea |
5.4
|
5.0
|
3.6
|
| QLQ-LC13 Pain in Chest |
10.0
|
9.5
|
8.6
|
| QLQ-LC13 Pain in Arm or Shoulder |
8.9
|
8.9
|
8.8
|
| QLQ-LC13 Pain in Other Parts |
9.7
|
8.9
|
5.8
|
Adverse Events
| Time Frame | Adverse events: from first dose of study treatment until the earlier of 90 days after last dose or the date of first subsequent anticancer therapy. All-cause mortality (death due to any cause): from randomization up to global cohort final analysis DCO (12 March 2021). Maximum timeframe of approximately 45 months. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Safety analysis set included all patients who received at least 1 dose of study treatment (analyzed according to actual treatment received). 1 patient randomized to T + D + SoC arm and 1 patient randomized to D + SoC arm only received SoC and were included in SoC alone arm of the safety analysis set. All-cause mortality was determined for patients in the FAS (analyzed according to randomized treatment arm, regardless of the treatment received). Results are reported for the global cohort only. | |||||
| Arm/Group Title | T + D + SoC | D + SoC | SoC Alone | |||
| Arm/Group Description | During chemotherapy (combination) stage: Patients received tremelimumab 75 mg + durvalumab 1500 mg combination therapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Patients also received an additional dose of tremelimumab 75 mg (in combination with durvalumab) at Week 16 post-chemotherapy. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received durvalumab 1500 mg monotherapy + SoC chemotherapy via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Patients then continued to receive durvalumab monotherapy 1500 mg IV infusion Q4W from Week 12 until PD, unless there was unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q4W from Week 12 until PD, unless contraindicated per the Investigator. | During chemotherapy (combination) stage: Patients received SoC chemotherapy alone via IV infusion Q3W for 4 doses/cycles (Weeks 0, 3, 6 and 9). Patients could also receive SoC chemotherapy for an additional 2 cycles Q3W on Weeks 12 and 15 if clinically indicated and at the Investigator's discretion before the patient entered follow-up. The SoC chemotherapy was the Investigator's choice of one of the following regimens: abraxane + carboplatin (squamous and non-squamous patients), pemetrexed + cisplatin or carboplatin (non-squamous patients only), or gemcitabine + cisplatin or carboplatin (squamous patients only). Post-chemotherapy (maintenance) stage: Non-squamous patients who received pemetrexed + carboplatin/cisplatin during chemotherapy stage could receive pemetrexed maintenance therapy, given Q3W or Q4W (dependent on Investigator decision and local standards) from Week 12 until PD, unless contraindicated per the Investigator. | |||
All Cause Mortality |
||||||
| T + D + SoC | D + SoC | SoC Alone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 251/338 (74.3%) | 265/338 (78.4%) | 285/337 (84.6%) | |||
Serious Adverse Events |
||||||
| T + D + SoC | D + SoC | SoC Alone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 146/330 (44.2%) | 134/334 (40.1%) | 117/333 (35.1%) | |||
| Blood and lymphatic system disorders | ||||||
| Leukopenia | 2/330 (0.6%) | 3 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Anaemia | 18/330 (5.5%) | 32 | 23/334 (6.9%) | 30 | 21/333 (6.3%) | 25 |
| Neutropenia | 4/330 (1.2%) | 5 | 6/334 (1.8%) | 8 | 3/333 (0.9%) | 5 |
| Pancytopenia | 2/330 (0.6%) | 2 | 5/334 (1.5%) | 6 | 3/333 (0.9%) | 4 |
| Thrombocytopenia | 8/330 (2.4%) | 8 | 6/334 (1.8%) | 7 | 3/333 (0.9%) | 3 |
| Disseminated intravascular coagulation | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Febrile neutropenia | 7/330 (2.1%) | 7 | 5/334 (1.5%) | 5 | 4/333 (1.2%) | 4 |
| Cardiac disorders | ||||||
| Acute coronary syndrome | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Acute myocardial infarction | 2/330 (0.6%) | 2 | 3/334 (0.9%) | 3 | 1/333 (0.3%) | 1 |
| Angina pectoris | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Angina unstable | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Atrial fibrillation | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Atrial tachycardia | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Autoimmune myocarditis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Bundle branch block left | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cardiac arrest | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cardiac failure | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 3/333 (0.9%) | 3 |
| Cardiac failure acute | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cardiac failure congestive | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Cardiac tamponade | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cardiopulmonary failure | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Coronary artery disease | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Myocardial infarction | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Pericardial effusion | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Right ventricular failure | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Supraventricular tachycardia | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Tachyarrhythmia | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Ventricular fibrillation | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Ear and labyrinth disorders | ||||||
| Deafness bilateral | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Deafness unilateral | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Endocrine disorders | ||||||
| Adrenal insufficiency | 3/330 (0.9%) | 3 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Diabetes insipidus | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Hypopituitarism | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Eye disorders | ||||||
| Cataract | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 2 |
| Gastrointestinal disorders | ||||||
| Abdominal discomfort | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Abdominal pain upper | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Autoimmune pancreatitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Colitis | 5/330 (1.5%) | 5 | 3/334 (0.9%) | 3 | 0/333 (0%) | 0 |
| Diarrhoea | 8/330 (2.4%) | 8 | 3/334 (0.9%) | 4 | 2/333 (0.6%) | 2 |
| Diverticular perforation | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Duodenal ulcer haemorrhage | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Dysphagia | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Enteritis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Enterocolitis | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Faecaloma | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Gastric ulcer | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Gastric ulcer haemorrhage | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Gastric ulcer perforation | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Gastritis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Gastrointestinal haemorrhage | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Gastrointestinal inflammation | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Inguinal hernia | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Intestinal obstruction | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Mesenteric vein thrombosis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Nausea | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 2 | 2/333 (0.6%) | 2 |
| Oesophageal obstruction | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Oesophageal stenosis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Oesophagitis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Pancreatitis | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Peptic ulcer | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Small intestinal obstruction | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Upper gastrointestinal haemorrhage | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Vomiting | 2/330 (0.6%) | 2 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| General disorders | ||||||
| Asthenia | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 2/333 (0.6%) | 2 |
| Cardiac death | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Death | 3/330 (0.9%) | 3 | 6/334 (1.8%) | 6 | 1/333 (0.3%) | 1 |
| Face oedema | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Fatigue | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| General physical health deterioration | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Malaise | 0/330 (0%) | 0 | 1/334 (0.3%) | 2 | 0/333 (0%) | 0 |
| Oedema peripheral | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Pyrexia | 8/330 (2.4%) | 8 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Sudden death | 1/330 (0.3%) | 1 | 3/334 (0.9%) | 3 | 0/333 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Autoimmune hepatitis | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cholangitis | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Cholecystitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Drug-induced liver injury | 3/330 (0.9%) | 3 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Hepatic failure | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Hepatitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Immune-mediated hepatitis | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Immune system disorders | ||||||
| Anaphylactic reaction | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Drug hypersensitivity | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Haemophagocytic lymphohistiocytosis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Hypersensitivity | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Infections and infestations | ||||||
| Abscess oral | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Acute hepatitis B | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Appendicitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Arthritis bacterial | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Bronchitis | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Bronchitis bacterial | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| COVID-19 | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| COVID-19 pneumonia | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Candida pneumonia | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cellulitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 3/333 (0.9%) | 4 |
| Chikungunya virus infection | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Cystitis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cytomegalovirus colitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Device related infection | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Diarrhoea infectious | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Disseminated tuberculosis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Empyema | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Encephalitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Encephalitis viral | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Enterocolitis infectious | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Gastroenteritis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Gastroenteritis viral | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Herpes zoster | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Infection | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Infective exacerbation of chronic obstructive airways disease | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Influenza | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Lower respiratory tract infection | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 2/333 (0.6%) | 2 |
| Neutropenic sepsis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 2/333 (0.6%) | 3 |
| Nosocomial infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Ophthalmic herpes zoster | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Oral candidiasis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Perirectal abscess | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Pharyngitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pleural infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pneumocystis jirovecii pneumonia | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pneumonia | 36/330 (10.9%) | 42 | 21/334 (6.3%) | 23 | 16/333 (4.8%) | 17 |
| Pneumonia bacterial | 1/330 (0.3%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pneumonia klebsiella | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Postoperative wound infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pulmonary sepsis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Pyelonephritis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Respiratory tract infection | 3/330 (0.9%) | 4 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Sepsis | 5/330 (1.5%) | 5 | 2/334 (0.6%) | 2 | 2/333 (0.6%) | 2 |
| Septic shock | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Staphylococcal infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Tracheitis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Tracheobronchitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Upper respiratory tract infection | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 2/333 (0.6%) | 2 |
| Urinary tract infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 2/333 (0.6%) | 2 |
| Vascular device infection | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Viral infection | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Femoral neck fracture | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Femur fracture | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Foot fracture | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Hip fracture | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 2/333 (0.6%) | 2 |
| Infusion related reaction | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Radiation oesophagitis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Road traffic accident | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Spinal compression fracture | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Subdural haematoma | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Subdural haemorrhage | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Toxicity to various agents | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Upper limb fracture | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Investigations | ||||||
| Alanine aminotransferase increased | 2/330 (0.6%) | 2 | 3/334 (0.9%) | 3 | 0/333 (0%) | 0 |
| Aspartate aminotransferase increased | 0/330 (0%) | 0 | 3/334 (0.9%) | 3 | 0/333 (0%) | 0 |
| Lipase increased | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Neutrophil count decreased | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 3/333 (0.9%) | 6 |
| Platelet count decreased | 2/330 (0.6%) | 2 | 2/334 (0.6%) | 2 | 1/333 (0.3%) | 1 |
| Transaminases increased | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| White blood cell count decreased | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Metabolism and nutrition disorders | ||||||
| Cachexia | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Decreased appetite | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Dehydration | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 2/333 (0.6%) | 2 |
| Fluid overload | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Hypercalcaemia | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Hyperglycaemia | 2/330 (0.6%) | 2 | 3/334 (0.9%) | 3 | 1/333 (0.3%) | 1 |
| Hyperkalaemia | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Hypokalaemia | 2/330 (0.6%) | 2 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Hyponatraemia | 3/330 (0.9%) | 4 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Type 1 diabetes mellitus | 1/330 (0.3%) | 2 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Arthritis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Back pain | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Bone pain | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Intervertebral disc protrusion | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Mandibular mass | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Muscular weakness | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Musculoskeletal chest pain | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Musculoskeletal pain | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Myositis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Polymyositis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Cancer fatigue | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Cancer pain | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Colon cancer | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Eyelid naevus | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Neuroendocrine carcinoma metastatic | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Rectal cancer | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Tumour associated fever | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Nervous system disorders | ||||||
| Brain oedema | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Cerebral infarction | 3/330 (0.9%) | 3 | 2/334 (0.6%) | 2 | 3/333 (0.9%) | 4 |
| Cerebral ischaemia | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Cerebrovascular accident | 4/330 (1.2%) | 4 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Coordination abnormal | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Dizziness | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Encephalitis autoimmune | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Haemorrhagic stroke | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Headache | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 2/333 (0.6%) | 2 |
| Hemiplegia | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Ischaemic stroke | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Leukoencephalopathy | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Nervous system disorder | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Polyneuropathy in malignant disease | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Seizure | 2/330 (0.6%) | 2 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Spinal cord disorder | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Syncope | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Transient ischaemic attack | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Vocal cord paralysis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 2/333 (0.6%) | 2 |
| Product Issues | ||||||
| Device occlusion | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Psychiatric disorders | ||||||
| Anxiety | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Completed suicide | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Suicide attempt | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Acute kidney injury | 6/330 (1.8%) | 6 | 4/334 (1.2%) | 4 | 1/333 (0.3%) | 1 |
| Autoimmune nephritis | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Bladder mass | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Calculus urinary | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Chronic kidney disease | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 2 |
| Glomerulonephritis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Nephritis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Renal failure | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Renal impairment | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| Uterine haemorrhage | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Atelectasis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Chronic obstructive pulmonary disease | 2/330 (0.6%) | 3 | 2/334 (0.6%) | 2 | 5/333 (1.5%) | 8 |
| Dyspnoea | 3/330 (0.9%) | 3 | 1/334 (0.3%) | 1 | 2/333 (0.6%) | 2 |
| Epistaxis | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Haemoptysis | 2/330 (0.6%) | 2 | 7/334 (2.1%) | 8 | 3/333 (0.9%) | 3 |
| Interstitial lung disease | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Lung infiltration | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Pleural effusion | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 2/333 (0.6%) | 2 |
| Pneumonia aspiration | 0/330 (0%) | 0 | 2/334 (0.6%) | 2 | 1/333 (0.3%) | 1 |
| Pneumonitis | 6/330 (1.8%) | 6 | 5/334 (1.5%) | 5 | 1/333 (0.3%) | 1 |
| Pneumothorax | 2/330 (0.6%) | 2 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pulmonary artery thrombosis | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Pulmonary embolism | 5/330 (1.5%) | 5 | 4/334 (1.2%) | 4 | 9/333 (2.7%) | 9 |
| Pulmonary haemorrhage | 0/330 (0%) | 0 | 2/334 (0.6%) | 3 | 3/333 (0.9%) | 3 |
| Respiratory failure | 1/330 (0.3%) | 1 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Drug eruption | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Pemphigoid | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Rash | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 0/333 (0%) | 0 |
| Rash maculo-papular | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Vascular disorders | ||||||
| Brachiocephalic vein thrombosis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Deep vein thrombosis | 3/330 (0.9%) | 3 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Embolism | 1/330 (0.3%) | 1 | 2/334 (0.6%) | 2 | 1/333 (0.3%) | 1 |
| Haematoma | 0/330 (0%) | 0 | 0/334 (0%) | 0 | 1/333 (0.3%) | 1 |
| Hypertensive crisis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Hypotension | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Lymphoedema | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Peripheral artery occlusion | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 0/333 (0%) | 0 |
| Shock | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Shock haemorrhagic | 0/330 (0%) | 0 | 1/334 (0.3%) | 1 | 1/333 (0.3%) | 1 |
| Superior vena cava syndrome | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
| Vasculitis | 1/330 (0.3%) | 1 | 0/334 (0%) | 0 | 0/333 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| T + D + SoC | D + SoC | SoC Alone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 309/330 (93.6%) | 302/334 (90.4%) | 301/333 (90.4%) | |||
| Blood and lymphatic system disorders | ||||||
| Leukopenia | 41/330 (12.4%) | 80 | 32/334 (9.6%) | 59 | 39/333 (11.7%) | 80 |
| Anaemia | 150/330 (45.5%) | 213 | 137/334 (41%) | 188 | 146/333 (43.8%) | 203 |
| Neutropenia | 98/330 (29.7%) | 177 | 75/334 (22.5%) | 135 | 77/333 (23.1%) | 161 |
| Thrombocytopenia | 56/330 (17%) | 83 | 38/334 (11.4%) | 67 | 54/333 (16.2%) | 77 |
| Endocrine disorders | ||||||
| Hyperthyroidism | 19/330 (5.8%) | 20 | 20/334 (6%) | 21 | 2/333 (0.6%) | 3 |
| Hypothyroidism | 39/330 (11.8%) | 42 | 21/334 (6.3%) | 24 | 4/333 (1.2%) | 4 |
| Gastrointestinal disorders | ||||||
| Abdominal pain | 19/330 (5.8%) | 22 | 16/334 (4.8%) | 19 | 10/333 (3%) | 10 |
| Constipation | 63/330 (19.1%) | 85 | 72/334 (21.6%) | 98 | 79/333 (23.7%) | 96 |
| Diarrhoea | 65/330 (19.7%) | 98 | 57/334 (17.1%) | 72 | 49/333 (14.7%) | 66 |
| Nausea | 136/330 (41.2%) | 281 | 120/334 (35.9%) | 258 | 121/333 (36.3%) | 243 |
| Stomatitis | 17/330 (5.2%) | 18 | 20/334 (6%) | 25 | 16/333 (4.8%) | 17 |
| Vomiting | 59/330 (17.9%) | 82 | 51/334 (15.3%) | 74 | 45/333 (13.5%) | 80 |
| General disorders | ||||||
| Asthenia | 56/330 (17%) | 67 | 31/334 (9.3%) | 42 | 39/333 (11.7%) | 49 |
| Fatigue | 81/330 (24.5%) | 116 | 80/334 (24%) | 119 | 74/333 (22.2%) | 93 |
| Mucosal inflammation | 17/330 (5.2%) | 19 | 11/334 (3.3%) | 15 | 6/333 (1.8%) | 6 |
| Oedema peripheral | 27/330 (8.2%) | 35 | 23/334 (6.9%) | 29 | 30/333 (9%) | 34 |
| Pyrexia | 48/330 (14.5%) | 65 | 30/334 (9%) | 38 | 22/333 (6.6%) | 30 |
| Infections and infestations | ||||||
| Upper respiratory tract infection | 22/330 (6.7%) | 32 | 12/334 (3.6%) | 13 | 18/333 (5.4%) | 27 |
| Investigations | ||||||
| Alanine aminotransferase increased | 45/330 (13.6%) | 66 | 43/334 (12.9%) | 63 | 44/333 (13.2%) | 59 |
| Amylase increased | 28/330 (8.5%) | 47 | 24/334 (7.2%) | 41 | 16/333 (4.8%) | 27 |
| Aspartate aminotransferase increased | 42/330 (12.7%) | 67 | 36/334 (10.8%) | 59 | 38/333 (11.4%) | 51 |
| Blood creatinine increased | 21/330 (6.4%) | 33 | 12/334 (3.6%) | 16 | 12/333 (3.6%) | 21 |
| Gamma-glutamyltransferase increased | 18/330 (5.5%) | 18 | 17/334 (5.1%) | 20 | 11/333 (3.3%) | 11 |
| Lipase increased | 20/330 (6.1%) | 34 | 12/334 (3.6%) | 23 | 7/333 (2.1%) | 12 |
| Neutrophil count decreased | 39/330 (11.8%) | 66 | 46/334 (13.8%) | 96 | 59/333 (17.7%) | 110 |
| Platelet count decreased | 22/330 (6.7%) | 28 | 19/334 (5.7%) | 24 | 29/333 (8.7%) | 35 |
| Weight decreased | 23/330 (7%) | 23 | 29/334 (8.7%) | 30 | 20/333 (6%) | 24 |
| White blood cell count decreased | 24/330 (7.3%) | 44 | 21/334 (6.3%) | 50 | 27/333 (8.1%) | 53 |
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 92/330 (27.9%) | 115 | 71/334 (21.3%) | 89 | 81/333 (24.3%) | 117 |
| Hyperglycaemia | 18/330 (5.5%) | 28 | 18/334 (5.4%) | 25 | 12/333 (3.6%) | 13 |
| Hypokalaemia | 25/330 (7.6%) | 38 | 11/334 (3.3%) | 19 | 14/333 (4.2%) | 20 |
| Hyponatraemia | 9/330 (2.7%) | 12 | 16/334 (4.8%) | 19 | 18/333 (5.4%) | 25 |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 41/330 (12.4%) | 55 | 28/334 (8.4%) | 31 | 20/333 (6%) | 23 |
| Back pain | 25/330 (7.6%) | 27 | 16/334 (4.8%) | 21 | 15/333 (4.5%) | 16 |
| Musculoskeletal chest pain | 18/330 (5.5%) | 21 | 9/334 (2.7%) | 9 | 20/333 (6%) | 20 |
| Pain in extremity | 17/330 (5.2%) | 20 | 8/334 (2.4%) | 9 | 8/333 (2.4%) | 8 |
| Nervous system disorders | ||||||
| Dizziness | 20/330 (6.1%) | 22 | 22/334 (6.6%) | 28 | 9/333 (2.7%) | 15 |
| Headache | 37/330 (11.2%) | 49 | 23/334 (6.9%) | 29 | 24/333 (7.2%) | 26 |
| Psychiatric disorders | ||||||
| Insomnia | 26/330 (7.9%) | 30 | 40/334 (12%) | 42 | 29/333 (8.7%) | 36 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 33/330 (10%) | 39 | 38/334 (11.4%) | 42 | 22/333 (6.6%) | 23 |
| Dyspnoea | 30/330 (9.1%) | 30 | 29/334 (8.7%) | 32 | 24/333 (7.2%) | 25 |
| Haemoptysis | 12/330 (3.6%) | 14 | 16/334 (4.8%) | 22 | 17/333 (5.1%) | 24 |
| Productive cough | 11/330 (3.3%) | 12 | 19/334 (5.7%) | 20 | 9/333 (2.7%) | 10 |
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 33/330 (10%) | 34 | 36/334 (10.8%) | 38 | 20/333 (6%) | 20 |
| Pruritus | 36/330 (10.9%) | 43 | 30/334 (9%) | 41 | 15/333 (4.5%) | 18 |
| Rash | 63/330 (19.1%) | 81 | 46/334 (13.8%) | 58 | 22/333 (6.6%) | 23 |
| Vascular disorders | ||||||
| Hypertension | 20/330 (6.1%) | 21 | 9/334 (2.7%) | 13 | 6/333 (1.8%) | 9 |
Limitations/Caveats
This study also incorporates a China tail, comprising additional patients randomized after the end of the global cohort recruitment. Efficacy and safety of patients randomized in China will be reported at a later date once this separate analysis has been completed.
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:
NCT03164616
Other Study ID Numbers:
- D419MC00004
First Posted:
May 23, 2017
Last Update Posted:
Aug 18, 2022
Last Verified:
Aug 1, 2022