Durvalumab and Tremelimumab ± Platinum-Based Chemotherapy in Patients With Metastatic Squamous or Non-Squamous NSCLC

• Sponsor: Canadian Cancer Trials Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03057106
• Collaborator: AstraZeneca (Industry), Fondazione IRCCS Istituto Nazionale dei Tumori, Milano (Other), National Health and Medical Research Council, Australia (Other)
• Enrollment: 301
• Locations: 49
• Arms: 2
• Anticipated Duration (Months): 70.5
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Durvalumab is a new type of drug for many kinds of cancer. It is considered "immunotherapy" and not "chemotherapy". Laboratory tests show that it works by allowing the immune system to detect cancer and reactivate the immune response. This may help to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals and has been studied in more than 5000 people and seems promising.

Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to durvalumab and may improve the effect of durvalumab. Tremelimumab may also help slow the growth of the cancer cells or may cause cancer cells to die. It has been shown to shrink tumours in animals and has been studied in over 1200 people and seems promising.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer Metastatic	Drug: Durvalumab; Drug: Tremelimumab; Drug: Platinum-Based Drug	Phase 2

Detailed Description

Combinations of durvalumab and tremelimumab have also been studied. While the combination has been studied in over 200 people, it is not clear if it can offer better results when it is combined with chemotherapy.

Recently, immunotherapies that target the PD-1/PD-L1 axis have shown promise in treating patients with non-small cell lung cancer.

Study Design

• Study Type: Interventional
• Actual Enrollment: 301 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Trial of Durvalumab and Tremelimumab ± Platinum-Based Chemotherapy in Patients With Metastatic (Stage IV) Squamous or Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: Feb 15, 2017
• Actual Primary Completion Date: Feb 24, 2020
• Anticipated Study Completion Date: Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Durvalumab and Tremelimumab Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses	Drug: Durvalumab; MEDI4736; Drug: Tremelimumab; Tremelimumab
Active Comparator: Platinum based chemotherapy + Durvalumab + Tremelimumab 4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD	Drug: Durvalumab; MEDI4736; Drug: Tremelimumab; Tremelimumab; Drug: Platinum-Based Drug; Pemetrexed, cisplatin, carboplatin or gemcitibine

Outcome Measures

Primary Outcome Measures

1. Overall Survival [33 months]

   time from randomization to the date of death

Secondary Outcome Measures

1. Progression-free Survival Using RECIST 1.1 [33 months]

   time from randomization to the date of the first documented disease progression. Progression was defined as: at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of ≥5 mm, or appearance of new lesions.

2. Objective Response Rate Using RECIST 1.1 and iRECIST [33 months]

   proportion of patients with a documented complete response, partial response (CR + PR) based on iRECIST criteria. The primary estimate of ORR will be based on all patients randomized, and compared using Cochran- Mantel-Haeszel test stratified by stratification factors at randomization between the study new treatment and the standard control arms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically and/or cytologically confirmed diagnosis of squamous or non-squamous, non-small cell carcinoma of the lung. Patients with poorly differentiated tumours will only be eligible if NSCLC is confirmed by immunohistochemistry markers (TTF1/P63 or P40/CK5). Patients with known sensitizing EGFR mutations or known ALK-fusion are not eligible.

• Patients must have stage IV disease according to the 8th TNM version staging.

• Patients must have an adequate histopathology specimen and must consent to release this specimen for protocol required testing. This is a mandatory component of the study.

• Patient must consent to provision of samples of blood in order that the specific correlative marker assays proscribed may be conducted.

• All patients must have measurable disease as defined by RECIST 1.1 All radiology studies must be performed within 28 days prior to randomization (within 35 days if negative).

The criteria for defining measurable disease are as follows:

• CT scan (with slice thickness of 5 mm) ≥ 10 mm --> longest diameter

• Physical exam (using calipers) ≥ 10 mm

• Lymph nodes by CT scan ≥ 15 mm --> measured in short axis

Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented.

• Patients must be 18 years of age or older.

• ECOG performance status of 0 or 1.

• Absolute neutrophils ≥ 1.5 x 10^9/L

• Platelets ≥ 100 x 10^9/L

• Hemoglobin ≥ 90 g/L

• Bilirubin ≤ 1.5 x UNL (upper limit of normal)

• AST and ALT ≤ 2.5 x UNL (if liver metastases are present, ≤5 x UNL) Creatinine < 1.25 UNL or Creatinine clearance ≥ 45 mL/min

• Cytotoxic Chemotherapy: Patients may not have received prior cytotoxic chemotherapy for advanced/metastatic disease.

• Adjuvant Chemotherapy: Patients may have had prior adjuvant therapy for completely resected disease, providing it has been completed at least 12 months prior to randomization.

• Patients treated with concurrent chemotherapy/radiation regimens for unresectable locally advanced Stage III disease will be eligible providing it has been completed at least 12 months prior to randomization.

• Other Systemic Therapy: Patients may not have received prior EGFR or alk inhibitors. Patients may not have received prior treatment with immune-based therapy, including durvalumab and tremelimumab vaccines or oncolytic viral therapy. Patients must have recovered from any reversible treatment related toxicities prior to randomization.

• Prior external beam radiation is permitted provided a minimum of 14 days (2 weeks) have elapsed between the last dose of radiation and date of randomization. Concurrent radiotherapy is not permitted.

Patients must have recovered from any acute toxic effects from radiation prior to randomization.

• Patients must have recovered from any acute toxic effects from radiation prior to randomization.

• Surgery: Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed (major surgery) prior to randomization.

• Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires.

• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements.

• Patients must be accessible for treatment and follow-up. All randomized patients must be followed and treated at participating centres.

• In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization.

• Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception while on study and for 6 months after the last dose of durvalumab and tremelimumab or for 3 months after the last dose of durvalumab alone

Exclusion Criteria:

• Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 3 years. Patients with a history of other malignancies detected at an early stage and whom the investigator believes have been curatively treated and are at low risk of recurrence MAY be eligible. Contact CCTG to discuss eligibility prior to enrolling.

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the exception of diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

• Patients with alopecia.

• Patients with Grave's disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years).

• Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement.

• History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.

• Live attenuated vaccination administered within 30 days prior to randomization

• History of hypersensitivity to durvalumab or tremelimumab or any excipient. Patients who have received other treatment or other antibodies must not have had intolerable toxicity or required steroids to manage toxicity.

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.

• Patients who have untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if now controlled, should have a LVEF ≥ 45%. (Note: patients with uncomplicated controlled hypertension do not require LVEF measurement in the absence of other significant cardiac history)

• Concurrent treatment with other investigational drugs or anti-cancer therapy

• Patients with untreated brain or meningeal metastases are not eligible. Patients with treated CNS disease who have radiologic AND clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization).

• Pregnant or Lactating Women: Women of childbearing potential must have a pregnancy test (urine or serum) proven negative within 14 days prior to randomization. If urine test is positive, pregnancy testing may then include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. Men and women of child-bearing potential must agree to use adequate contraception.

• Patients with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol (including corticosteroid administration), or would put the patient at risk. This includes but is not limited to:

• Contraindications to the use of pemetrexed, gemcitabine, cisplatin and/or carboplatin (consult product monograph);

• History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements;

• Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or tuberculosis);

• Active peptic ulcer disease or gastritis;

• Known pneumonitis or pulmonary fibrosis with clinically significant impairment of pulmonary function.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Campbelltown Hospital	Campbelltown	New South Wales	Australia	2560
2	Coffs Habour Health Campus - NCCI	Coffs Harbour	New South Wales	Australia	2450
3	Concord Repatriation General Hospital	Concord	New South Wales	Australia	2139
4	Nepean Hospital	Kingswood	New South Wales	Australia	2751
5	St. George Hospital, Cancer Care Centre	Kogarah	New South Wales	Australia	2217
6	The Tweed Hospital	Lismore	New South Wales	Australia	2480
7	Liverpool Cancer Therapy Centre, Liverpool Hospital	Liverpool	New South Wales	Australia	2170
8	Prince of Wales Hospital	Randwick	New South Wales	Australia	2031
9	Princess Alexandra Hospital	Brisbane	Queensland	Australia	4102
10	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
11	Mater Research Institute South Brisbane	South Brisbane	Queensland	Australia	4101
12	Gold Coast University Hospital	Southport	Queensland	Australia	4215
13	Toowoomba Hospital	Toowoomba	Queensland	Australia	4350
14	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
15	Ballarat Health Services	Ballarat	Victoria	Australia	3350
16	Epworth HealthCare - Richmond	Richmond	Victoria	Australia	3121
17	Border Medical Oncology	Wodonga	Victoria	Australia	3690
18	Saint John of God Hospital Subiaco	Subiaco	Western Australia	Australia	6008
19	St. Vincent's Hospital	Victoria Park		Australia	3065
20	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
21	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia	Canada	V3V 1Z2
22	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
23	Horizon Health Network	Fredericton	New Brunswick	Canada	E3B 5N5
24	The Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
25	The Vitalite Health Network - Dr. Leon Richard	Moncton	New Brunswick	Canada	E1C 8X3
26	Regional Health Authority B, Zone 2	Saint John	New Brunswick	Canada	E2L 4L2
27	Cambridge Memorial Hospital	Cambridge	Ontario	Canada	N1R 3G2
28	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
29	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
30	Grand River Regional Cancer Centre	Kitchener	Ontario	Canada	N2G 1G3
31	Stronach Regional Health Centre at Southlake	Newmarket	Ontario	Canada	L3Y 2P9
32	Ottawa Hospital Research Institute	Ottawa	Ontario	Canada	K1H 8L6
33	Algoma District Cancer Program	Sault Ste. Marie	Ontario	Canada	P6B 0A8
34	Niagara Health System	St. Catharines	Ontario	Canada	L2S 0A9
35	Health Sciences North	Sudbury	Ontario	Canada	P3E 5J1
36	North York General Hospital	Toronto	Ontario	Canada	M2K 1E1
37	Humber River Regional Hospital	Toronto	Ontario	Canada	M3M 0B2
38	Michael Garron Hospital	Toronto	Ontario	Canada	M4C 3E7
39	University Health Network	Toronto	Ontario	Canada	M5G 2M9
40	Windsor Regional Cancer Centre	Windsor	Ontario	Canada	N8W 2X3
41	PEI Cancer Treatment Centre	Charlottetown	Prince Edward Island	Canada	C1A 8T5
42	Hopital de la Cite-de-la-Sante	Laval	Quebec	Canada	H7M 3L9
43	CHUM-Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec	Canada	H2X 3E4
44	The Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
45	CHU de Quebec-Hopital l'Enfant-Jesus (HEJ)	Quebec City	Quebec	Canada	G1J 1Z4
46	University Institute of Cardiology and	Quebec City	Quebec	Canada	G1V 4G5
47	Centre hospitalier universitaire de Sherbrooke	Sherbrooke	Quebec	Canada	J1H 5N4
48	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
49	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

• Canadian Cancer Trials Group
• AstraZeneca
• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• National Health and Medical Research Council, Australia

Investigators

• Study Chair: Natasha Leighl, Princess Margaret Hospital, Toronto, ON Canada

Study Documents (Full-Text)

• Study Protocol - Feb 19, 2021
• Statistical Analysis Plan - Nov 1, 2019

More Information

Publications

None provided.

• Responsible Party: Canadian Cancer Trials Group
• ClinicalTrials.gov Identifier: NCT03057106
• Other Study ID Numbers: BR34
• First Posted: Feb 17, 2017
• Last Update Posted: Jun 27, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lung Neoplasms; Durvalumab; Tremelimumab

Study Results

Participant Flow

Arm/Group Title	Durvalumab and Tremelimumab	Platinum Based Chemotherapy + Durvalumab + Tremelimumab
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab	4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine
Period Title: Overall Study
STARTED	149	148
COMPLETED	149	148
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Durvalumab and Tremelimumab	Platinum Based Chemotherapy + Durvalumab + Tremelimumab	Total
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab	4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine	Total of all reporting groups
Overall Participants	150	151	301
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	86 57.3%	69 45.7%	155 51.5%
>=65 years	64 42.7%	82 54.3%	146 48.5%
Sex: Female, Male (Count of Participants)
Female	69 46%	70 46.4%	139 46.2%
Male	81 54%	81 53.6%	162 53.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 1.3%	2 0.7%
Asian	6 4%	7 4.6%	13 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.7%	1 0.3%
Black or African American	4 2.7%	0 0%	4 1.3%
White	138 92%	138 91.4%	276 91.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1.3%	3 2%	5 1.7%
Smoking history (Count of Participants)
Never smoke	14 9.3%	12 7.9%	26 8.6%
Ever smoked	136 90.7%	139 92.1%	275 91.4%
Histology type (Count of Participants)
Non-squamous	123 82%	123 81.5%	246 81.7%
Squamous	27 18%	28 18.5%	55 18.3%
ECOG Performance Status (Count of Participants)
0	45 30%	47 31.1%	92 30.6%
1	105 70%	104 68.9%	209 69.4%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	time from randomization to the date of death
Time Frame	33 months

Outcome Measure Data

Analysis Population Description

ITT population, included patients who refused the study treatments (4 patients)

Arm/Group Title	Durvalumab and Tremelimumab	Platinum Based Chemotherapy + Durvalumab + Tremelimumab
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab	4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine
Measure Participants	150	151
Median (90% Confidence Interval) [Months]	14.1	16.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Durvalumab and Tremelimumab, Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments	2-sided, adjusted for stratification factors at rtandomization.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 90%; 0.67 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival Using RECIST 1.1
Description	time from randomization to the date of the first documented disease progression. Progression was defined as: at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of ≥5 mm, or appearance of new lesions.
Time Frame	33 months

Outcome Measure Data

Analysis Population Description

ITT population, included the 4 patents who refused study treatments.

Arm/Group Title	Durvalumab and Tremelimumab	Platinum Based Chemotherapy + Durvalumab + Tremelimumab
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab	4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine
Measure Participants	150	151
Median (90% Confidence Interval) [Months]	3.22	7.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Durvalumab and Tremelimumab, Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0035
	Comments	2-sided, adjusted for stratification factors at randomization.
	Method	Log Rank
	Comments	Adjusted for stratification factors at randomization.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate Using RECIST 1.1 and iRECIST
Description	proportion of patients with a documented complete response, partial response (CR + PR) based on iRECIST criteria. The primary estimate of ORR will be based on all patients randomized, and compared using Cochran- Mantel-Haeszel test stratified by stratification factors at randomization between the study new treatment and the standard control arms.
Time Frame	33 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Durvalumab and Tremelimumab	Platinum Based Chemotherapy + Durvalumab + Tremelimumab
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab	4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine
Measure Participants	150	151
Partial Response	44 29.3%	64 42.4%
Stable Disease	47 31.3%	53 35.1%
Progressive Disease	53 35.3%	25 16.6%
Inevaluable	6 4%	9 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Durvalumab and Tremelimumab, Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments	2-sided, adjusted for stratification factors at randomization.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.69
	Confidence Interval	(2-Sided) 95%; 1.04 to 2.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	33 months
Adverse Event Reporting Description	Adverse events graded according to CTCAE Version 4.0.
Arm/Group Title	Durvalumab and Tremelimumab		Platinum Based Chemotherapy + Durvalumab + Tremelimumab
Arm/Group Description	Durvalumab q4 weeks until PD + Tremelimumab q 4 wk x 4 doses Durvalumab: MEDI4736 Tremelimumab: Tremelimumab		4 cycles platinum plus gem or pem + Durva + Treme (q 3 wk x 4 cycles) Followed by: Squamous Cell: Maintenance Durva q 4 wk until PD Non-Squamous Cell: Pemetrexed + Durva q 4 wk until PD Durvalumab: MEDI4736 Tremelimumab: Tremelimumab Platinum-Based Drug: Pemetrexed, cisplatin, carboplatin or gemcitibine
All Cause Mortality
	Durvalumab and Tremelimumab		Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/149 (53.7%)		77/148 (52%)
Serious Adverse Events
	Durvalumab and Tremelimumab		Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/149 (56.4%)		102/148 (68.9%)
Blood and lymphatic system disorders
Anemia	1/149 (0.7%)	1	12/148 (8.1%)	12
Febrile neutropenia	0/149 (0%)	0	7/148 (4.7%)	7
Thrombotic thrombocytopenic purpura	0/149 (0%)	0	1/148 (0.7%)	1
Cardiac disorders
Acute coronary syndrome	0/149 (0%)	0	1/148 (0.7%)	1
Asystole	0/149 (0%)	0	1/148 (0.7%)	1
Atrial fibrillation	0/149 (0%)	0	4/148 (2.7%)	4
Atrial flutter	2/149 (1.3%)	2	1/148 (0.7%)	1
Cardiac arrest	1/149 (0.7%)	1	1/148 (0.7%)	1
Chest pain - cardiac	0/149 (0%)	0	1/148 (0.7%)	1
Myocardial infarction	0/149 (0%)	0	1/148 (0.7%)	1
Pericardial effusion	3/149 (2%)	3	2/148 (1.4%)	2
Pericardial tamponade	2/149 (1.3%)	2	0/148 (0%)	0
Pericarditis	0/149 (0%)	0	1/148 (0.7%)	1
Sinus tachycardia	0/149 (0%)	0	2/148 (1.4%)	2
Ear and labyrinth disorders
Vertigo	0/149 (0%)	0	1/148 (0.7%)	1
Endocrine disorders
Adrenal insufficiency	3/149 (2%)	3	3/148 (2%)	3
Hyperthyroidism	0/149 (0%)	0	1/148 (0.7%)	1
Hypothyroidism	0/149 (0%)	0	2/148 (1.4%)	2
Eye disorders
Scleral disorder	0/149 (0%)	0	1/148 (0.7%)	1
Gastrointestinal disorders
Abdominal pain	1/149 (0.7%)	1	2/148 (1.4%)	2
Ascites	0/149 (0%)	0	1/148 (0.7%)	1
Colitis	14/149 (9.4%)	14	11/148 (7.4%)	11
Constipation	2/149 (1.3%)	2	3/148 (2%)	3
Diarrhea	16/149 (10.7%)	16	10/148 (6.8%)	10
Duodenal obstruction	0/149 (0%)	0	1/148 (0.7%)	1
Dyspepsia	1/149 (0.7%)	1	0/148 (0%)	0
Dysphagia	0/149 (0%)	0	1/148 (0.7%)	1
Enterocolitis	4/149 (2.7%)	4	2/148 (1.4%)	2
Gastric hemorrhage	1/149 (0.7%)	1	0/148 (0%)	0
Gastric perforation	0/149 (0%)	0	1/148 (0.7%)	1
Gastric ulcer	0/149 (0%)	0	1/148 (0.7%)	1
Gastrointestinal pain	1/149 (0.7%)	1	0/148 (0%)	0
Ileus	0/149 (0%)	0	1/148 (0.7%)	1
Lower gastrointestinal hemorrhage	2/149 (1.3%)	2	1/148 (0.7%)	1
Nausea	4/149 (2.7%)	4	5/148 (3.4%)	5
Oral hemorrhage	0/149 (0%)	0	1/148 (0.7%)	1
Other gastrointestinal disorders	0/149 (0%)	0	1/148 (0.7%)	1
Pancreatitis	2/149 (1.3%)	2	2/148 (1.4%)	2
Vomiting	4/149 (2.7%)	4	4/148 (2.7%)	4
General disorders
Death NOS	0/149 (0%)	0	2/148 (1.4%)	2
Fatigue	1/149 (0.7%)	1	2/148 (1.4%)	2
Fever	5/149 (3.4%)	5	11/148 (7.4%)	11
Flu like symptoms	1/149 (0.7%)	1	2/148 (1.4%)	2
Infusion related reaction	0/149 (0%)	0	1/148 (0.7%)	1
Non-cardiac chest pain	0/149 (0%)	0	1/148 (0.7%)	1
Other general disorders, administration site conditions	1/149 (0.7%)	1	1/148 (0.7%)	1
Pain	1/149 (0.7%)	1	1/148 (0.7%)	1
Sudden death NOS	1/149 (0.7%)	1	0/148 (0%)	0
Immune system disorders
Allergic reaction	0/149 (0%)	0	2/148 (1.4%)	2
Autoimmune disorder	0/149 (0%)	0	1/148 (0.7%)	1
Cytokine release syndrome	0/149 (0%)	0	1/148 (0.7%)	1
Other immune system disorders	2/149 (1.3%)	2	6/148 (4.1%)	6
Infections and infestations
Appendicitis	0/149 (0%)	0	1/148 (0.7%)	1
Gallbladder infection	0/149 (0%)	0	1/148 (0.7%)	1
Joint infection	0/149 (0%)	0	1/148 (0.7%)	1
Lung infection	11/149 (7.4%)	11	12/148 (8.1%)	12
Other infections and infestations	0/149 (0%)	0	6/148 (4.1%)	6
Sepsis	2/149 (1.3%)	2	2/148 (1.4%)	2
Sinusitis	0/149 (0%)	0	1/148 (0.7%)	1
Skin infection	0/149 (0%)	0	3/148 (2%)	3
Upper respiratory infection	3/149 (2%)	3	1/148 (0.7%)	1
Urinary tract infection	0/149 (0%)	0	2/148 (1.4%)	2
Injury, poisoning and procedural complications
Fall	0/149 (0%)	0	1/148 (0.7%)	1
Fracture	1/149 (0.7%)	1	0/148 (0%)	0
Spinal fracture	2/149 (1.3%)	2	1/148 (0.7%)	1
Investigations
Alanine aminotransferase increased	4/149 (2.7%)	4	4/148 (2.7%)	4
Alkaline phosphatase increased	3/149 (2%)	3	0/148 (0%)	0
Aspartate aminotransferase increased	4/149 (2.7%)	4	6/148 (4.1%)	6
Blood bilirubin increased	0/149 (0%)	0	1/148 (0.7%)	1
Creatinine increased	1/149 (0.7%)	1	4/148 (2.7%)	4
GGT increased	3/149 (2%)	3	1/148 (0.7%)	1
Lipase increased	4/149 (2.7%)	4	4/148 (2.7%)	4
Neutrophil count decreased	0/149 (0%)	0	4/148 (2.7%)	4
Platelet count decreased	0/149 (0%)	0	10/148 (6.8%)	10
Serum amylase increased	2/149 (1.3%)	2	2/148 (1.4%)	2
Weight loss	0/149 (0%)	0	1/148 (0.7%)	1
White blood cell decreased	0/149 (0%)	0	2/148 (1.4%)	2
Metabolism and nutrition disorders
Acidosis	0/149 (0%)	0	1/148 (0.7%)	1
Anorexia	2/149 (1.3%)	2	1/148 (0.7%)	1
Dehydration	1/149 (0.7%)	1	4/148 (2.7%)	4
Hypercalcemia	1/149 (0.7%)	1	1/148 (0.7%)	1
Hypocalcemia	0/149 (0%)	0	1/148 (0.7%)	1
Hypokalemia	0/149 (0%)	0	3/148 (2%)	3
Hyponatremia	1/149 (0.7%)	1	2/148 (1.4%)	2
Hypophosphatemia	0/149 (0%)	0	1/148 (0.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/149 (0%)	0	2/148 (1.4%)	2
Arthritis	0/149 (0%)	0	1/148 (0.7%)	1
Back pain	2/149 (1.3%)	2	1/148 (0.7%)	1
Bone pain	2/149 (1.3%)	2	0/148 (0%)	0
Generalized muscle weakness	0/149 (0%)	0	1/148 (0.7%)	1
Muscle weakness left-sided	1/149 (0.7%)	1	0/148 (0%)	0
Muscle weakness lower limb	1/149 (0.7%)	1	1/148 (0.7%)	1
Myositis	1/149 (0.7%)	1	0/148 (0%)	0
Neck pain	0/149 (0%)	0	1/148 (0.7%)	1
Pain in extremity	0/149 (0%)	0	1/148 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other neoplasms benign, malignant and unspecified	13/149 (8.7%)	13	18/148 (12.2%)	18
Tumor pain	2/149 (1.3%)	2	0/148 (0%)	0
Nervous system disorders
Depressed level of consciousness	0/149 (0%)	0	1/148 (0.7%)	1
Dizziness	1/149 (0.7%)	1	0/148 (0%)	0
Dysesthesia	1/149 (0.7%)	1	0/148 (0%)	0
Edema cerebral	1/149 (0.7%)	1	1/148 (0.7%)	1
Encephalopathy	0/149 (0%)	0	1/148 (0.7%)	1
Facial nerve disorder	1/149 (0.7%)	1	1/148 (0.7%)	1
Headache	1/149 (0.7%)	1	1/148 (0.7%)	1
Intracranial hemorrhage	1/149 (0.7%)	1	0/148 (0%)	0
Lethargy	1/149 (0.7%)	1	0/148 (0%)	0
Other nervous system disorders	0/149 (0%)	0	1/148 (0.7%)	1
Peripheral sensory neuropathy	1/149 (0.7%)	1	0/148 (0%)	0
Radiculitis	1/149 (0.7%)	1	0/148 (0%)	0
Seizure	3/149 (2%)	3	1/148 (0.7%)	1
Stroke	4/149 (2.7%)	4	1/148 (0.7%)	1
Transient ischemic attacks	1/149 (0.7%)	1	0/148 (0%)	0
Psychiatric disorders
Anxiety	0/149 (0%)	0	1/148 (0.7%)	1
Confusion	2/149 (1.3%)	2	0/148 (0%)	0
Delirium	2/149 (1.3%)	2	2/148 (1.4%)	2
Renal and urinary disorders
Acute kidney injury	2/149 (1.3%)	2	3/148 (2%)	3
Other renal and urinary disorders	0/149 (0%)	0	1/148 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/149 (0.7%)	1	1/148 (0.7%)	1
Chylothorax	1/149 (0.7%)	1	0/148 (0%)	0
Cough	1/149 (0.7%)	1	0/148 (0%)	0
Dyspnea	4/149 (2.7%)	4	4/148 (2.7%)	4
Hypoxia	0/149 (0%)	0	1/148 (0.7%)	1
Other respiratory, thoracic and mediastinal disorders	3/149 (2%)	3	1/148 (0.7%)	1
Pleural effusion	6/149 (4%)	6	2/148 (1.4%)	2
Pneumonitis	7/149 (4.7%)	7	7/148 (4.7%)	7
Pneumothorax	0/149 (0%)	0	3/148 (2%)	3
Pulmonary edema	0/149 (0%)	0	1/148 (0.7%)	1
Respiratory failure	0/149 (0%)	0	1/148 (0.7%)	1
Skin and subcutaneous tissue disorders
Other skin and subcutaneous tissue disorders	0/149 (0%)	0	1/148 (0.7%)	1
Pruritus	2/149 (1.3%)	2	0/148 (0%)	0
Rash acneiform	0/149 (0%)	0	1/148 (0.7%)	1
Rash maculo-papular	5/149 (3.4%)	5	7/148 (4.7%)	7
Stevens-Johnson syndrome	1/149 (0.7%)	1	0/148 (0%)	0
Vascular disorders
Hypotension	1/149 (0.7%)	1	2/148 (1.4%)	2
Other vascular disorders	0/149 (0%)	0	1/148 (0.7%)	1
Superficial thrombophlebitis	0/149 (0%)	0	1/148 (0.7%)	1
Superior vena cava syndrome	0/149 (0%)	0	1/148 (0.7%)	1
Thromboembolic event	7/149 (4.7%)	7	9/148 (6.1%)	9
Other (Not Including Serious) Adverse Events
	Durvalumab and Tremelimumab		Platinum Based Chemotherapy + Durvalumab + Tremelimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	149/149 (100%)		148/148 (100%)
Cardiac disorders
Sinus tachycardia	2/149 (1.3%)	2	8/148 (5.4%)	8
Ear and labyrinth disorders
Ear pain	1/149 (0.7%)	1	8/148 (5.4%)	8
Tinnitus	6/149 (4%)	6	17/148 (11.5%)	17
Endocrine disorders
Hypothyroidism	19/149 (12.8%)	19	18/148 (12.2%)	18
Eye disorders
Blurred vision	10/149 (6.7%)	10	10/148 (6.8%)	10
Other eye disorders	5/149 (3.4%)	5	15/148 (10.1%)	15
Watering eyes	1/149 (0.7%)	1	20/148 (13.5%)	20
Gastrointestinal disorders
Abdominal pain	26/149 (17.4%)	26	29/148 (19.6%)	29
Bloating	4/149 (2.7%)	4	11/148 (7.4%)	11
Colitis	11/149 (7.4%)	11	8/148 (5.4%)	8
Constipation	60/149 (40.3%)	60	84/148 (56.8%)	84
Diarrhea	50/149 (33.6%)	50	72/148 (48.6%)	72
Dry mouth	15/149 (10.1%)	15	19/148 (12.8%)	19
Dyspepsia	8/149 (5.4%)	8	18/148 (12.2%)	18
Dysphagia	4/149 (2.7%)	4	9/148 (6.1%)	9
Gastroesophageal reflux disease	13/149 (8.7%)	13	14/148 (9.5%)	14
Mucositis oral	12/149 (8.1%)	12	22/148 (14.9%)	22
Nausea	60/149 (40.3%)	60	101/148 (68.2%)	101
Vomiting	36/149 (24.2%)	36	54/148 (36.5%)	54
General disorders
Chills	8/149 (5.4%)	8	11/148 (7.4%)	11
Edema limbs	21/149 (14.1%)	21	42/148 (28.4%)	42
Fatigue	105/149 (70.5%)	105	125/148 (84.5%)	125
Fever	22/149 (14.8%)	22	28/148 (18.9%)	28
Flu like symptoms	11/149 (7.4%)	11	17/148 (11.5%)	17
Non-cardiac chest pain	31/149 (20.8%)	31	24/148 (16.2%)	24
Pain	24/149 (16.1%)	24	30/148 (20.3%)	30
Immune system disorders
Other immune system disorders	5/149 (3.4%)	5	11/148 (7.4%)	11
Infections and infestations
Lung infection	12/149 (8.1%)	12	15/148 (10.1%)	15
Other infections and infestations	12/149 (8.1%)	12	7/148 (4.7%)	7
Skin infection	2/149 (1.3%)	2	8/148 (5.4%)	8
Upper respiratory infection	27/149 (18.1%)	27	18/148 (12.2%)	18
Urinary tract infection	6/149 (4%)	6	16/148 (10.8%)	16
Injury, poisoning and procedural complications
Bruising	2/149 (1.3%)	2	10/148 (6.8%)	10
Investigations
Creatinine increased	1/149 (0.7%)	1	8/148 (5.4%)	8
Weight gain	3/149 (2%)	3	12/148 (8.1%)	12
Weight loss	41/149 (27.5%)	41	37/148 (25%)	37
Metabolism and nutrition disorders
Anorexia	68/149 (45.6%)	68	78/148 (52.7%)	78
Dehydration	4/149 (2.7%)	4	12/148 (8.1%)	12
Hypokalemia	15/149 (10.1%)	15	17/148 (11.5%)	17
Hypomagnesemia	5/149 (3.4%)	5	17/148 (11.5%)	17
Hyponatremia	9/149 (6%)	9	6/148 (4.1%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	25/149 (16.8%)	25	22/148 (14.9%)	22
Back pain	57/149 (38.3%)	57	55/148 (37.2%)	55
Bone pain	18/149 (12.1%)	18	17/148 (11.5%)	17
Chest wall pain	16/149 (10.7%)	16	16/148 (10.8%)	16
Flank pain	6/149 (4%)	6	9/148 (6.1%)	9
Generalized muscle weakness	9/149 (6%)	9	17/148 (11.5%)	17
Myalgia	9/149 (6%)	9	10/148 (6.8%)	10
Neck pain	12/149 (8.1%)	12	12/148 (8.1%)	12
Other musculoskeletal and connective tissue disorder	8/149 (5.4%)	8	8/148 (5.4%)	8
Pain in extremity	33/149 (22.1%)	33	41/148 (27.7%)	41
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	11/149 (7.4%)	11	7/148 (4.7%)	7
Nervous system disorders
Dizziness	16/149 (10.7%)	16	32/148 (21.6%)	32
Dysgeusia	13/149 (8.7%)	13	23/148 (15.5%)	23
Headache	29/149 (19.5%)	29	41/148 (27.7%)	41
Paresthesia	9/149 (6%)	9	8/148 (5.4%)	8
Peripheral sensory neuropathy	13/149 (8.7%)	13	30/148 (20.3%)	30
Psychiatric disorders
Anxiety	26/149 (17.4%)	26	24/148 (16.2%)	24
Confusion	4/149 (2.7%)	4	9/148 (6.1%)	9
Depression	16/149 (10.7%)	16	15/148 (10.1%)	15
Insomnia	46/149 (30.9%)	46	56/148 (37.8%)	56
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/149 (1.3%)	2	15/148 (10.1%)	15
Cough	65/149 (43.6%)	65	79/148 (53.4%)	79
Dyspnea	93/149 (62.4%)	93	95/148 (64.2%)	95
Epistaxis	1/149 (0.7%)	1	11/148 (7.4%)	11
Hoarseness	6/149 (4%)	6	8/148 (5.4%)	8
Nasal congestion	6/149 (4%)	6	9/148 (6.1%)	9
Other respiratory, thoracic and mediastinal disorders	11/149 (7.4%)	11	12/148 (8.1%)	12
Productive cough	19/149 (12.8%)	19	24/148 (16.2%)	24
Sore throat	1/149 (0.7%)	1	8/148 (5.4%)	8
Skin and subcutaneous tissue disorders
Alopecia	8/149 (5.4%)	8	23/148 (15.5%)	23
Dry skin	10/149 (6.7%)	10	15/148 (10.1%)	15
Other skin and subcutaneous tissue disorders	10/149 (6.7%)	10	20/148 (13.5%)	20
Pruritus	39/149 (26.2%)	39	44/148 (29.7%)	44
Rash acneiform	8/149 (5.4%)	8	15/148 (10.1%)	15
Rash maculo-papular	42/149 (28.2%)	42	45/148 (30.4%)	45
Vascular disorders
Hypertension	9/149 (6%)	9	15/148 (10.1%)	15
Hypotension	7/149 (4.7%)	7	13/148 (8.8%)	13
Thromboembolic event	12/149 (8.1%)	12	14/148 (9.5%)	14

Limitations/Caveats

The small sample size may prevent the study to find identify the biomarker defined subgroup that may be benefit from the study treatment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.