A Global Study to Assess the Effects of MEDI4736 (Durvalumab), Given as Monotherapy or in Combination With Tremelimumab Determined by PD-L1 Expression Versus Standard of Care in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer
- Conditions
- Non - Small Cell Lung Cancer NSCLC
- Interventions
- Drug: MEDI4736 (durvalumab)Drug: MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4)
- Registration Number
- NCT02352948
- Lead Sponsor
- AstraZeneca
- Brief Summary
This study is a Phase III, randomised, open label, multi-centre study assessing the efficacy and safety of MEDI4736 (durvalumab) versus Standard of Care in NSCLC patients with PD-L1 positive tumours and the combination of MEDI4736 (durvalumab) plus tremelimumab (MEDI4736+treme) versus Standard of Care in NSCLC patients with PD-L1-negative tumours in the treatment of male and female patients with locally advanced or metastatic NSCLC (Stage IIIB-IV), who have received at least 2 prior systemic treatment regimens including 1 platinum-based chemotherapy regimen for NSCLC. Patients with known EGFR (Epidermal growth factor receptor) tyrosine kinase (TK) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements are not eligible for the study (prospective testing is not planned within this study). The Standard of Care options are: an EGFR tyrosine kinase inhibitor (erlotinib \[TARCEVA®\]), gemcitabine or vinorelbine (NAVELBINE®)
- Detailed Description
The study has an umbrella design with 2 sub-studies: sub-study A (randomizing patients with PD-L1 positive tumours 1:1 into MEDI4736 (durvalumab) vs. Standard of Care) and sub-study B (randomizing patients with PD-L1 negative tumours 2:3:1:2 into MEDI4736 (durvalumab) vs. MEDI4736 (durvalumab) plus tremelimumab vs. tremelimumab vs. Standard of Care. The two substudies may have different durations of recruitment periods due to differences in patient population (PD-L1 expression). They may not run concurrently with start and completion of recruitment potentially occurring at different time points.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 597
- Aged at least 18 years
- Documented evidence of NSCLC (Stage IIIB/ IV disease)
- Disease progression or recurrence after both a platinum-based chemotherapy regimen and at least 1 additional regimen for treatment of NSCLC
- World Health Organization (WHO) Performance Status of 0 or 1
- Estimated life expectancy more than 12 weeks
- Prior exposure to any anti-PD-1 or anti-PD-L1 antibody or anti-CTLA4
- Brain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids)
- Active or prior documented autoimmune disease within the past 2 years
- Evidence of severe or uncontrolled systemic disease, including active bleeding diatheses or active infections including hepatitis B, C and HIV
- Any unresolved toxicity CTCAE (Common Terminology Criteria of Adverse Events) >Grade 2 from previous anti-cancer therapy
- Known EGFR TK activating mutations or ALK rearrangements
- Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
- Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MEDI4736 (durvalumab) monotherapy in Sub-study A MEDI4736 (durvalumab) MEDI4736 (durvalumab) by intravenous infusion. Sub-study A for patients with PD-L1 positive tumors. Standard of Care in Sub-study A Vinorelbine Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors. MEDI4736 (durvalumab) + tremelimumab in Sub-study B MEDI4736 (durvalumab) in combination with tremelimumab (anti-CTLA4) MEDI4736 (durvalumab) by intravenous infusion and tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. Standard of Care in Sub-study B Erlotinib Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors. MEDI4736 (durvalumab) monotherapy in Sub-study B MEDI4736 (durvalumab) MEDI4736 (durvalumab) by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. tremelimumab in Sub-study B tremelimumab (anti-CTLA4) tremelimumab by intravenous infusion. Sub-study B for patients with PD-L1 negative tumors. Standard of Care in Sub-study A Erlotinib Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors. Standard of Care in Sub-study A Gemcitabine Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study A for patients with PD-L1 positive tumors. Standard of Care in Sub-study B Vinorelbine Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors. Standard of Care in Sub-study B Gemcitabine Investigator choice from Vinorelbine, Gemcitabine and Erlotinib. Sub-study B for patients with PD-L1 negative tumors.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From randomization (Day 1) until death due to any cause, approximately 36 months The OS was defined as the time from the date of randomization until death due to any cause.
Progression-Free Survival (PFS) Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to response evaluation criteria in solid tumours (RECIST) version 1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
- Secondary Outcome Measures
Name Time Method Percentage of Participants Alive and Progression Free at 12 Months (APF12) Tumour scans performed at baseline then every ~8 weeks up to 12 months. The APF12 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 12 months after randomization per Kaplan-Meier estimate of PFS at 12 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
OS, Contribution of the Components Analysis of Sub-study B From randomization (Day 1) until death due to any cause, approximately 36 months The OS was defined as the time from the date of randomization until death due to any cause.
Percentage of Participants Alive at 12 Months (OS12) From randomization (Day 1) up to 12 months The OS12 was defined as the percentage of participants who were alive at 12 months after randomisation per Kaplan-Meier estimate of OS at 12 months.
PFS, Contribution of the Components Analysis of Sub-study B Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. The PFS was defined as the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression. The PFS was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Objective Response Rate (ORR) Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. The ORR was defined as the percentage of participants with at least 1 visit response of complete response (CR) or partial response (PR) among ITT participants who had measurable disease at baseline. CR was defined as disappearance of all target lesions (any pathological lymph nodes selected as target lesions must have a reduction in short axis to \<10 mm) and PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum of diameters as long as criteria for PD are not met). The ORR was measured using Investigator assessments according to RECIST v1.1.
Duration of Response (DoR) Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until confirmed disease progression. Assessed up to a maximum of approximately 3 years. The DoR was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. The DoR was determined by Investigator assessments according to RECIST v1.1. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Percentage of Participants Alive and Progression Free at 6 Months (APF6) Tumour scans performed at baseline then every ~8 weeks up to 6 months The APF6 was defined as the percentage of participants who were alive and progression free per RECIST v1.1 at 6 months after randomization per Kaplan-Meier estimate of PFS at 6 months. PD was defined as at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions or the appearance of a new lesion
Time From Randomisation to Second Progression (PFS2) of Sub-study B Tumour scans performed at baseline then every ~8 weeks up to 48 weeks, then every ~12 weeks thereafter until first progression. Disease then assessed per local practice until 2nd progression. Assessed up to a maximum of approximately 3 years. The PFS2 was defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the PFS endpoint or death and determined by local standard clinical practice and have included any of the following: objective radiological, symptomatic progression, or death. PFS2 was reported for sub-study B only.
Trial Locations
- Locations (1)
Research Site
🇬🇧Wolverhampton, United Kingdom