A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination With Tremelimumab Therapy or MEDI4736 Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in First Line Treatment of Patients With Advanced or Metastatic Non Small-Cell Lung Cancer (NSCLC)(MYSTIC).
Overview
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 1,118
- Locations
- 1
- Primary Endpoint
- Overall Survival (OS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs SoC Chemotherapy
Overview
Brief Summary
This is a randomized, open-label, multi-center, global, Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination therapy and MEDI4736 monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of patients with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type locally advanced or metastatic NSCLC
Detailed Description
Patients will be randomized in a 1:1:1 ratio to receive treatment with MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or Standard of Care (SoC) therapy.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 130 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •For inclusion in the study, patients should fulfill the following criteria:
- •Aged at least 18 years
- •Documented evidence of Stage IV NSCLC
- •No sensitizing EGFR mutation or ALK rearrangement
- •No prior chemotherapy or any other systemic therapy for recurrent/metastatic NSCLC
- •World Health Organization (WHO) Performance Status of 0 or 1
Exclusion Criteria
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled:
- •Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant
- •Brain metastases or spinal cord compression unless asymptomatic, treated and stable (not requiring steroids)
- •Prior exposure to Immunomodulatory therapy (IMT), including, but not limited to, other anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), anti-programmed cell death1 (PD-1), anti-programmed cell death ligand 1 (PD-L1), or anti PD-L2 antibodies, excluding therapeutic anticancer vaccines
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\]
Arms & Interventions
Monotherapy
PD-L1 monoclonal Antibody monotherapy.
Intervention: MEDI4736 (Durvalumab) (Biological)
Combination Therapy
PD-L1+Tremelimumab combination therapy
Intervention: MEDI4736 (Durvalumab)+Tremelimumab (Biological)
Combination Therapy
PD-L1+Tremelimumab combination therapy
Intervention: Tremelimumab (Biological)
Standard of Care
Standard of Care chemotherapy treatment
Intervention: Paclitaxel + Carboplatin (Drug)
Standard of Care
Standard of Care chemotherapy treatment
Intervention: Gemcitabine + Cisplatin (Drug)
Standard of Care
Standard of Care chemotherapy treatment
Intervention: Gemcitabine + Carboplatin (Drug)
Standard of Care
Standard of Care chemotherapy treatment
Intervention: Pemetrexed + Cisplatin (Drug)
Standard of Care
Standard of Care chemotherapy treatment
Intervention: Pemetrexed + Carboplatin (Drug)
Outcomes
Primary Outcomes
Overall Survival (OS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs SoC Chemotherapy
Time Frame: From baseline (Day 1, Week 0) until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
Progression-Free Survival (PFS); PD-L1 (TC >=25%) Analysis Set Population, Durvalumab + Tremelimumab Vs SoC Chemotherapy
Time Frame: Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).
The PFS per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) using blinded independent central review (BICR) assessments 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 withdraw from randomized therapy or received another anti-cancer therapy prior to progression (ie, date of PFS event or censoring - date of randomization + 1). Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of at least 5 millimeter (mm), taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters. Median PFS was calculated using the Kaplan-Meier technique.
Secondary Outcomes
- OS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab + Tremelimumab Vs Durvalumab Monotherapy(From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).)
- OS; PD-L1 (TC >=1%) Analysis Set Population(From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).)
- OS; FAS Population(From baseline until death due to any cause, assessed up to the data cut-off date (a maximum of approximately 3 years).)
- PFS; PD-L1 (TC >=25%) Analysis Set Population, Durvalumab Monotherapy Vs SoC Chemotherapy and Durvalumab + Tremelimumab Vs Durvalumab Monotherapy(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- PFS; PD-L1 (TC >=1%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- PFS; FAS Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- Objective Response Rate (ORR); PD-L1 (TC >=25%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- ORR; PD-L1 (TC >=1%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- ORR; FAS Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- Duration of Response (DoR); PD-L1 (TC >=25%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- DoR; PD-L1 (TC >=1%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- DoR; FAS Population(Tumour scans performed at baseline then every 6 weeks up to 48 weeks relative to the date of randomization, then every 8 weeks thereafter until confirmed disease progression. Assessed up to the data cut-off date (a maximum of approximately 3 years).)
- Percentage of Participants Alive and Progression Free at 12 Months (APF12); PD-L1 (TC >=25%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 12 months.)
- Percentage of Participants APF12; PD-L1 (TC >=1%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to 12 months.)
- Percentage of Participants APF12; FAS Population(Tumour scans performed at baseline then every 6 weeks up to 12 months.)
- Time From Randomization to Second Progression (PFS2); PD-L1 (TC >=25%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).)
- PFS2; PD-L1 (TC >=1%) Analysis Set Population(Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).)
- PFS2; FAS Population(Tumour scans performed at baseline then every 6 weeks up to Week 48, then every 8 weeks thereafter until 1st progression. Disease then assessed per local practice until 2nd progression. Assessed up to data cut-off date (maximum of approximately 3 years).)
- Change From Baseline in Disease-Related Symptoms as Assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ) at 12 Months(At baseline then every 4 weeks for the first 8 weeks relative to the date of randomization, then every 8 weeks until second progression/death, whichever comes first. Assessed up to 12 months.)
- Serum Concentrations of Durvalumab(Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, and at follow-up Month 3.)
- Serum Concentrations of Tremelimumab(Pre-dose and within 1 hour after end of infusion at Week 0 and 12, and at follow-up Month 3.)
- Maximum Serum Concentration at Steady State (Cmax_ss) of Durvalumab(Within 1 hour after end of infusion on infusion day at Week 12.)
- Cmax_ss of Tremelimumab(Within 1 hour after end of infusion on infusion day at Week 12.)
- Trough Serum Concentration at Steady State (Ctrough_ss) of Durvalumab(Pre-dose at Week 12.)
- Ctrough_ss of Tremelimumab(Pre-dose at Week 12.)
- Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab(At Weeks 0, 12, and 24; 3 and 6 months after last dose of study treatment.)
- Number of Participants With ADA Response to Tremelimumab(At Weeks 0 and 12; 3 and 6 months after last dose of study treatment.)