Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial

Abstract

Importance: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.

Objective: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.

Design, setting, and participants: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.

Interventions: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.

Main outcomes and measures: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

Results: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.

Conclusions and relevance: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.

Trial registration: ClinicalT rials.gov Identifier: NCT02453282.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Rizvi reports personal fees from AstraZeneca, AbbVie, Bellicum, Bristol-Myers Squibb, Boehringer Ingelheim, Brooklyn Immunotherapeutics, Calithera, Dracen, Eli Lilly and Company, EMD Serono, G1 Therapeutics, Genentech, Gilead, GlaxoSmithKline, Illumina, Janssen, Merck, Neogenomics, Novartis, Pfizer, Regeneron, Takeda, and Gritstone; grants from Bristol-Myers Squibb; equity in Bellicum, Brooklyn Immunotherapeutics, and Gritstone; and has a patent pending for PCT/US2015/062208 with royalties paid. Dr Cho reports research funding from Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and Merck Sharp & Dohme; serving as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly and Company, Janssen, Takeda, and Merck Sharp & Dohme; stock ownership in TheraCanVac Inc, Gencurix Inc, and Bridgebio Therapeutics; and royalties from Champions Oncology. Dr Reinmuth reports personal fees and nonfinancial support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Takeda, and Pfizer. Dr Lee reports grants from AstraZeneca and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, and AstraZeneca. Dr Ahn reports personal fees from Merck Sharp & Dohme, Eli Lilly and Company, Takeda, AstraZeneca, Novartis, Alpha Pharmaceutical, Yuhan, Ono Pharmaceutical, Merck, and Bristol-Myers Squibb. Dr Vicente reports grants from AstraZeneca and personal fees from AstraZeneca, Roche, Bristol-Myers Squibb, and Pfizer. Dr Smolin reports grants from AstraZeneca, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, and Biocad; nonfinancial support from Roche; and advisory board participation for Boehringer Ingelheim. Dr Antonia reports personal fees from AstraZeneca, Bristol-Myers Squibb, Achilles Therapeutics, Celsius, Cellular Biomedicine Group, Samyang Biopharma, GlaxoSmithKline, Rapt Therapeutics, Memgen, Venn Therapeutics, Amgen, and Merck. Dr Robinet reports grants and personal fees from AstraZeneca, Roche, Merck Sharp & Dohme, and Bristol-Myers Squibb, and personal fees from Bayer. Dr Natale reports that his spouse is an employee of AstraZeneca. Dr Schneider reports stock ownership in Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Pfizer. Dr Shepherd reports personal fees from and stock ownership in AstraZeneca. Dr Geater reports grants from AstraZeneca, Boehringer Ingelheim, Roche, and Novartis. Dr Garon reports grants from AstraZeneca, Bristol-Myers Squibb, Dracen, EMD Serono, Genentech, Eli Lilly and Company, Novartis, Merck, Neon, Mirati, Dynavax, and Iovance, and personal fees from Dracen, EMD Serono, and Novartis. Dr Goldberg reports grants from AstraZeneca and Boehringer Ingelheim and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Spectrum, Bristol-Myers Squibb, Amgen, and Genentech. Dr Nakagawa reports grants and personal fees from Merck Sharp & Dohme KK, Eli Lilly Japan KK, Bristol-Myers Squibb, Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical Co, AstraZeneca KK, Astellas Pharma, Novartis Pharma KK, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda, SymBio Pharmaceuticals, and Daiichi-Sankyo; grants from Merck Serono, Icon Japan KK, Parexel International, IQVIA Services Japan KK, A2 Healthcare Corp, AbbVie, EP-CRSU Co, Linical Co, Otsuka Pharmaceutical Co, EPS International Holdings Co, Quintiles, CMIC Shift Zero KK, Eisai Co, Kissei Pharmaceutical Co, Kyowa Hakko Kirin Co, EPS Corp, Bayer Yakuhin, inVentiv Health Japan, Gritstone Oncology, GlaxoSmithKline KK, Yakult Honsha Co, and Covance; and personal fees from Kyorin Pharmaceutical Co, CareNet, Nichi-Iko Pharmaceutical Co, Hisamitsu Pharmaceutical Co, Yodosha Co, Clinical Trial Co, Medicus Shuppan Publishers Co, Ayumi Pharmaceutical Corp, Nikkei Business Publications, Thermo Fisher Scientific KK, Nanzando Co, Medical Review Co, Yomiuri Telecasting Corp, and Reno Medical KK. Drs Raja and Higgs report a patent pending related to tumor mutational burden, and employment at and stock ownership in AstraZeneca. Drs Boothman, Scheuring, and Stockman report employment at and stock ownership in AstraZeneca. Dr Zhao reports employment at AstraZeneca. Dr Chand reports employment at and stock ownership in AstraZeneca and stock ownership in Bristol-Myers Squibb. Dr Peters reports grants from AstraZeneca and personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi-Sankyo, Debiopharm, Eli Lilly and Company, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Pharmamar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, and Vaccibody, from whom she has received honoraria. No other disclosures were reported.

Figures

Figure 1. CONSORT Diagram

Data cutoff date: October 4, 2018. bTMB indicates blood tumor mutational burden; mut/Mb, mutations per megabase; PD-L1, programmed cell death ligand 1; TC, tumor cell; tTMB, tissue tumor mutational burden. aScreening consent received for PD-L1 status. bOnly applicable for patients completing study treatment before implementation of clinical study protocol amendment, which allowed patients to continue receiving immunotherapy until disease progression, whereas previously a maximum of 12 months was allowed. cReason for discontinuation applies to the latest component discontinued. dIntention-to-treat population includes all randomized patients. eAs-treated population includes all patients who received at least 1 dose of study treatment.

Figure 2.. Overall Survival and Progression-free Survival Among Patients With Programmed Cell Death Ligand 1 TC ≥25%

Primary analysis population. A and B, Data cutoff date: October 4, 2018. C and D, Data cutoff date: June 1, 2017. Progression-free survival was determined by blinded independent central review according to Response Evaluation in Solid Tumors (RECIST) version 1.1. Parts A, B, and D depict primary end points; part C, secondary end point. HR indicates hazard ratio; OS, overall survival; PFS, progression-free survival; TC, tumor cell.

Figure 3.. Exploratory Analysis of Overall Survival and Progression-free Survival According to Blood Tumor Mutational Burden

A and B, Data cutoff date: October 4, 2018. C and D, Data cutoff date: June 17, 2017. Progression-free survival was determined by blinded independent central review according to Response Evaluation in Solid Tumors (RECIST) version 1.1. bTMB indicates blood tumor mutational burden; HR, hazard ratio; mut/Mb, mutations per megabase; NR, not reached; OS, overall survival; PFS, progression-free survival.