First-Line Durvalumab With or Without Tremelimumab vs Chemotherapy for Metastatic NSCLC: MYSTIC Study

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As reported in JAMA Oncology by Naiyer A. Rizvi, MD, and colleagues, the phase III MYSTIC trial showed no overall survival benefit with durvalumab vs chemotherapy, or overall or progression-free survival benefit with durvalumab/tremelimumab vs chemotherapy, as first-line treatment in patients with non–small cell lung cancer (NSCLC) with PD-L1 tumor expression ≥ 25%.

Naiyer A. Rizvi, MD

Naiyer A. Rizvi, MD

Study Details

In the open-label trial, 1,118 patients from sites in 17 countries with no sensitizing EGFR or ALK genetic alterations were randomly assigned 1:1:1 between July 2015 and June 2016 to receive the anti­–programmed cell death ligand 1 agent durvalumab at 20 mg/kg every 4 weeks, durvalumab plus the anti–cytotoxic T-lymphocyte–associated protein 4 agent tremelimumab at 1 mg/kg every 4 weeks (up to four doses), or four to six cycles of investigator’s choice platinum-based doublet chemotherapy.

The primary endpoints were overall survival for durvalumab vs chemotherapy and overall and progression-free survival for durvalumab/tremelimumab vs chemotherapy among patients with PD-L1 expression ≥ 25%.

Primary Analysis Outcomes

The primary analysis population consisted of 163 patients in the durvalumab group, 163 in the durvalumab/tremelimumab group, and 162 in the chemotherapy group. Median follow-up for overall survival was 30.2 months.

In the primary analyses, median overall survival was 16.3 months in the durvalumab group vs 12.9 months in the chemotherapy group (hazard ratio [HR] = 0.76, 97.54% confidence interval [CI] = 0.56–1.02; P = .04 [nonsignificant]), with 24-month rates of 38.3% vs 22.7%. Median overall survival was 11.9 months in the durvalumab/tremelimumab group (HR vs chemotherapy = 0.85, 98.77% CI = 0.61–1.17; P = .20), with a 24-month rate of 35.4% in the durvalumab/tremelimumab group. Median progression-free survival was 3.9 months with durvalumab/tremelimumab vs 5.4 months with chemotherapy (HR = 1.05, 99.5% CI =0.72–1.53; P = .71).

Objective response rates were 35.6%, 34.4%, and 37.7% for patients treated with durvalumab, durvalumab/tremelimumab, and chemotherapy, respectively. Median response duration was not reached in either immunotherapy group and was 4.4 months in the chemotherapy group.

Tumor Mutational Burden Analysis

An exploratory analysis of outcomes according to blood tumor mutational burden (TMB), which was not found to be correlated with PD-L1 expression, was performed in a total of 809 patients in the trial with available data.

Among patients with TMB ≥ 20 mut/Mb, median overall survival was 21.9 months among patients receiving durvalumab/tremelimumab vs 10.0 months in those receiving chemotherapy (unadjusted HR = 0.49, 95% CI = 0.32–0.74), with 24-month rates of 48.1% vs 19.4%. Median overall survival among patients receiving durvalumab alone was 12.6 months (unadjusted HR vs chemotherapy = 0.72, 95% CI = 0.50–1.05). The unadjusted hazard ratio for durvalumab/tremelimumab vs durvalumab alone was 0.74 (95% CI = 0.48–1.11).

Adverse Events

Among all patients, treatment-related grade ≥ 3 adverse events occurred in 14.9% of the durvalumab group, 22.9% of the durvalumab/tremelimumab group, and 33.8% of the chemotherapy group. Death related to treatment occurred in two (0.5%), six (1.6%), and three (0.9%) patients, respectively.

The investigators concluded: “The phase III MYSTIC study did not meet its primary endpoints of improved overall survival with durvalumab vs chemotherapy or improved overall survival or progression-free survival with durvalumab plus tremelimumab vs chemotherapy in patients with ≥ 25% of tumor cells expressing PD-L1. Exploratory analyses identified a TMB threshold of ≥ 20 mut/Mb for optimal overall survival benefit with durvalumab plus tremelimumab.”

Dr. Rizvi, of the Division of Hematology/Oncology, Columbia University Medical Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by AstraZeneca. For full disclosures of the study authors, visit

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