Durvalumab Reduces Mortality Risk vs Chemo in NSCLC With PD-L1 Expression
A phase 3 clinical trial examining durvalumab therapy for non–small-cell lung cancer (NSCLC) did not meet its primary end points, but did show a numerically reduced risk for death with durvalumab versus chemotherapy in patients with PD-L1 expression on ≥25% of tumor cells (JAMA Oncol. 2020 Apr 9. Epub ahead of print).
“Checkpoint inhibitors targeting [PD-L1] as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic [NSCLC],” said Naiyer A. Rizvi, MD, Division of Hematology/Oncology, Columbia University Medical Center, New York, and colleagues.
Between July 2015 and June 2016, Dr Rizvi et al compared the use of durvalumab with or without tremelimumab with chemotherapy as a first-line therapy in 1118 patients with metastatic NSCLC in the open-label MYSTIC study.
MYSTIC was conducted at 203 cancer treatment centers across 17 countries and included treatment-naïve patients who had no sensitizing EGFR or ALK genetic alterations. All patients were randomized in a 1:1:1 ratio to receive durvalumab 20 mg/kg every 4 weeks, durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg every 4 weeks (for up to 4 doses), or platinum-based doublet chemotherapy.
The primary end points of the MYSTIC trial were overall survival (OS) with durvalumab versus chemotherapy, and OS and progression-free survival (PFS) with durvalumab plus tremelimumab versus chemotherapy, assessed in patients with ≥25% of tumor cells expressing PD-L1.
Blood tumor mutational burden (bTMB) analysis was exploratory, and data collection took place between July 21, 2015, and October 30, 2018.
In patients with ≥25% of tumor cells expressing PD-L1 (n = 488), the median OS rates were 16.3 months (95% CI, 12.2-20.8) with durvalumab versus 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), and 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).
Furthermore, the median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab versus 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71).
In patients with evaluable bTMB (n = 809), those with a bTMB ≥20 mutations per megabase had improvements in OS with durvalumab plus tremelimumab versus 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, respectively).
Among the 369 patients given durvalumab, 55 (14.9%) had treatment-related adverse events of grade ≥3. The same was observed in 85 (22.9%) of 371 patients given durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received chemotherapy. Overall, 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients died from adverse events, respectively.
“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,” Dr Rizvi and colleagues concluded.
“Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab,” they added.—Hina Porcelli