Milestone Analyses of Immune Checkpoint Inhibitors, Targeted Therapy, and Conventional Therapy in Metastatic Non-Small Cell Lung Cancer Trials A Meta-analysis

IMPORTANCE Novel intermediate end points may be useful to detect signals of early activity and prioritize new therapies to treat patients with advanced malignant neoplasms, including metastatic non-small cell lung cancer (mNSCLC). OBJECTIVE To explore milestone rate, a proposed intermediate end point for immunotherapy trials. DATA SOURCES Trials submitted to the US Food and Drug Administration with more than 150 patients and in which the intention-to-treat population was assessed were identified. STUDY SELECTION An initial meta-analysis identified 14 randomized clinical trials for treatment of mNSCLC with active controls submitted to the US Food and Drug Administration from January 1, 2003, through December 31, 2013. An additional 11 randomized clinical trials submitted from January 1, 2014, through December 31, 2016 were included. DATA EXTRACTION AND SYNTHESIS Two investigators abstracted data and pooled data to compare trial-level milestone ratios with conventional end points. MAIN OUTCOMES AND MEASURES Trial-level milestone ratios for milestone rates were calculated for overall response rate (ORR) within 6 months, 9-month progression-free survival (PFS), 9-month overall survival (OS), and 12-month OS. A weighted linear regression model evaluated associations between milestone ratios and hazard ratios (HRs). Experimental and control arms of trials testing immunotherapy, targeted therapy, and other trials were pooled to compare Kaplan-Meier survival estimates in the 3 therapeutic classes. RESULTS A total of 20 013 unique patients (65.4% male and 34.6% female; mean age, 60 [ range, 18-92] years) with advanced lung cancer were identified in 25 unique trials. A moderate association was observed between 12-month OS milestone ratio and OS HR (R-2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio and OS HR (R-2 = 0.67; 95% CI, 0.49-0.82). No associations were observed between 9-month PFS milestone ratio and OS HR (R-2 = 0.19; 95% CI, 0.03-0.49) or 6-month ORR and OS HR (R-2 = 0.05; 95% CI, 0.0001-0.31). The aggregated Kaplan-Meier analysis of immunotherapy trials vs chemotherapy revealed an OS HR of 0.69 (95% CI, 0.63-0.75) and PFS HR of 0.82 (95% CI, 0.76-0.89). Targeted therapy trials vs chemotherapy had an OS HR of 0.98 (95% CI, 0.80-1.19) and PFS HR of 0.48 (95% CI, 0.42-0.56). CONCLUSIONS AND RELEVANCE This analysis of milestone rates suggests a moderate association between OS milestones at 12 or 9 months and OS HR but not 9-month PFS or 6-month ORR milestones and OS HR. Although OS at 12 months had the strongest association with OS HR, it may not be the optimal time for future trials, which will increasingly have immunotherapy as the control, deploy new biomarker-enrichment strategies, and likely enroll patients with longer survival. Milestone rates may be useful as a complementary tool to summarize or interpret trial results or as a secondary end point in exploratory studies.