The 12-month overall survival (OS) milestone rate correlates with OS hazard ratio in trials of metastatic non–small cell lung cancer (NSCLC) and could be a valuable secondary endpoint, according to a meta-analysis published in the JAMA Oncology.1

The development of immune checkpoint inhibitors and targeted therapies has raised questions regarding the need for intermediate endpoints in clinical trials for the detection of early activity, allowing the prioritization of combinations and interpret exploratory study results. The purpose of this milestone meta-analysis was to determine if intermediate endpoints could predict OS.

This analysis expanded a previous milestone analysis of 14 randomized, active-controlled trials to 25, all of which were submitted to the US Food and Drug Administration (FDA).

Continue Reading

Of the trials, 4 were molecularly enriched for oncogene-driver mutations to test targeted therapies, 6 evaluated immunotherapies, and the remaining 15 evaluated neither immunotherapies nor targeted therapies in non–molecularly enriched populations.

This analysis included 20,013 patients with advanced lung cancer with a mean age of 60. Across all 25 trials, the median follow-up for progression-free survival (PFS) was 16 months (range, 8 to 31 months) and OS was 19 months (range, 10 to 32 months).

Targeted therapy resulted in the highest rates of 6-month objective response rate (ORR), 9-month PFS, and 12-month OS. There was no association, however, between OS hazard ratios and 6-month ORR milestone ratio (R2 = .19; 95% CI, 0.30-0.49) or 9-month PFS milestone ratio (R2 = .05; 95% CI, 0.0001-0.31).

There was a moderate association between OS HR and 12-month OS milestone ratio (R2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio (R2 =0.67; 95% CI, 0.49-0.82).

Kaplan-Meier analyses showed a separation of PFS curves earliest with targeted therapy and somewhat later — at about 6 months — with immunotherapy, and no separation was apparent with conventional therapies.

Only immunotherapy resulted in separation of the Kaplan-Meier curves for OS, which occurred beginning at 3 months. The failure of separation in the OS curves with targeted therapy was “likely owing to the high rates of crossover from chemotherapy groups to the targeted therapy groups,” the authors wrote.

RELATED: Midtreatment FDG-PET-Driven RT Escalation Promising in NSCLC

Although the 12-month OS milestone ratio had the strongest association among the milestones evaluated, the authors acknowledged that “it may not 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.”


  1. Blumenthal GM, Zhang L, Zhang H, et al. Milestone analyses of immune checkpoint inhibitors, targeted therapy, and conventional therapy in metastatic non-small cell lung cancer trials. A meta-analysis. JAMA Oncol. 2017 Jun 15. doi: 10.1001/jamaoncol.2017.1029 [Epub ahead of print]