First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC

Abstract

Background: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.

Methods: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group) and the overall intention-to-treat population. Crossover from the control group to the selpercatinib group was allowed if disease progression as assessed by blinded independent central review occurred during receipt of control treatment.

Results: In total, 212 patients underwent randomization in the intention-to-treat-pembrolizumab population. At the time of the preplanned interim efficacy analysis, median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001). The percentage of patients with an objective response was 84% (95% CI, 76 to 90) with selpercatinib and 65% (95% CI, 54 to 75) with control treatment. The cause-specific hazard ratio for the time to progression affecting the central nervous system was 0.28 (95% CI, 0.12 to 0.68). Efficacy results in the overall intention-to-treat population (261 patients) were similar to those in the intention-to-treat-pembrolizumab population. The adverse events that occurred with selpercatinib and control treatment were consistent with those previously reported.

Conclusions: Treatment with selpercatinib led to significantly longer progression-free survival than platinum-based chemotherapy with or without pembrolizumab among patients with advanced RET fusion-positive NSCLC. (Funded by Eli Lilly and others; ClinicalTrials.gov number, NCT04194944.).

Figure 1.. Progression-Free Survival Assessed by Blinded Independent Central Review.

Panel A shows Kaplan–Meier estimates of progression-free survival assessed by blinded independent central review in the intention-to-treat–pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were assigned to the control group). Panel B shows Kaplan–Meier estimates of progression-free survival assessed by blinded independent central review in overall intention-to-treat population. Tick marks on the survival curves indicate censoring of data.

Figure 2.. Best Overall Responses Assessed by Blinded Independent Central Review.

Panels A and B show waterfall plots of the maximum change from baseline in tumor size for patients with at least one evaluable postbaseline assessment according to blinded independent central review; data were available for 123 patients in the selpercatinib group and 77 patients in the control group in the intention-to-treat–pembrolizumab population. Panels C and D show waterfall plots of the maximum change from baseline in intracranial tumor size according to blinded independent central review for 15 patients in the selpercatinib group and 11 patients in the control group who had measurable brain metastases at baseline and at least one evaluable postbaseline assessment.