Selpercatinib Improved PFS Compared to Standard Chemotherapy With or Without Pembrolizumab in Unresectable RET Fusion-Positive NSCLC

According to results from a phase 3 study, selpercatinib, a highly selective, potent, and brain-penetrant RET inhibitor, significantly prolonged progression-free survival (PFS) among patients with unresectable RET fusion-positive non-small cell lung cancer (NSCLC), compared to standard chemotherapy with or without pembrolizumab.

“Retrospective analyses suggest that checkpoint inhibitors may also have limited effectiveness for patients with RET fusion-positive NSCLC,” stated Caicun Zhou, MD, PhD, Tongji University, Shanghai, China, and coauthors. This study was created to “define the treatment regimen to be used for newly diagnosed, advanced RET fusion-positive NSCLC.” 

In this study, 261 patients with unresectable stage IIIB, IIIC, or IV nonsquamous RET fusion-positive NSCLC who had not received previous treatment for metastatic disease were randomized to receive 160 mg selpercatinib twice daily (n = 129), or platinum-based chemotherapy with or without pembrolizumab at the investigator’s discretion (control arm; n = 83). The primary end point was PFS as assessed by blinded independent central review in both the intention-to-treat (ITT)-pembrolizumab population (patients whose physicians would have treated them with pembrolizumab had they been assigned to the control arm; n = 212) and the overall ITT population. Secondary end points included percentage of patients with response and duration of response (DOR). 

At pre-planned interim efficacy analysis, median PFS was 24.8 months in the selpercatinib arm and 11.2 months in the control arm (hazard ratio [HR] for progression or death, 0.46; 95% confidence interval [CI], 0.31 to 0.70; P <0.001). The percentage of patients with objective response was 84% in the selpercatinib arm and 65% in the control arm. The cause-specific HR for the time to progression affecting the central nervous system was 0.28. Efficacy results were similar in both the overall ITT population and the ITT-pembrolizumab population. Adverse events were consistent with those previously reported. 

“In this randomized trial of a targeted agent in comparison with a PD-1 inhibitor plus chemotherapy for patients with biomarker-defined, advanced NSCLC, the efficacy of selpercatinib was superior in patients with RET fusion–positive NSCLC…highlight[ing] the importance of comprehensive genomic testing for RET fusions at the time of diagnosis to inform first-line therapy for this patient population,” concluded Dr Zhou and coauthors. 

Source: 

Zhou C, Solomon B, Loong HH, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion–Positive NSCLC. N Eng J Med. Published online: November 16, 2023. doi:10.1056/NEJMoa2309457