1. The progression-free survival was 24.8 months in the selpercatinib group vs 11.2 months in the control group (chemotherapy ± pembrolizumab), with an HR of 0.46.
2. Grade ≥3 adverse events occurred in 70% vs 57% respectively, with elevations in liver enzymes, hypertension, diarrhea, edema, and prolonged QTc occurring more in the selpercatinib group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Selpercatinib (a RET kinase inhibitor) has been shown to have efficacy in RET fusion–positive non-small-cell lung cancer (NSCLC). Retrospective analysis suggested that checkpoint inhibitors may also have some efficacy in RET-positive NSCLC. This trial compared selpercatinib vs platinum-based chemotherapy with or without pembrolizumab for advanced RET fusion–positive NSCLC. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), duration of response (DoR), intracranial response, time to progression, and well as patient-reported outcomes. Median PFS was 24.8 months in the selpercatinib group vs 11.2 months in the control group, HR 0.46 (p<0.001). Objective response was 84% vs 65% and median DoR was 24.2 months vs 11.5 months, respectively. It was shown that PFS was longer with selpercatinib than with control treatment across all subgroups (race, geographic region, ECOG, fusion partner, PD-L1 status, and intracranial disease at baseline). OS data was not mature at the time of this analysis. Intracranial response, in those who had brain metastasis, occurred in 82% of those in the selpercatinib group vs 58% of those in the control group. Grade ≥3 adverse events occurred in 70% in the selpercatinib group vs 57% in the control group, with elevations in liver enzymes, hypertension, diarrhea, edema, and a prolonged QTc occurring more in the selpercatinib group. For patient-reported outcomes, patients reported worsening symptoms as defined by the NSCLC-SAQ total score was 23% in the selpercatinib group vs 43% in the control group. The strengths of this study included its methodology, and the limitations included small sample size, immature data, and collaboration with the drug sponsor. Overall, it was found that selpercatinib had favorable endpoints compared with platinum-based chemotherapy with or without pembrolizumab in advanced RET fusion–positive NSCLC.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: This phase 3 trial enrolled adults with untreated, unresectable IIIB-IV non-squamous RET fusion-positive NSCLC and randomized them (1.6:1) into either selpercatinib (159 patients) or platinum-based chemotherapy (pemetrexed with either carboplatin or cisplatin) with or without pembrolizumab (102 patients, with 83 getting pembrolizumab). The median follow-up time was 19 months. When comparing selpercatinib to control with pembrolizumab, the median PFS was 24.8 months (95%CI, 16.9-NA) vs 11.2 months (95%CI, 8.8-16.8), with a HR 0.46 (95%CI, 0.31-0.70, p<0.001), and similar results were found when compared to overall control. Objective response was 84% (95%CI, 76-90) vs 65% (95%CI, 54-75). Median DoR was 24.2 months (95%CI, 17.9-NA) vs 11.5 months (95%CI, 9.7-23.3). In the preplanned subgroup analyses, PFS was longer with selpercatinib than with control treatment across all subgroups (race, geographic region, ECOG, fusion partner, PD-L1 status, and intracranial disease at baseline). OS data was not mature at the time of this analysis. Intracranial response, in those who had brain metastasis, occurred in 82% (95%CI, 57-96) of those in the selpercatinib group vs 58% (95%CI, 28-85) of those in the control group. Grade ≥3 adverse events occurred in 70% in the selpercatinib group vs 57% in the control group, with elevations in liver enzymes, hypertension, diarrhea, edema, and a prolonged QTc occurring more in the selpercatinib group. For patient-reported outcomes, patients reported worsening symptoms as defined with the NSCLC-SAQ total score was 23% in the selpercatinib group vs 43% in the control group. Overall, it was found that selpercatinib had favorable endpoints compared with platinum-based chemotherapy with or without pembrolizumab in advanced RET fusion–positive NSCLC.
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