Second- and third-line outcomes after selective RET inhibitor failure in RET fusion-positive metastatic lung cancer: A real-world analysis from the RET-MAP registry

Purpose: Selective RET inhibitors (SRIs) are the first-line standard for RET fusion-positive NSCLC, but no treatment is established after progression. Real-world outcomes are needed to inform trial design and contextualize single-arm studies in this rare population. Experimental design: Using the international RET-MAP registry (52 centers), we evaluated second-line platinum-pemetrexed with or without immunotherapy after first-line SRI progression and characterized third-line treatments after exposure to both regimens in any order. Results: Among 207 patients treated with first-line SRI, 81 (39%) discontinued because of progression; 65 (80%) received subsequent therapy, most commonly platinum-pemetrexed with or without immunotherapy (n=35, 54%). At 53 months' median follow-up, real-world objective response rate was 41% (12/29), median real-world progression-free survival (rwPFS) 6.1 months (95% CI 4.8-11.4), and median overall survival (OS) 13.7 months (95% CI 8.7-26.5). Outcomes were similar with chemotherapy alone (n=12) versus chemo-immunotherapy (n=23) for rwPFS (5.9 vs 6.8 months; HR 1.05, p=0.903) and OS (18.5 vs 13.7 months; HR 0.83, p=0.674). Three patients had rwPFS beyond 24 months with chemo-immunotherapy, all after short first-line SRI exposure. Among 32 patients receiving third-line therapy, taxane with or without antiangiogenic therapy was most common (n=11), with no responses and median rwPFS of 1.5 months (95% CI 0.8-NR). Conclusions: Second-line platinum-pemetrexed with or without immunotherapy achieved a median rwPFS of 6.1 months. Third-line outcomes were poor, highlighting the need for new treatment strategies.