Real-world second- and third-line outcomes after selective RET inhibitor failure in RET fusion-positive metastatic lung cancer

Selective RET inhibitors (SRIs) are the first-line standard of care for RET fusion-positive non-small cell lung cancer (NSCLC). No treatment is established after progression. Information on real-world outcomes is needed to inform trial design and contextualize studies in this population. Analysis of the RET-MAP registry (52 centers worldwide) evaluated second-line platinum-pemetrexed (Pt-Pem) with or without immunotherapy (IO) after failure of first-line SRI. Among 207 patients treated with first-line SRI, 81 (39%) discontinued because of progression; 65 (80% of 81) received subsequent therapy, most commonly Pt-Pem with or without IO (n=35; 54%). At median 53 months follow-up, the real-world objective response rate was 41%, median real-world progression-free survival (rwPFS) was 6.1 months (95% CI 4.8-11.4) and median overall survival (OS) was 13.7 months (8.7-26.5). Outcomes were similar with chemotherapy alone (n=12) versus chemoimmunotherapy (n=23) for rwPFS (5.9 versus 6.8 months; HR 1.05; p=0.903) and OS (18.5 versus 13.7 months; HR 0.83; p=0.674). Three patients had rwPFS beyond 24 months with chemoimmunotherapy, all after short first-line SRI exposure. Among 32 patients receiving third-line therapy, taxane with or without angiogenic therapy was the most common (n=11), with no responses and a median rwPFS of 1.5 months. The authors conclude that second-line Pt-Pem with or without IO achieved a median rwPFS of 6.1 months, while third-line outcomes were poor, highlighting the need for new treatment strategies.