Retreatment with First-Generation Selective RET Inhibitors in RET-Rearranged NSCLC Pretreated with Selpercatinib or Pralsetinib - Results from the RET-MAP Registry.

Abstract

In RET-rearranged non-small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRIs) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment. This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AEs). Among 41 patients, 14 (34%) discontinued the initial SRI due to toxicity and 27 (66%) due to progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs re-occurred in 9 patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued for progression, SRI monotherapy (n=13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligo-progression, or dose reduction on first SRI. Combination therapy (n=14; targeted agents, n=11; chemotherapy, n=3) achieved an ORR of 39%, median PFS of 4 months and 6-month PFS of 27.3%. Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression appears limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.