Resistance to first-generation TRK inhibitor therapy in NTRK fusion-positive adult and pediatric cancers conditions next-generation TRK inhibitor activity: a phase I study of selitrectinib

Purpose: Next-generation TRK inhibitor benefit in NTRK fusion-positive cancers has not been prospectively characterized in relation to the wide variety of first-generation TRK inhibitor resistance mechanisms. Data from the global, multicenter, adult and pediatric phase 1 basket trial of selitrectinib (NCT03215511) was thus analyzed. Experimental design: Eligible patients were aged ≥1 month with any type of solid tumors harboring NTRK fusions. Patients had previously received a TRK inhibitor and progressed on or after, or become intolerant of, this prior therapy, with resistance determined by pre-selitrectinib tumor/plasma sample sequencing. Patients were enrolled in a 3+3 dose-escalation design (aged ≥12 years) or a rolling-6 design (aged <12 years). The primary objective was to determine the maximum-tolerated dose and/or recommended dose for further study. Secondary endpoints included safety, overall response rate (ORR), and pharmacokinetics. Results: Most patients were larotrectinib (70%) or entrectinib (30%) pretreated. Pre-selitrectinib NTRK resistance mutation(s) were identified in 46% of patients. Selitrectinib ORR was highest in on-target only resistance (45%, 95% CI 17–77). Responses were achieved only in solvent-front (e.g., NTRK1 G595R, NTRK3 G623X) and gatekeeper (e.g., NTRK1 F589L, NTRK3 F617X) mutant cancers. MAPK/PI3K pathway alteration-containing cancers did not respond to selitrectinib. Median progression-free survival was worse in MAPK/PI3K alteration-containing cancers (1.8 months, 95% CI 1.6–3.5) than cancers without these alterations (7.0 months, 95% CI 5.3–9.1). Conclusion: Selitrectinib demonstrated antitumor activity after prior TRK inhibition, but this varied according to the resistance mechanism. Thus, molecular characterization of resistance may help inform clinical use of next-generation TRK inhibitors.