1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: Update from the phase I/II TRIDENT-1 trial

Repotrectinib, a next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI), has shown clinical activity and manageable safety in pts with ROS1+ NSCLC or NTRK+ locally advanced/metastatic solid tumors in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). This is the first report of repotrectinib efficacy by Blinded Independent Central Review (BICR), with 8.7 mo minimum follow-up in pts with TKI-naïve and -pretreated NTRK+ solid tumors, including NSCLC, and safety in all pts treated at the recommended phase 2 dose (RP2D). Pts with NTRK+ solid tumors were enrolled in TKI-naïve and -pretreated cohorts. RP2D was 160 mg QD for 14 d, then 160 mg BID. Phase 2 primary endpoint: confirmed objective response rate (cORR) by BICR. At data cutoff (19 Dec 2022), median follow-up was 17.8 mo (range, 8.7–64.6) in the TKI-naïve cohort (n = 40), and 20.1 mo (8.7–69.4) in the TKI-pretreated cohort (n = 48). The table shows efficacy in pts with NTRK+ solid tumors and subgroups of interest. NSCLC was the most common tumor (TKI-naïve, 52%; TKI-pretreated, 29%). In TKI-naïve NTRK+ NSCLC, cORR was 62% (95% CI, 38–82) and estimated 12-mo duration of response (DOR) and progression-free survival (PFS) was 92% (95% CI, 76–100) and 64% (43–86), respectively. In TKI-pretreated NTRK+ NSCLC, cORR was 42% (18–71) and estimated 12-mo DOR and PFS was 44% (1–88) and 23% (0–49), respectively. In all pts treated at RP2D in TRIDENT-1 (n = 426), dizziness (62%; grade ≥3, 3%) was the most common treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 51% of pts (29% treatment-related AEs). Treatment discontinuation rate due to TEAEs was 7% (3% due to treatment-related AEs). In TRIDENT-1, with 8.7 mo minimum follow-up, repotrectinib showed robust responses and durable clinical activity in both TKI-naïve and -pretreated pts with NTRK+ solid tumors, including NSCLC. Repotrectinib safety at RP2D was manageable, consistent with prior reports.Table: 1372PRepotrectinib in NTRK+ solid tumorsNTRK+ solid tumorsaTKI-naïve (n = 40)TKI-pretreated (n = 48)Efficacy, % (95% CI)cORRb58 (41–73)50 (35–65)12-mo DOR86 (71–100)39 (16–62)12-mo PFS56 (40–72)22 (8–36)NTRK+ solid tumors by prior TKIccORR,b % (95% CI)Prior larotrectinib (n = 23)—43 (23–66)Prior entrectinib (n = 24)—54 (33–74)NTRK+ solid tumors with solvent front mutations(n = 25)Efficacy, % (95% CI)cORRb—60 (39–79)12-mo DOR—33 (7–58)12-mo PFS—21 (4–39)aTumors included NSCLC (52% TKI-naïve; 29% TKI-pretreated), salivary gland cancer (8%; 17%), thyroid cancer (12%; 8%), soft tissue sarcoma (8%; 12%); others <10% each. bPer RECIST v1.1. cMay have received 1-2 prior TKI. Open table in a new tab