Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: An updated integrated analysis.

Abstract

3605 Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]