Growth modulation index (GMI) as a comparative efficacy measure of larotrectinib versus prior systemic treatments for TRK fusion cancer patients.

Abstract

e15638 Background: Larotrectinib is a highly selective TRK inhibitor that demonstrated high response rates and durable disease control in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. While single-arm studies are often used for rare cancer populations, they do not provide comparative data. GMI utilizes pts as their own control and can be used in this setting. GMI is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the most recent prior line of therapy. A GMI ≥1.33 has been used as a threshold of meaningful clinical activity. We report GMI for TRK fusion cancer pts treated with larotrectinib. Methods: Data were pooled from 3 clinical trials of pts with TRK fusion cancer treated with larotrectinib. A retrospective, exploratory analysis of GMI was conducted in pts who had been on larotrectinib and followed up for ≥6 mos or pts who discontinued early, and had ≥1 prior line of systemic treatment for locally advanced or metastatic disease. TTP on the prior line of therapy was investigator assessed. PFS on larotrectinib was determined by independent review committee per RECIST 1.1. Pts who had not progressed were not censored from the analysis. Results: As of July 15, 2019, 122 pts were eligible for analysis. Fifteen different tumor types were represented, the most common being soft tissue sarcoma in 26 pts (21%), infantile fibrosarcoma in 22 (18%), and thyroid in 21 (17%). Median GMI was 3.35 (range 0.00–337.00; Table); In metastatic pts (n = 81), the proportion with a GMI ≥1.33 was higher in pts with a complete or partial response vs non-responders (88% vs 42%). In the whole analysis set (N = 122), median TTP on prior line of treatment was 2.7 mos (95% CI 2.0–3.1) and median PFS on larotrectinib was 33.4 mos (95% CI 13.8–NE; HR 0.20 [95% CI 0.14–0.29]). In metastatic pts (n = 81), median TTP on prior line of treatment was 2.3 mos (95% CI 1.9–3.0) and median PFS on larotrectinib was 23.4 mos (95% CI 10.9–NE; HR 0.24 [95% CI 0.16–0.36]). Conclusions: Greater than two-thirds of pts with TRK fusion cancer treated with larotrectinib had a GMI ≥1.33, demonstrating a clinically meaningful improvement in PFS compared to TTP on their prior treatment. Clinical trial information: NCT02122913, NCT02576431, NCT02637687.