Abstract CT062: Efficacy and safety of larotrectinib in patients with cancer and NTRK gene fusions or other alterations
Authors: Hong David S. , Dowlati Afshin , Burris Howard , Chu Edward , Brose Marcia S. , Farago Anna F. , van Tilburg Cornelis M. , Kummar Shivaani , Mascarenhas Leo , Reeves John A. , Rudolph Marion , Maeda Patricia , Childs Barrett H. , Laetsch Theodore W. , Drilon Alexander 
Published: September 2020

Abstract
Introduction: A variety of alterations in NTRK genes have been identified in various cancers, including amplifications, rearrangements, deletions, splice variants as well as fusions. Larotrectinib is a highly selective TRK inhibitor that is active in patients (pts) with TRK fusion cancer. Here, we report post hoc efficacy and safety outcomes of larotrectinib treatment in pts with cancer and NTRK gene fusions (Fusion) vs those with Non-fusion alterations. Methods: Data were pooled from three clinical trials of adult and pediatric pts with TRK fusion cancer treated with larotrectinib (NCT02122913, NCT02576431, NCT02637687). NTRK gene status was assessed using local molecular testing; two studies (NCT02122913 and NCT02637687) initially enrolled pts regardless of TRK fusion status. Efficacy outcomes included objective response rate (ORR), assessed by investigators using RECIST 1.1, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were also assessed. The data cut-off was February 19, 2019. Results: This analysis included 159 pts (153 evaluable for efficacy) with NTRK fusions, with 17 different tumor types, and 73 Non-fusion pts with various genomic alterations, with 25 different tumor types. NTRK alterations reported in the Non-fusion pts included point mutations in 8 pts, amplifications in 7, rearrangements in 4 and deletions in 1. The ORR was 79% (95% confidence interval [CI] 72-85) in the Fusion group, with complete responses (CR) in 24 (16%), partial responses (PR) in 97 (63%), stable disease (SD) in 19 (12%), and progressive disease (PD) in 9 (6%). Median DOR was 35.2 months (95% CI 22.8-not estimable [NE]). In the Non-fusion group treated with larotrectinib, there were no responses except for one pt with NTRK1 amplification who had a PR of short duration (3.7 months); 17 Non-fusion pts (23%) had SD and 48 (66%) had PD as best response. Similarly, differences were seen in survival endpoints between pts in the overall Fusion and Non-fusion groups: median PFS 28.3 mo vs 1.8 mo and median OS 44.4 mo vs 10.7 mo, respectively. Median time of treatment was 7.9 months in the Fusion group and 1.7 months in the Non-fusion group. Incidences of Grade 3 or 4 AEs were lower in the Fusion group (49%) vs the Non-fusion group (58%). Discontinuation due to AEs occurred in 6% of pts in the Fusion group vs 25% in the Non-fusion group. Conclusion: Larotrectinib is highly efficacious in pts with TRK fusion cancer and has demonstrated durable responses. Pts with other NTRK alterations, including point mutations and amplifications, had only limited benefit from larotrectinib.
Citation Format: David S. Hong, Afshin Dowlati, Howard Burris, Edward Chu, Marcia S. Brose, Anna F. Farago, Cornelis M. van Tilburg, Shivaani Kummar, Leo Mascarenhas, John A. Reeves, Marion Rudolph, Patricia Maeda, Barrett H. Childs, Theodore W. Laetsch, Alexander Drilon. Efficacy and safety of larotrectinib in patients with cancer and NTRK gene fusions or other alterations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT062.