Larotrectinib in Patients With Tumors With NTRK Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-Z1E

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PURPOSE Recurrent chromosomal fusions in neurotrophic tropomyosin receptor kinase ( NTRK ) have been reported as an oncogenic driver across human cancer. Herein, we report results from subprotocol Z1E of the NCI-MATCH (Molecular Analysis for Therapy Choice) trial investigating the efficacy and safety of larotrectinib, a highly selective inhibitor of all three TRK proteins, in TRK fusion–positive cancers. METHODS From August 21, 2017, to July 8, 2021, patients with solid tumors or lymphomas progressing on standard therapy were genomically profiled and enrolled to NCI-MATCH, a genomically driven, signal-seeking, precision medicine platform trial. They were assigned to subprotocol Z1E if a NTRK fusion–positive tumor was identified. Patients received larotrectinib 100 mg twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, overall survival (OS), and safety. RESULTS In total, 12 patients with centrally confirmed NTRK fusion–positive tumors were treated with larotrectinib across six distinct tumor histologies. The ORR was 75% (90% CI, 47.3% to 92.8%) with median PFS and OS of 14.4 (90% CI, 8.48 to not reached [NR]) months and 23.9 (90% CI, 11.1 to NR) months, respectively. Treatment was well tolerated, with adverse events predominantly being grade 1. CONCLUSION NCI-MATCH subprotocol Z1E demonstrates that larotrectinib offers clinically significant benefit with marked ORR across NTRK fusion–positive tumors with no clinically significant toxicities. These findings support the rationale for the US Food and Drug Administration's tissue-agnostic approval of larotrectinib for NTRK fusion–positive tumors. Our findings demonstrate the necessity of including NTRK1 , NTRK2 , and NTRK3 within comprehensive molecular assays of cancer to navigate patients to an easily administered and highly effective therapy.

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