(P 353) UPDATED EFFICACY AND SAFETY OF LAROTRECTINIB IN ADULT PATIENTS WITH TRK FUSION SARCOMAS

Objective: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in multiple tumor types, including sarcoma. Larotrectinib is a first-in-class, highly selective, central nervous system-active tropomyosin receptor kinase (TRK) inhibitor, approved for tumor-agnostic use in patients (pts) with TRK fusion cancer, based on a rapid, robust, and durable objective response rate (ORR) in both adult and pediatric pts with various cancers. Here, we report updated long-term efficacy and safety of larotrectinib in adult pts with TRK fusion sarcomas.

Methods: Adult (≥18 years old) pts with TRK fusion sarcomas treated with larotrectinib were identified from three clinical trials (NCT02122913, NCT02576431, and NCT02637687). Most pts received larotrectinib 100 mg twice daily (BID); one pt received 150 mg BID. Responses were assessed by an independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors v1.1. Data cut off date was July 20, 2022.

Results: At data cut off, 37 adult pts with locally advanced or metastatic disease were eligible for efficacy assessment by IRC. Two (5%) pts had bone sarcomas (one not otherwise specified [NOS] and one chondrosarcoma), five (14%) had gastrointestinal stromal tumors, and 30 (81%) had soft tissue sarcomas (nine NOS; six malignant peripheral nerve sheath tumors; four spindle cell sarcomas; three epithelioid spindle sarcomas; two each of myopericytomas, stromal tumors, and inflammatory myofibroblastic tumors; and one each of fibrosarcoma, dedifferentiated liposarcoma, and synovial sarcoma; Table 1). NTRK gene fusions were identified by next-generation sequencing (NGS) and fluorescence in situ hybridization in 36 and one pt, respectively. Median age was 41 (range 19–70) years. Thirteen (35%), 12 (32%), and 12 (32%) pts had received zero, one, and two or more prior systemic therapies, respectively.
The ORR was 57% (95% confidence interval [CI] 39–73): nine (24%) pts had complete responses (CR; including one pathological CR), 12 (32%) had partial responses, nine (24%) had stable disease, and six (16%) had progressive disease; response in one pt (3%) was not evaluable (Table 2). Median time to response was 1.8 months (range 1.0–22.9). Median DoR was 54.7 months (95% CI 17.3–not estimable [NE]); median follow-up (f/u) was 26.7 months. Median PFS was 24.8 months (95% CI 5.5–NE); median f/u was 28.4 months. Median OS was 60.2 months (95% CI 38.5–NE); median f/u was 39.4 months (Table 2). The 48-month rates for DoR, PFS, and OS were 53% (95% CI 27–78), 40% (95% CI 22–59), and 56% (95% CI 35–78), respectively.
Treatment-related adverse events (TRAEs) occurred in 31 (84%) pts, with only one Grade 3 TRAE reported (increased weight). There were two Grade 5 adverse events (both due to disease progression), neither of which were considered related to larotrectinib. There were no discontinuations due to TRAEs.

Conclusion: In this updated analysis, larotrectinib continues to demonstrate a rapid and durable response, extended survival benefit, and a favorable safety profile in adult pts with TRK fusion sarcomas. These results support the wider adoption of NGS panels that include NTRK gene fusions to identify pts who may benefit from treatment.