(P 107) LONG-TERM 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. Larotrectinib is a first-in-class, highly selective, central nervous system-active tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 65% in 31 evaluable adult patients with various TRK fusion sarcomas, as of July 2020 (Kummar et al, CTOS 2021). Here, we report the long-term efficacy and safety of larotrectinib in an updated dataset of adult patients with TRK fusion sarcomas.

Methods: Adult patients (≥ 18 years old) with sarcomas harboring NTRK gene fusions and treated with larotrectinib were identified from three clinical trials (NCT02122913, NCT02576431, and NCT02637687). Patients received 100 mg larotrectinib twice daily (BID). One patient received 150 mg BID. Tumor response was investigator-assessed per Response Evaluation Criteria in Solid Tumors version 1.1. Data cut-off date was July 20, 2021.

Results: At the data cut-off, 36 adult patients with locally advanced or metastatic TRK fusion sarcomas had initiated larotrectinib treatment, including 33 with an additional year of follow-up (f/u). Two (6%) patients had bone sarcomas (one not otherwise specified [NOS] and one chondrosarcoma), four (11%) had gastrointestinal stromal tumors, and 30 (83%) had soft tissue sarcomas (eight NOS; six malignant peripheral nerve sheath tumor; four spindle cell sarcoma; three epithelioid spindle sarcoma; two each of myopericytoma, stromal tumor, and inflammatory myofibroblastic tumor; and one each of fibrosarcoma, dedifferentiated liposarcoma; and synovial sarcoma; Table 1). Median age was 41 (range 19–70) years. Ten (28%), 12 (33%), and 14 (39%) patients had received 0, 1, and ≥ 2 prior systemic therapies, respectively. ORR was 58% (95% confidence interval [CI] 41–74): seven (19%) patients had complete responses, 14 (39%) had partial responses, 12 (33%) had stable disease, and two (6%) had progressive disease; response in one patient (3%) was not determined (Table 2). Median time to response was 1.8 months (range 0.9–3.5). Median progression-free survival (PFS) was 28.3 months (95% CI 7.6–55.7); median f/u was 20.7 months. Median overall survival (OS) was not reached (95% CI 38.3–not estimable); median f/u was 34.0 months (Table 2). The Kaplan-Meier 24-month rates for duration of response, PFS, and OS were 71% (95% CI 51–91), 55% (95% CI 37–72), and 77% (95% CI 61–92), respectively. Duration of treatment ranged from 0.1 to 56 months. Treatment-related adverse events (AEs) occurred in 30 (83%) patients and were mostly Grade 1/2, with only one (3%) Grade ≥ 3 larotrectinib-related AE reported (increased weight). There were two Grade 5 AEs (both due to disease progression), neither of which were considered related to larotrectinib. There were no discontinuations due to larotrectinib-related AEs.

Conclusion: In this updated analysis, larotrectinib demonstrated a robust, durable response with extended benefits and a favorable safety profile in adult patients with TRK fusion sarcomas. These data support the importance of testing for NTRK gene fusions in patients with sarcomas, as this is the only definitive way to identify sarcoma patients who may benefit from TRK inhibitors.

22-06-20_Kummar_CTOS2022_Table1_for approval.docx

22-06-20_Kummar_CTOS2022_Table2_for approval.docx