(P 161) EFFICACY, SAFETY, AND TREATMENT HOLD WAIT-AND-SEE OUTCOMES OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TRK FUSION SARCOMAS

Objective: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in a diverse range of tumor types. Larotrectinib is a highly selective, CNS-active tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of pediatric and adult patients (pts) with TRK fusion cancer. We report updated larotrectinib efficacy and safety data in pediatric pts with TRK fusion sarcomas, and outcomes in the subset of pts who stopped larotrectinib in the absence of disease progression.

Methods: Pediatric pts ( < 18 years old) with TRK fusion sarcomas treated with larotrectinib were identified from two clinical trials (NCT02576431, NCT02637687 [SCOUT]). Most pts received larotrectinib 100 mg/m2 (maximum dose of 100 mg) twice daily. Responses were assessed by an independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Pts in the SCOUT study were permitted to stop larotrectinib in the absence of on-treatment disease progression (wait-and-see); pts who stopped treatment for ≥28 days were actively followed for progression according to protocol for a post-hoc analysis. If re-treated due to progression, response was re-assessed by investigator per RECIST v1.1.

Results: As of July 20, 2022, 89 pediatric pts with TRK fusion sarcomas were included: 49 (55%) infantile fibrosarcoma (IFS), 39 (44%) other soft tissue sarcomas (STS), and one (1%) bone sarcoma. Median age at enrollment was 2.2 years (range 0–18). Thirty-seven (42%) pts had prior surgery and 61 (69%) had prior systemic therapy. Testing methods are shown in Table 1. Among 88 IRC-eligible pts, the objective response rate was 85% (95% confidence interval [CI] 76–92; Table 2), including 43 pts (49%) with complete response (CR) or pathological CR (pCR). Median time to response was 1.8 months (mo; range 0.9–5.4). Median duration of response, progression-free survival, and overall survival are shown in Table 2. Treatment duration ranged from 0+ to 75+ mo. At data cutoff, 58 (66%) pts were still on treatment or in wait-and-see. Thirty (34%) pts had permanently discontinued treatment, with 16 discontinuing due to tumor progression. Treatment-related adverse events (TRAEs) were mostly Grade 1/2. Grade 3/4 TRAEs occurred in 31 (35%) pts. Four (5%) pts discontinued due to a TRAE.
For the post-hoc analysis, 44 pts stopped larotrectinib in the absence of on-treatment progression: 28 (64%) with IFS and 16 (36%) with other STS. Median time to discontinuation in these pts was 14.6 mo (range 3.0–64.6). Twenty-three (52%) pts discontinued after achieving CR (including 9 with pCR), 18 (41%) with partial response (PR), and three (7%) with stable disease (SD). Of these 44 pts, 15 (34%) who stopped treatment had documented subsequent progression (Table 3). Median time from discontinuation to subsequent progression was not reached at the time of data cutoff; however, the range from discontinuation to subsequent progression for these 15 pts was 0.9–15.3 mo. Fourteen pts resumed treatment after documented progression. Nine of these 14 pts showed re-response to treatment (five CR, four PR); four pts had SD and one had no post-resumption disease assessments. All 44 pts were alive at data cutoff.

Conclusion: Larotrectinib demonstrated robust and durable responses, extended survival benefit, and a favorable safety profile in pediatric pts with TRK fusion sarcomas. These data support the wider adoption of next-generation sequencing panels that include NTRK gene fusions to identify pts who may benefit from treatment. In the post-hoc analysis, 15 of 44 pts who stopped treatment had documented subsequent progression. The majority of patients that progressed derived clinical benefit from retreatment with larotrectinib with 64% experiencing an objective response. The post-hoc analysis suggests that treatment discontinuation is feasible, with possibility to resume therapy as needed. Longer follow-up is required to better determine which pts could be candidates for treatment discontinuation.