Long-term efficacy and safety of larotrectinib in an integrated dataset of patients with TRK fusion cancer.
Authors: David S. Hong, Lin Shen, Cornelis Martinus van Tilburg, Daniel Shao-Weng Tan, Shivaani Kummar, Jessica Jiyeong Lin, Francois P. Doz, Raymond S. McDermott, Catherine M. Albert, Jordan Berlin, Stefan S. Bielack, Ulrik Niels Lassen, Makoto Tahara, Ricarda Norenberg, Anna Shurshalina, Marc Mardoche Fellous, Hendrik Nogai, Rui-hua Xu, Theodore Willis Laetsch, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2021)

3108 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions encode tropomyosin receptor kinase (TRK) fusion proteins, which are oncogenic drivers in various tumor types. Larotrectinib is a first-in-class, highly selective, CNS-active TRK inhibitor approved to treat adult and pediatric patients with TRK fusion cancer. Larotrectinib demonstrated an objective response rate (ORR) of 78% and a median progression-free survival (PFS) of 36.8 months in an integrated analysis of 175 patients with non-primary CNS TRK fusion cancer (McDermott et al, ESMO 2020). We report updated efficacy and safety data with longer follow-up in an expanded dataset. Methods: Data were pooled from three clinical trials of patients with non-primary CNS TRK fusion cancer treated with larotrectinib. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was assessed by investigators using RECIST v1.1. Data cutoff: July 20, 2020. Results: As of data cutoff, 218 patients were treated with larotrectinib, of which 206 were evaluable for efficacy. There were 21 different tumor types, the most common being soft tissue sarcoma (STS [46%], including infantile fibrosarcoma [20%] and other STS [26%]), thyroid (13%), salivary gland (11%), lung (9%), and colorectal (5%). The median age was 38.0 years (range 0.1–84.0). Patients were heavily pretreated with 45% having received 2 or more prior lines of systemic therapy; 27% had 0 prior lines of systemic therapy. The ORR was 75% (95% CI 68–81): 45 (22%) complete response, 109 (53%) partial response (PR), 33 (16%) stable disease (SD), and 13 (6%) progressive disease (PD). Nineteen patients had brain metastases at baseline, with 15 evaluable for efficacy. The ORR for patients with brain metastases was 73% (95% CI 45–92): 11 PR, 2 SD, and 2 PD. Among all evaluable patients, the median time to response was 1.8 months (range 0.9–9.1). With a median follow up of 22.3 months, the median duration of response was 49.3 months (95% CI 27.3–not estimable). Treatment duration ranged from 0.03+ to 60.4+ months. Median PFS was 35.4 months (95% CI 23.4–55.7) with a median follow up of 20.3 months. At a median follow-up of 22.3 months, median overall survival (OS) was not reached and 36-month OS was 77% (95% CI 69–84). Treatment-related adverse events (TRAEs) were mainly Grade 1–2, with 18% having Grade 3–4 TRAEs. Only 2% of patients discontinued due to TRAEs. Conclusions: These results highlight the importance of testing for NTRK gene fusions in patients with cancer because the majority of patients with TRK fusion cancer treated with larotrectinib had long-term clinical benefit. The safety profile continued to be favorable and no new safety signals were identified. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.