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

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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.