Early Evidence that Larotrectinib Is Safe and Effective in Adults With Solid Tumors Characterized by TRK Fusions

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Results from a phase 1 study suggest that larotrectinib could be a new standard of care in TRK-fusion cancers.
Results from a phase 1 study suggest that larotrectinib could be a new standard of care in TRK-fusion cancers.

Larotrectinib, a small-molecule inhibitor of the TRK kinases, can be safely administered to adults with advanced solid tumors, according to results from a phase 1 study published online on January 8, 2019, in Annals of Oncology.Furthermore, an objective response, according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, was achieved in 100% of evaluable patients who had disease characterized by a TRK fusion. 

In this phase 1 dose-escalation study, the primary end point was the safety of oral larotrectinib, including dose-limiting toxicity, and determination of maximum tolerated dose. Secondary end points included determination of pharmacokinetic parameters and antitumor activity. The presence of a TRK-fusion cancer was not a requirement for study enrollment.

Seventy patients with 23 different types of locally advanced or metastatic solid tumors (median age of 59.5 years) were enrolled to 6 dose cohorts. Only 8 patients had NTRK-fusion cancers. The majority of patients had received at least 3 prior systemic therapies, and median follow-up was 26.9 months.

Larotrectinib was well tolerated in this adult population; most treatment-related adverse events were classified as grade 1 or grade 2. Larotrectinib-related grade 3 adverse events, most commonly anemia, occurred in 19% of patients. No grade 4 or grade 5 treatment-related adverse events were reported. A maximum tolerated dose was not reached, although a phase 2 dose of 100 mg/m2 twice daily was determined based on tolerability and antitumor activity.

According to an independent radiology review of all evaluable patients (67 individuals), the overall objective response rate was 12%. Remarkably, all 8 patients with TRK-fusion cancers achieved an objective response, with a complete response observed in 2 patients.

Furthermore, these responses were durable, although following an initial response, 2 patients with TRK-fusion cancers developed progressive disease characterized by acquired mutations conferring resistance to larotrectinib. 

“Larotrectinib offers a potential new standard of care for patients with TRK-fusion cancer, which is contingent on effective tissue-agnostic routine screening to detect tumours harbouring NTRK gene fusions,” the authors concluded.


  1. Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients with solid tumours: a multicentre, open-label, phase I dose-escalation study [published online January 8, 2019]. Ann Oncol. doi: 10.1093/annonc/mdy539

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