FDA Approves Larotrectinib for NTRK-Positive Cancers

The FDA has granted an accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.

The approval is based on findings from patients with TRK-positive tumors enrolled across three clinical trials. In results published in the New England Journal of Medicine (NEJM) in February 2018, larotrectinib induced an objective response rate of 75 percent by independent review and 80 percent by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13 percent) complete responses, 34 (62 percent) partial responses and 7 (13 percent) patients with stable disease.

At one year, 71 percent of responses were ongoing. More than half (55 percent) of patients remained progression-free at one year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

The FDA reviewed data from 55 adult and pediatric patients with TRK fusion—positive cancers enrolled across a phase I adult trial, the phase 2 NAVIGATE trial, and the phase 1/2 SCOUT pediatric trial. The data cutoff for the NEJM findings was July 17, 2017.

The breakdown by tumor type included salivary gland tumor (12 patients), other soft-tissue sarcoma (11 patients), infantile fibrosarcoma (seven patients), thyroid tumor (five patients), colon cancer (four patients), lung cancer (four patients), melanoma (four patients), GIST (three patients), cholangiocarcinoma (two patients), appendix tumor (one patient), breast cancer (one patient) and pancreatic cancer (one patient).

The median patient age was 45 years (range, 0.3-76.0), with 56 percent of patients 40 years of age or older. A third of patients (35 percent) had received at least three prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 had a status of 2.

The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38 percent), dizziness (25 percent), fatigue (16 percent), nausea (16 percent), constipation (16 percent), vomiting (11 percent), increased body weight (11 percent), anemia (9 percent), decreased neutrophil count (9 percent) and diarrhea (5 percent).

Grade 3 TRAEs included increased ALT/AST level (5 percent), anemia (2 percent), decreased neutrophil count (2 percent), nausea (2 percent), and dizziness (2 percent). There were no grade 4/5 TRAEs. Dose reductions were required in eight of the 55 patients.

TRK gene fusions are genetic alterations that appear across a wide range of tumors — including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas — and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2 and 3).

This article originally appeared on OncLive with the title, "FDA Approves Larotrectinib for NTRK+ Cancers."