Larotrectinib shows marked responses with NTRK gene fusions, limited response in non-fusion mutations

In an analysis of three clinical trials, the targeted therapy larotrectinib resulted in a 79% overall response rate and median overall survival of 44.4 months in adult and pediatric patients with advanced cancers and NTRK gene fusions, regardless of cancer type. In contrast, those with other mutations in NTRK that were not gene fusions saw only a 1% overall response rate of median overall survival of just 10.7 months, highlighting the importance of clinical testing for NTRK fusions.

These findings were presented today at the American Association of Cancer Research (AACR) Virtual Annual Meeting by David Hong, M.D., professor of Investigational Cancer Therapeutics and principal investigator of the clinical trials.

“After analyzing multiple studies and more than 150 patients with NTRK fusions, there is a clear benefit to treating these individuals with larotrectinib. However, that benefit does carry over to other non-fusion mutations in NTRK, as these individuals had only limited benefit,” says Hong. “These data strongly support the importance of clinical testing for NTRK gene fusions in order to identify those patients most likely to benefit from larotrectinib.”

Larotrectinib approval for solid tumors with NTRK fusions

Larotrectinib was approved by the Food and Drug Administration (FDA) in 2018 for patients with advanced solid tumors with NTRK fusions, which occur when a portion of the chromosome containing NTRK breaks off and joins with a gene on another chromosome. The resulting product of the two genes is called a fusion protein and is known to cause cancer development.

This targeted therapy represents the first cancer therapy to be approved by the FDA regardless of cancer type. The approval of larotrectinib was based on early data from 55 patients on three multi-center, open-label clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687) and NAVIGATE (NCT02576431).

Study examines additional types of NTRK mutations

The current study represents an expanded analysis of the same three trials, with the goal of investigating clinical response in patients with non-fusion NTRK mutations. The analysis included 159 patients with NTRK fusions in 17 different tumor types, as well as 73 patients with non-fusion mutations in NTRK with 25 different tumor types. A detailed analysis of the 159 fusion-positive patients was previously published in Lancet Oncology.

Among those in the fusion group, 16% experienced a complete response, 63% showed a partial response and 12% had stable disease. Comparatively, the non-fusion group saw no complete responses, one partial response, 23% stable disease and 67% progressive disease.

The duration of response was 35.2 months in the fusion group, compared to 3.7 months in the non-fusion group. Progression-free survival was 28.3 months and 1.8 months in the two groups, respectively.

Adverse events experienced by the patients were primarily Grade 1 or 2 in both groups, with the non-fusion group being slightly more likely to discontinue treatment due to adverse events.

“We are again encouraged to see such strong responses in those with NTRK gene fusions and glad to have an effective targeted therapy option for these patients,” says Hong. “However, these findings underscore the unmet need for patients with non-fusion NTRK mutations and indicate that treating with larotrectinib is not warranted.”