Larotrectinib: Promising for All TRK-Positive Tumors

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Larotrectinib may have durable antitumor activity in patients with TRK fusion-positive cancers, regardless of tumor type.
Larotrectinib may have durable antitumor activity in patients with TRK fusion-positive cancers, regardless of tumor type.

Larotrectinib is an oral drug being developed for patients with a variety of solid tumors that show abnormalities in the tropomyosin receptor kinases (TRKs).

Early research showed that the NTRK genes, which encode for the TRKs, can become fused to other genes — and that this fusion can lead to cancer.

“There are 3 NTRK genes involved that can fuse with other partners and cause activities that cause tumors: NTRK1, NTRK2, and NTRK3,” explained David Hong, MD, professor of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center in Houston. 

Dr Hong and colleagues recently conducted a pooled analysis published in The New England Journal of Medicine that suggested larotrectinib had durable antitumor activity in patients with TRK fusion-positive cancers.1 The study pooled data from a phase 1 study involving adults, a phase 1/2 study involving children, and a phase 2 study involving adolescents and adults. Fifty-five patients with 17 unique consecutively and prospectively identified TRK-fusion positive cancers were included in the analysis.

The overall response rate was 75% according to independent review (the primary endpoint). Thirteen percent of patients had a complete response, 62% had a partial response, 13% had stable disease, 9% had progressive disease, and 4% could not be evaluated. According to investigator assessment, the overall response rate was 80%.

Responses were durable, with 71% of responses ongoing at 1 year. Median duration of response and progression-free survival were not reached.

With a median follow-up of 9.4 months, the majority (86%) of patients who responded were continuing on treatment or had undergone curative surgery.

The drug was, furthermore, extremely well-tolerated, according to Dr Hong. The majority of significant adverse events were grade 1 or 2. The most common grade 3 or 4 events were anemia, an increase in alanine aminotransferase or aspartate aminotransferase levels, weight increase, and a decrease in neutrophil count.

TRK fusions were prospectively identified in the 3 studies using next-generation sequencing or fluorescence in situ hybridization.

“These mutations should be detectable by most current commercial next-generation sequencing platforms, like Foundation,” Dr Hong said. “The best way to detect it would be with a next-generation sequencing platform with an RNA component.”

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