Larotrectinib OK'd for Cancers with TRK Fusions

A first-in-class TRK inhibitor has received accelerated approval for patients of all ages who have solid tumors harboring fusions in NTRK1, NTRK2, or NTRK3.

The tissue-agnostic approval of larotrectinib (Vitrakvi; Loxo Oncology) marks only the second time the FDA has granted marketing authorization based on a common molecular marker, irrespective of tissue of origin, but it's the first time the agency has done so for a targeted therapy. It's also the first time a drug's initial approval has been site-independent. “This is an affirmation of the precision-medicine approach,” says David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who led larotrectinib's clinical development.

In May 2017, the PD-1 inhibitor pembrolizumab (Keytruda; Merck) became the first agent approved for cancer independent of tumor site—specifically for tumors exhibiting two forms of genomic instability: mismatch repair deficiency and microsatellite instability–high. The immunotherapeutic was initially greenlighted 3 years earlier for patients with melanoma.

The efficacy and safety of larotrectinib were demonstrated in three trials that included two cohorts: a primary group of 55 patients, an analysis of which was published earlier this year (N Engl J Med 2018;378:731–9); and a supplementary group of 67 patients described at the European Society for Medical Oncology 2018 Congress in October. Thirty-two of the 122 patients were younger than 15; the youngest was just 1 month old. Collectively, they had 24 types of NTRK fusion–positive tumors, the most common being salivary gland cancer, thyroid cancer, infantile fibrosarcoma, and various soft-tissue carcinomas.

Overall, the response rate was 81%, with 63% experiencing partial responses and 17% exhibiting complete responses. Importantly, “the responses were pretty uniform across histologies,” notes Trever Bivona, MD, PhD, of the University of California, San Francisco, who was not involved in the drug's testing. “You're seeing efficacy across the board,” he says—regardless of age, tumor type, the NTRK gene involved, or the fusion partner.

In the primary group of 55 patients, 75% of responders remained disease-free a year after treatment, and the median duration of response had not yet been met after a median follow-up of nearly 18 months. One patient—the first ever treated—is still on therapy with a response that's lasted more than 3.5 years.

These kinds of responses are unprecedented, says trial investigator Noah Federman, MD, of the University of California, Los Angeles. “In over a decade of experience treating advanced solid tumors in children, adolescents, and young adults, I have never witnessed the responses seen with larotrectinib,” he says.

Larotrectinib proved safe, with only one of the 122 patients discontinuing treatment due to side effects; 9% of recipients needed a dose reduction owing to spikes in liver enzymes, drops in neutrophil count, or other tolerability issues. “You'd be hard-pressed to find any agent in oncology that has such a low rate of dose reduction,” says Hyman, who describes the toxicity profile as more akin to an antihypertensive agent than an anticancer one.

Other clinical-stage drug candidates directed at TRK fusions include entrectinib (Roche), repotrectinib (TP Therapeutics), DS-6051b (Daiichi Sankyo), and LOXO-195 (Loxo Oncology). Of these, repotrectinib and LOXO-195 are designed to treat tumors that develop resistance to larotrectinib. All except LOXO-195 are less-selective agents that target tyrosine kinase receptors such as ALK and ROS1 as well as TRK fusions. The drug that's closest to a regulatory filing, entrectinib, seems to be slightly less effective and somewhat more toxic than larotrectinib when tested in patients with NTRK fusion–positive tumors. –Elie Dolgin

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