Larotrectinib safe, effective in TRK fusion-positive cancers in adults, children

Reuters Health Information: Larotrectinib safe, effective in TRK fusion-positive cancers in adults, children

Larotrectinib safe, effective in TRK fusion-positive cancers in adults, children

Last Updated: 2018-02-26

By Marilynn Larkin

NEW YORK (Reuters Health) - Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, had "marked and durable antitumor activity" in both children and adults with TRK-fusion positive cancer, regardless of the tumor type, researchers say.

Fusions involving one of three TRKs occur in various cancers in children and adults. The current study is unusual in that it enrolled both adults and children simultaneously. The 55 participants ranged in age from four months to 76 years (median, 45 years) with 17 unique TRK fusion-positive tumor types, including thyroid, colon, melanoma and gastrointestinal, among others.

The study combined results from an adult phase 1 trial; a pediatric phase 1-2 trial; and an adolescent-adult phase 2 trial. The primary endpoint for the combined analysis was overall response rate, as assessed by independent review.

As reported online February 21 in The New England Journal of Medicine, the overall response rate was 75% by central assessment and 80% by investigator assessment. The median time to response was 1.8 months.

According to the central assessment, 7 of the 55 participants (13%) achieved a complete response to larotrectinib and 34 (62%) had a partial response; 7 (13%) had stable disease, 5 (9%) had progressive disease, and 2 (4%) could not be evaluated because of early withdrawal due to clinical deterioration.

At one year, 71% of responses were continuing and 55% of patients remained progression-free; the median duration of response and progression-free survival had not been reached.

At a median follow-up of 9.4 months, 86% of patients with a response (38 of 44) remained on treatment or had undergone surgery intended as curative. Most (93%) adverse events were grade 1 or 2.

Three coauthors from different institutions provided perspectives in emails to Reuters Health.

Dr. David Hyman of Memorial Sloan Kettering Cancer Center in New York City said, "These data demonstrate that TRK fusions define a set of diverse cancer types for which larotrectinib treatment is extremely effective. This has never before been achieved with a targeted therapy."

Dr. Theodore Laetsch of UT Southwestern's Department of Pediatrics and Simmons Cancer Center advised, "My advice for clinicians is to consider sequencing their patients' tumors to identify targetable genetic changes. While TRK fusions are relatively rare, they occur across a broad spectrum of cancers."

"The responses seen with larotrectinib . . . don't depend on a specific diagnosis," he said, "which means that testing tumors is required to identify patients who may benefit."

"The presence of a TRK fusion was tested locally by the treating site and not centrally as part of the study, (which is) what happens in the 'real world' for U.S. Food and Drug Administration-approved therapies," he added.

"However," he said, "this means that we can't determine the percentage of all patients with cancer who have TRK fusions based on the results of our study."

Dr. Ramamoorthy Nagasubramanian, Chief, Division of Pediatric Hematology-Oncology at Nemours Children's Hospital in Orlando, Florida, observed, "Some tumors have a high incidence of TRK fusions, such as infantile fibrosarcoma in children and salivary gland tumors in adults, but overall, their true incidence is unknown. . . . As we screen more rare tumors, we might find a higher incidence."

Dr. Douglas B. Johnson, Clinical Director, Melanoma Program at Vanderbilt University Medical Center in Nashville, who was not involved in the study, told Reuters Health, "The authors should be congratulated in their persistence and dedication in identifying patients with such a rare genetic alteration."

"Unfortunately, TRK fusions are extremely rare, and this study will benefit only a few patients," he acknowledged. "However, for the patients who do benefit, the results can be completely transformative."

"These types of 'basket' studies (which target a genetic mutation, regardless of where the cancer originated) will become increasingly important as we learn more about the molecular biology of different tumors and their common features," Dr. Johnson concluded.

The study was supported in part by Loxo Oncology, which produces larotrectinib. Several of the study authors disclose financial relationships with the company.

SOURCES: http://bit.ly/2CbUHJw and http://bit.ly/2BTfSPF

N Engl J Med 2018.

© Copyright 2013-2018 GI Health Foundation. All rights reserved.
This site is maintained as an educational resource for US healthcare providers only. Use of this website is governed by the GIHF terms of use and privacy statement.