Several types of cancer can result from gene fusions involving the NTRK1, NTRK2, or NTRK3 genes. Tumors with NTRK fusions seldom have other driver mutations, limiting the effectiveness of most targeted agents. But recent years have seen the emergence of novel agents targeting TRK (tropomyosin receptor kinase) proteins, and clinical trials of two oral TRK inhibitors are now under way at The University of Texas MD Anderson Cancer Center.
“NTRK fusion is a unique genomic alteration that can occur in almost any type of solid tumor,” said David Hong, M.D., a professor in the Department of Investigational Cancer Therapeutics. “But in general, patients with NTRK fusions tend to be younger and have no known cancer risk factors or other driver mutations.”
The largest subclass of tumors that tend to have these fusions is sarcomas, especially gastrointestinal stromal tumors. And although NTRK fusion is found in only a small subset of many cancers—including glioblastoma and pancreatic and lung cancers—the aberration occurs in almost all cases of certain rare cancers, such as mammary analogue secretory carcinoma and infantile fibrosarcoma. NTRK fusion is also seen in 70% of a rare subset of colorectal tumors with high levels of microsatellite instability, which is a predisposition to mutation.
Dr. Hong is MD Anderson’s principal investigator of three multi-institutional clinical trials of TRK inhibitors—two of larotrectinib and one of LOXO-195— that are currently enrolling adult and pediatric patients who have solid tumors with NTRK fusions.
A phase I trial (No. 2014-1056) of larotrectinib is enrolling adult patients who have locally advanced or metastatic solid tumors with NTRK fusions (see Experimental Drug LOXO-101 Shrinks Tumors with NTRK Fusions, OncoLog, July 2016). The trial’s dose escalation phase established that a dose of 100 mg was well tolerated, and this dose is used in the trial’s ongoing expansion phase and also in a phase II trial (No. 2015-0728) of the drug. The phase II trial is enrolling patients 12 years and older who have locally advanced or metastatic solid tumors with NTRK fusions.
An early analysis of patients treated in these two trials and a non–MD Anderson phase I/II pediatric trial of larotrectinib looked at the outcomes of 55 patients with fibrosarcoma, soft tissue sarcoma, melanoma, and cancers of the thyroid, colon, lung, and other organs. At a median follow-up of 9.4 months, the total response rate was 80%: 16% of patients experienced a complete response, and 64% experienced a partial response. An additional 9% of patients had stable disease, and 11% experienced disease progression. Responses were determined according to the Response Evaluation Criteria In Solid Tumors.
Among the 55 patients studied, the only grade 3 treatment-related adverse events were elevated aspartate transaminase and alanine transaminase levels, dizziness, nausea, anemia, and decreased neutrophil count. No treatment-related adverse events led to larotrectinib dose reductions. Dr. Hong and colleagues reported the study’s results in the February 2018 issue of the New England Journal of Medicine.
“In this series of studies, larotrectinib has demonstrated rapid, potent, and durable antitumor activity in children and adults who had solid tumors with NTRK fusions,” Dr. Hong said.
In nine patients whose disease responded to larotrectinib but later progressed, repeat genetic analysis indicated the drug resistance was caused by mutations that altered the TRK kinase domain. This finding was important because an agent, LOXO-195, has already been developed to target such drug resistance mutations.
LOXO-195 is a selective TRK inhibitor designed in anticipation of acquired resistance to other TRK inhibitors. A phase I/II trial (No. 2017-0418) of LOXO-195 is enrolling children and adults who have solid tumors with NTRK fusion mutations and whose disease did not respond to or progressed during treatment with larotrectinib or entrectinib, a similar experimental TRK inhibitor.
The trial is currently in its dose escalation phase, the goals of which are to determine the maximum tolerated dose and the recommended dose for the expansion phase. The goals of the expansion phase are to determine patients’ best overall response and the incidence and severity of adverse effects.
The promise of TRK inhibition
No TRK inhibitors are currently approved by the U.S. Food and Drug Administration (FDA). However, the early results of the larotrectinib trials are so promising that the FDA granted the drug breakthrough therapy, rare pediatric disease, and orphan drug designations for the treatment of unresectable or metastatic solid tumors with NTRK fusions.
“If I were a community oncologist and had a patient who doesn’t respond to standard therapy and who has no typical risk factors—such as a young patient with papillary thyroid cancer or a lung cancer patient who’s a nonsmoker—I would consider next-generation sequencing to see if there’s an NTRK fusion,” Dr. Hong said. “Efficacious drugs that target such tumors are available in clinical trials.”
For more information, contact Dr. David Hong at 713-563-5844 or firstname.lastname@example.org. To learn more about clinical trials at MD Anderson, visit www.clinicaltrials.org and search by physician, cancer type, or treatment.
Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N Engl J Med. 2018;378: 731–739.
OncoLog, May-June 2018, Volume 63, Issue 5-6