Larotrectinib Highly Active in Cancers With TRK Fusions

Larotrectinib Highly Active in Cancers With TRK Fusions

Dr. David M. Hyman presents Abstract 2501.
The novel TRK inhibitor larotrectinib showed consistent and durable antitumor activity in advanced cancers with TRK fusions, according to results from early trials (Abstract LBA2501).

TRK is uncommonly expressed in normal tissues and in most cancers. TRK fusions are found in a diverse range of cancer types. In common cancers, they tend to be very rare, occurring in between 0.2% and 3.0% of cases. But in some rare cancers the fusions appear to be a defining characteristic and are present in nearly every case.

Larotrectinib is the first and only selective pan-TRK inhibitor currently under development, David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center, said as he presented results of the drug’s early development program during the Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Oral Abstract Session on June 3. That program included 55 patients: eight from an adult phase I study of advanced solid tumors, 12 from a pediatric phase I/II trial of advanced solid tumors, and 35 from the phase II NAVIGATE study—a basket trial of patients age 12 years or older with advanced solid tumors that were TRK fusion–positive.

The median age in the study was 45 (range: 0.3-76.0), and the 55 patients had 17 distinct cancer types. The most commonly represented were salivary gland tumors (22%), infantile fibrosarcoma (13%), and thyroid cancer (9%). Notably, there was no central screening for TRK fusions in these patients; instead, the investigators accepted identification of TRK fusion cancers from any certified laboratory in the field, and 15 unique labs contributed at least one case.

Among the 50 patients with confirmatory response data, the objective response rate (ORR) was 76%, and 12% had a complete response (CR). Five patients who did not yet have a confirmatory scan performed had an objective response as well, and if confirmed, that would yield an ORR of 78% for the full cohort.

Dr. Trever G. Bivona discusses Abstract 2501.
In the full cohort, 11% had stable disease, and 11% had progressive disease; in the 50 patients with confirmatory data, these rates were 12% and 12%, respectively. Neither the median duration of response nor the median progression-free survival has been reached.

In total, 93% of patients with a response and 75% of all 55 patients either remain on the therapy or have undergone surgery with curative intent. Dr. Hyman noted that there was no apparent relationship between the likelihood of response and the type of cancer, the specific fusion partner, which of three NTRK genes was involved, or the age of the patient.

Seven patients (13%) required a dose reduction because of toxicity; there were no discontinuations because of adverse events (AEs). The most common treatment-related AEs with larotrectinib included dizziness (20%), fatigue (18%), nausea (18%), and increased aspartate transaminase (18%). Most AEs were grade 1 or 2; there were four grade 3 cases of increased alanine transaminase, but no other grade 3 treatment-related AE occurred in more than three patients.

Dr. Hyman noted several novel aspects of the larotrectinib development program. It is potentially the first new targeted therapy developed in a tissue-agnostic fashion, and it is the first targeted therapy developed simultaneously in children and adults. He said a New Drug Application is likely to be submitted to the U.S. Food and Drug Administration in late 2017 or early 2018.

“We believe [these data] demonstrate that larotrectinib is profoundly effective in a durable manner in patients with TRK fusion cancers,” Dr. Hyman said.

The discussant for the abstract, Trever Bivona, MD, PhD, of the University of California, San Francisco, said the study yielded “very striking results.” The CR rate in particular, in advanced cancers, “is nearly unheard of.” Furthermore, he pointed out that “routine pan-cancer screening will be increasingly important to identify and treat patients with fusion-driven cancers.”  

–Dave Levitan