Novel Agent Shows Antitumor Activity in TRK-Fusion Cancers

CHICAGO – An investigational agent that targets tropomysin receptor kinase (TRK) fusions offered "consistent and durable antitumor activity" in a range of tumor types in adults and children, researchers reported here.

In 46 evaluable patients with a variety of tumors, the objective response rate (ORR) was 78% (95% CI 64%–89%) with responses in 12 unique tumor types, while a median duration of response (DOR) had not been reached as the majority of responders remain on treatment without progression, according to David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.

"Larotrectinib delivers consistent and durable responses in TRK fusion patients across all ages, regardless of tumor context, and does so with few side effects," said Hyman in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting.

"In this way, the larotrectinib TRK fusion story fulfills the promise of precision medicine, where tumor genetics rather than tumor site of origin define the treatment approach," he explained. "It is now incumbent upon the clinical oncology and pathology communities to examine our testing paradigms, so that TRK fusions and other actionable biomarkers become part of the standard patient work-up."

Hyman's group also reported that responses were observed in 17 different tumor types. In addition, larotrectinib was not associated with treatment-related serious adverse events, and none of the patients in the study discontinued treatment due to adverse events, he said.

Larotrectinib is a selective small-molecule pan-TRK inhibitor. "TRK fusions appear oncogenic independent of tumor lineage, are widely distributed across cancers, and affect all ages," the authors wrote.

Hyman estimated that about 5,000 patients in the U.S. have TRK-modulated tumors, although he said that number by be underestimated because TRK mutations are not often identified in gene-mutation panels.

The study enrolled all NTRK fusion patients with RECIST measurable disease who were also enrolled to adult and pediatric phase I trials, as well as an adult/adolescent phase II trial. TRK fusion status was determined by local testing prior to enrollment.

The drug dose was generally 100 mg BID on a continuous 28-day schedule. The primary objective was investigator-assessed ORR per RECIST v1.1. Secondary endpoints included DOR and safety. Data was reported through January 2017.

Among the 55 TRK fusion patients, there were 12 children and 43 adults (age range 4 months to 76 years). They had a median of two prior treatments. Fusions involved NTRK1 (n=25), NTRK2 (n=1), and NTRK3 (n=29), and 14 unique partners.

The tumor types treated were salivary (12), sarcoma (10), infantile fibrosarcoma (7), lung (5), thyroid (5), colon (4), melanoma (4), cholangiocarcinoma (2), gastrointestinal stromal tumor (2), and other (4).

The authors reported that the longest responder remained on treatment at 23 months, with eight patients remaining in response at >12 months, and 16 patients at >6 months.

NTRK solvent front mutations were detected in all four patients who developed resistance. A solvent front mutation is an amino acid substitution in a kinase that reduces the binding potency of a targeted drug.

The most common treatment-emergent adverse events were fatigue (30%), dizziness (28%), and nausea (28%). Five (11%) patients required dose reductions. Still, all of these patients achieved clinical benefit from treatment, the authors pointed out.

"Though the study is small and early, it demonstrates compelling evidence that may pave the way for a new class of drugs for rare tumors that could inform the future of precision medicine," said ASCO expert Sumanta Pal, MD, of the City of Hope in Duarte, Calif.

But larotrectinib has a way to go before it can be considered ready for prime-time use.

Hyman noted that a randomized, controlled trial in the setting of advanced solid tumor malignancies might be difficult because of the lack of any comparator treatment, and the overwhelming responses seen in the 6 months of treatment with larotrectinib.

Richard Carvajal, MD, of New York-Presbyterian Hospital/Columbia University Medical Center in New York City told MedPage Today that "the incidence of TRK fusion mutations is a relatively low frequency event across a wide variety of cancers, but there are a few rare tumors that have this mutation in a very high frequency, such as secretory breast cancers."

He said that while there are a variety of available laboratory tests that can identify TRK mutations, it is not likely to be a routine test since it is likely to be found in only about 5% of patients with solid organ cancers.

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