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Novel Drug “Home Run” for TRK Mutation–Positive Tumors

TOP - November 2017, Vol 10, No 4


Chicago, IL—Larotrectinib (LOXO-101), an investigational agent that targets tropomyosin receptor kinase (TRK) fusions, has demonstrated excellent, consistent, and durable antitumor activity in a range of tumor types in adults and children, reported lead investigator David M. Hyman, MD, Chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York City, at the 2017 ASCO annual meeting. Larotrectinib was called “the first oral tumor-agnostic therapy,” because of its unprecedented high response rates in 17 tumor types that express TRK.

Among the 50 evaluable patients with different tumor types, the objective response rate was 76%, and complete responses were reported in 12% of patients, all of whom had advanced cancers.

TRK fusions represent a newly identified genetic alteration found in dozens of cancer types in children and adults. The fusion event activates the TRK protein to turn on and the cancer to grow, and the cancer becomes addicted to this event,” explained Dr Hyman.

“Larotrectinib is the only pan TRK inhibitor under development, and it is the only drug developed to be used in a truly tumor agnostic model in adults and children,” he added.

Study Details

The study included 55 patients with TRK fusions who were enrolled in 2 clinical trials. The patients had 17 distinct tumor types that were common and rare. Regardless of the tumor type, the objective response rate was 76%, and the complete response rate was 12% in the 50 evaluable patients. The other 5 patients were not evaluable for response at the time of the ASCO meeting, but all 5 had at least a partial response; these patients are continuing to participate in the clinical trial and are awaiting a confirmatory scan.

“This response rate is striking. More than 3 out of every 4 patients responded to therapy. You would be hard-pressed to find these results elsewhere,” said Dr Hyman.

“Most patients had deep tumor regressions,” he continued. “Two were downstaged and taken forward to potentially curative surgery. Once in surgery, they had pathological complete response in the surgical specimen.”

No trend was observed for one tumor type having a better response than the other tumor types.

“You see a dramatic improvement in symptoms once you start therapy,” said Dr Hyman.

The median duration of treatment has not yet been reached. Overall, 93% of patients whose cancer responded to larotrectinib and 75% of all the patients continue to receive treatment or have undergone surgery with curative intent.

Larotrectinib was well-tolerated. Overall, 5 (11%) patients required dose modifications. There were no treatment discontinuations resulting from adverse events. The most common adverse effects that were reported with larotrectinib therapy were fatigue (30%), nausea (28%), and dizziness (28%).

“Larotrectinib is tumor and age agnostic. The drug has had a rapid path from the first to last patients, and a New Drug Application will be submitted to the FDA. These results support the potential for this as a new standard of care for patients whose tumors harbor TRK fusions,” said Dr Hyman.

In the future, if this drug is approved, more universal testing for TRK fusions will be required. “We will have to change the paradigm for our tests,” he added.

Expert Opinion

“This novel drug brings us into a new era for treatment based on mutations. This would have been a pipe dream when I was in training not that long ago. We may now be poised to treat cancers agnostic of their site of origin, and is instead based on molecular criteria,” said ASCO expert Sumanta K. Pal, MD, Co-Director, Kidney Cancer Program, City of Hope Comprehensive Cancer Center, Duarte, CA.

“It will be challenging to develop treatment algorithms. We have to determine how larotrectinib compares with existing treatments, especially for more common types of cancers, such as breast or prostate, where we have existing standards of care,” noted Dr Pal. For more rare TRK-positive cancers with no established standard of care, it may be important to screen for these mutations at diagnosis.

“You can only find what you look for. In lung cancer, we are used to testing for EGFR and ALK. TRK fusions are not commonly captured by most tumor assays, so we can underestimate how common they are. It is important to look for TRK fusions, because we have a treatment that works for it, and patients who have this treatment have a dramatic benefit,” said ASCO expert John V. Heymach, MD, PhD, Chairman, Department of Thoracic/Head and Neck Medical Oncology, M.D. Ander­son Cancer Center, Houston.

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