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Larotrectinib shows durable efficacy in TRK fusion cancers

Pearl Toh
01 Nov 2017

Larotrectinib delivers durable response across diverse cancer types, including paediatric and adult cancers, according to an interim analysis of three ongoing trials presented at the ASCO 2017 Annual Meeting.

Larotrectinib, a novel small molecule oral therapy, selectively inhibits tropomyosin receptor kinase (TRK) fusion proteins which occur in many cancers─more than 90 percent of certain rare cancers (eg, infantile fibrosarcoma, one form of juvenile breast cancer and salivary gland cancer) and about 0.5–1.0 percent of common cancers.  

“[A]t this point it is hard to find a cancer type where TRK fusions have not been reported,” said lead author Dr David Hyman from Memorial Sloan Kettering Cancer Center in New York City, New York, US.

Among the first 50 patients (presenting with 17 different cancers) who had at least two scans during the study, 38 patients (76 percent) responded to larotrectinib. Of these, three patients with paediatric sarcomas who were previously unfit for surgery were subsequently able to undergo surgery after larotrectinib shrank their tumours. [ASCO 2017, abstract LBA2501]

As of data cutoff for the interim analysis, the patients had not yet reached the median duration of response because most of them were still responding to the treatment. The longest duration of response to date was 25 months, which is still ongoing.

At 12 months after starting treatment, 79 percent of the responding patients remained free of disease progression.

Five patients (11 percent) required dose reduction but none discontinued treatment due to side effects. Side effects that occurred most commonly included fatigue (rate, 30 percent), nausea (28 percent), and dizziness (28 percent).

“Because larotrectinib was designed to target only TRK, it … does not cause many of the side effects associated with chemotherapy and multitargeted therapy,” said Hyman.

The study included 55 patients (12 children and 43 adults) with locally advanced or metastatic cancer who were tested to carry TRK fusions in ongoing phase I and phase II trials. Patients were treated with oral larotrectinib 100 mg twice daily on a continuous 28-day schedule. Cancers presented included melanoma, sarcoma, lung, colon, thyroid, pancreatic, salivary, and gastrointestinal cancers, among others.

Currently, >50 different partner genes capable of fusing with any of the three TRK genes (NTRK 1–3) have been identified, according to the researchers. 

“These findings embody the original promise of precision oncology … [and] supports widespread genetic testing in patients with advanced cancer to see if they have this abnormality,” said Hyman, adding that technology advances, such as next-generation sequencing, have enabled systematic detection of abnormal genes.

“If approved, larotrectinib could become the first therapy of any kind to be developed and approved simultaneously in adults and children, and the first targeted therapy to be indicated for a molecular definition of cancer that spans all traditionally defined types of tumours,” he added. 

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