Larotrectinib May Provide Durable Efficacy Across Many Tumor Types

CHICAGO—Larotrectinib, a selective inhibitor of tropomyosin receptor kinase (TRK) fusion proteins, may provide consistent and durable antitumor activity in TRK fusion cancers, across a wide range of ages and tumor types. In addition, it is well tolerated, according to new data (abstract LBA2501) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6.

Investigators reported that this agent could be the first targeted therapy developed in a tissue-agnostic manner. These new findings also set the stage for a new class of agents for rare tumors.

Researchers analyzed data from 55 patients with TRK fusions enrolled in three ongoing phase I and phase II clinical trials. All patients (12 children and 43 adults) had locally advanced or metastatic cancer, including colon, lung, pancreatic, thyroid, salivary, and gastrointestinal cancers, as well as melanoma and sarcoma. The researchers found that in clinical trials of adults and children with 17 different types of advanced cancer, larotrectinib treatment resulted in responses in 76% of patients. The responses to larotrectinib were durable, with 79% of responses ongoing 12 months after starting treatment.

“This is the first definitive study to evaluate the efficacy of a TRK inhibitor in a broad range of TRK fusion–positive cancers,” said lead study author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York.

He said that TRK fusions are rare, but they do occur in many different types of cancer. Hyman said that these data embody the original promise of precision oncology. They demonstrate how it may be possible to treat a patient based on the type of mutation, regardless of where the cancer originated. Hyman said that the dramatic response from tumors with TRK fusions to this new agent supports widespread genetic testing in patients with advanced cancer to see if they are candidates.

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“We found that larotrectinib was effective in both adult and pediatric TRK fusion–positive cancers, regardless of tumor type. The ORR was 76%, and the median duration of response not yet reached due to insufficient events,” Hyman concluded.

The current data on larotrectinib are now being reviewed and will be submitted to the US Food and Drug Administration (FDA) for regulatory approval. If approved, larotrectinib could become the first therapy 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 tumors, according to Hyman.

The most common side effects associated with larotrectinib are fatigue, dizziness, and nausea. Some patients required dose reductions, but no patients stopped treatment due to side effects.

TRK fusions were first discovered in colon cancer in 1982, but only recent technological advances, particularly next-generation sequencing, have enabled systematic detection of this abnormality.

The FDA granted larotrectinib a Breakthrough Therapy Designation in 2016 for the treatment of pediatric and adult TRK fusion–positive unresectable or metastatic solid tumors that had worsened despite systemic therapy or that have no acceptable alternative treatments.

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