Basket Trial Finds New Tumor Types That Respond to BRAF Inhibition


A basket trial of patients with various nonmelanoma BRAF-mutated cancers has shown that additional tumor types may also be responsive to vemurafenib.

A basket trial of patients with various nonmelanoma BRAF-mutated cancers has shown that additional tumor types may also be responsive to vemurafenib, a drug used in BRAF-mutated metastatic melanoma patients. Patients with non–small-cell lung cancer (NSCLC), as well as Erdheim–Chester disease and Langerhans’-cell histiocytosis, showed relatively high response rates.

Basket trials are a relatively new clinical trial design, in which targeted agents are tested among a variety of different tumors that express the corresponding biomarkers. The goals of these tumor histology-independent trials are to speed up drug testing and to understand whether targeting a mutation or biomarker can effectively block tumor growth.

This trial, led by David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, enrolled 122 patients divided into six cohorts of prespecified tumor types-NSCLC, ovarian cancer, colorectal cancer, breast cancer, cholangiocarcinoma, and multiple myeloma, as well as an additional cohort that included all other tumor types with BRAF mutation–positive disease. Because vemurafenib alone had insufficient activity in colorectal cancer patients, the study protocol was amended to study the combination of the BRAF inhibitor plus cetuximab in these patients. The results of the study were published in the New England Journal of Medicine.

The response rate among the NSCLC patients on study was 42% and the median progression-free survival was 7.3 months. The vast majority of these patients had already received platinum-based chemotherapy in the first-line setting. Of the patients with either Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43%-one complete response and five partial responses.

There were also anecdotal responses among other BRAF-mutated cancers, including ovarian, salivary duct, and anaplastic thyroid cancer, as well as cholangiocarcinoma, pleomorphic xanthoastrocytoma, and clear-cell sarcoma. One of 27 colorectal cancer patients treated with vemurafenib plus cetuximab had a partial response and 18 patients had stable disease. Adverse events were similar to what has previously been seen with metastatic melanoma patients treated with vemurafenib.

BRAF V600 mutations, which are associated with aggressive disease and shorter overall survival, have been identified in many non-melanoma cancers but their incidence is typically low-below 5%. Treatment with BRAF inhibitors has largely not been tested outside of melanoma.

“The BRAF V600 mutation is a targetable oncogene in some, but not all, cancer types,” concluded the authors. They also noted that it can be challenging to interpret results from basket trials that enroll small patient cohorts.

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