BRAF^V600 Is Targetable in Some Nonmelanoma Cancers

Vemurafenib selectively inhibits the oncogenic BRAF ^V600 kinase and has shown clinical efficacy in patients with BRAF^V600E-mutant cutaneous melanoma. BRAF^V600 mutations are also present at low incidence in many nonmelanoma cancers, including non–small cell lung cancer (NSCLC), colorectal cancer, and glioma; however, the efficacy of vemurafenib treatment in these tumor types has not been systematically evaluated. To detect preliminary evidence of vemurafenib activity across BRAF^V600-mutant tumor types, Hyman and colleagues performed a histology-independent, flexible, early phase II basket study, in which 122 patients with various cancer types were enrolled into distinct cohorts. Clinical responses to vemurafenib treatment were observed in a subset of BRAF^V600-mutant tumor types, including 8 of 20 patients with NSCLC, 6 of 18 patients with Erdheim–Chester disease or Langerhans cell histiocytosis, 2 of 7 patients with anaplastic thyroid cancer, and 1 of 8 patients with cholangiocarcinoma. In addition, anecdotal responses were reported in patients with various other tumor types. The objective response rate was highest in patients with NSCLC (42%) and Erdheim–Chester disease or Langerhans cell histiocytosis (43%), and tumor regression was observed in the majority of patients in both cohorts, whereas patients with multiple myeloma or colorectal cancer did not respond to vemurafenib monotherapy. Amendment of the study protocol allowed for treatment of 27 patients with colorectal cancer with the combination of vemurafenib and the anti-EGFR antibody cetuximab; dual treatment resulted in modest clinical activity in this heavily pretreated cohort of patients, with tumor regression in many patients and one confirmed partial response. Of note, the safety profile of vemurafenib monotherapy was similar to that reported in studies of cutaneous melanoma, with the most common adverse events being rash, fatigue, and arthralgia. These findings demonstrate that BRAF^V600-mutant tumor types vary in their sensitivity to targeted BRAF^V600 inhibition and suggest that vemurafenib is effective in a subset of BRAF^V600-mutant nonmelanoma cancers.

Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015;373:726–36.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.