Pan-Cancer Efficacy of Vemurafenib in BRAF V600-Mutant Non-Melanoma Cancers

Abstract

BRAF ^V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAF ^V600 mutations have historically been considered a clear demonstration of tumor lineage context-dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort "basket" study of the BRAF inhibitor vemurafenib in non-melanoma BRAF ^V600 mutation-positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. SIGNIFICANCE: These data suggest that BRAF ^V600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.See related commentary by Ribas and Lo, p. 640.This article is highlighted in the In This Issue feature, p. 627.

Fig 1A.

Tumor response to vemurafenib. Plot of time on treatment and time to first response, in individual patients. “Others” includes neuroendocrine, head and neck, cervix, squamous cell, and esophageal cancers. NSCLC, non-small-cell lung cancer. Fig 1B. Waterfall plot of maximum percent decrease from baseline in the sum of diameters of target tumors based on investigator assessment in patients with measurable disease. NSCLC, non-small-cell lung cancer; SLD, sum of the longest diameters. “Others” includes neuroendocrine, head and neck, cervix, squamous cell, and esophageal cancers. The dashed line at −30% represents the cut-off for RECIST response.*>100%.

Fig 1A.

Tumor response to vemurafenib. Plot of time on treatment and time to first response, in individual patients. “Others” includes neuroendocrine, head and neck, cervix, squamous cell, and esophageal cancers. NSCLC, non-small-cell lung cancer. Fig 1B. Waterfall plot of maximum percent decrease from baseline in the sum of diameters of target tumors based on investigator assessment in patients with measurable disease. NSCLC, non-small-cell lung cancer; SLD, sum of the longest diameters. “Others” includes neuroendocrine, head and neck, cervix, squamous cell, and esophageal cancers. The dashed line at −30% represents the cut-off for RECIST response.*>100%.

Fig 2.

Kaplan Meier plots showing a) duration of response, b) progression-free survival and c) overall survival of 179 patients with BRAF V600 mutation-positive cancers treated with vemurafenib. The 3-, 6-, and 12-month PFS rates were 73.4%, 48.1% and 28.0% respectively. The 3-, 6-, and 12-month survival probabilities were 89.3%, 77.3% and 60.0%, respectively.