This study evaluated the efficacy and safety of vemurafenib in patients with nonmelanoma cancers harboring BRAF V600 mutations. A histology-independent, phase 2 "basket" study was conducted, enrolling 122 patients across six prespecified cancer cohorts and one cohort for all other tumor types. The primary endpoint was the response rate, while secondary endpoints included progression-free and overall survival. Vemurafenib showed preliminary activity in non–small-cell lung cancer (NSCLC) with a response rate of 42% and a median progression-free survival of 7.3 months. Erdheim–Chester disease or Langerhans’-cell histiocytosis also demonstrated a response rate of 43%, with no disease progression during therapy. Anaplastic thyroid cancer, cholangiocarcinoma, and other rare cancers showed anecdotal responses. Safety was similar to previous studies of vemurafenib for melanoma. The study highlights the potential of BRAF V600 as a targetable oncogene in certain nonmelanoma cancers, but the histologic context remains crucial for response.This study evaluated the efficacy and safety of vemurafenib in patients with nonmelanoma cancers harboring BRAF V600 mutations. A histology-independent, phase 2 "basket" study was conducted, enrolling 122 patients across six prespecified cancer cohorts and one cohort for all other tumor types. The primary endpoint was the response rate, while secondary endpoints included progression-free and overall survival. Vemurafenib showed preliminary activity in non–small-cell lung cancer (NSCLC) with a response rate of 42% and a median progression-free survival of 7.3 months. Erdheim–Chester disease or Langerhans’-cell histiocytosis also demonstrated a response rate of 43%, with no disease progression during therapy. Anaplastic thyroid cancer, cholangiocarcinoma, and other rare cancers showed anecdotal responses. Safety was similar to previous studies of vemurafenib for melanoma. The study highlights the potential of BRAF V600 as a targetable oncogene in certain nonmelanoma cancers, but the histologic context remains crucial for response.