A phase 2 basket study evaluated vemurafenib in patients with BRAFV600-mutated nonmelanoma cancers. The study enrolled 122 patients across six prespecified cancer types and a seventh "all-others" cohort. The primary endpoint was response rate, with secondary endpoints including progression-free and overall survival. Vemurafenib showed a 42% response rate in non–small-cell lung cancer, with a median progression-free survival of 7.3 months. In Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43%, with no disease progression during treatment. Anecdotal responses were observed in several other cancer types, including anaplastic thyroid cancer, cholangiocarcinoma, and ovarian cancer. Safety was similar to prior studies in melanoma patients. The study found that BRAFV600 mutations are present in various nonmelanoma cancers, but responses varied by tumor type. Vemurafenib showed activity in non–small-cell lung cancer and Erdheim–Chester disease, but not in colorectal cancer when used alone. Combination therapy with cetuximab improved responses in some colorectal cancer patients. The study highlights the importance of histologic context in determining response to BRAFV600-targeted therapy. While some cancers showed promising responses, others did not, indicating that BRAFV600 is not uniformly responsive across all nonmelanoma cancers. The study underscores the need for further research to confirm these findings and explore the role of molecular profiling in cancer treatment. The results suggest that BRAFV600 mutations may be a targetable oncogene in certain cancers, but not all. The study design, which allows for flexible enrollment of patients with various cancer types, provides a valuable framework for future research in molecularly targeted cancer therapy.A phase 2 basket study evaluated vemurafenib in patients with BRAFV600-mutated nonmelanoma cancers. The study enrolled 122 patients across six prespecified cancer types and a seventh "all-others" cohort. The primary endpoint was response rate, with secondary endpoints including progression-free and overall survival. Vemurafenib showed a 42% response rate in non–small-cell lung cancer, with a median progression-free survival of 7.3 months. In Erdheim–Chester disease or Langerhans’-cell histiocytosis, the response rate was 43%, with no disease progression during treatment. Anecdotal responses were observed in several other cancer types, including anaplastic thyroid cancer, cholangiocarcinoma, and ovarian cancer. Safety was similar to prior studies in melanoma patients. The study found that BRAFV600 mutations are present in various nonmelanoma cancers, but responses varied by tumor type. Vemurafenib showed activity in non–small-cell lung cancer and Erdheim–Chester disease, but not in colorectal cancer when used alone. Combination therapy with cetuximab improved responses in some colorectal cancer patients. The study highlights the importance of histologic context in determining response to BRAFV600-targeted therapy. While some cancers showed promising responses, others did not, indicating that BRAFV600 is not uniformly responsive across all nonmelanoma cancers. The study underscores the need for further research to confirm these findings and explore the role of molecular profiling in cancer treatment. The results suggest that BRAFV600 mutations may be a targetable oncogene in certain cancers, but not all. The study design, which allows for flexible enrollment of patients with various cancer types, provides a valuable framework for future research in molecularly targeted cancer therapy.