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Vemurafenib shows promise for BRAFV600 -mutated nonmelanoma cancers
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The BRAF V600 oncogene appeared targetable in certain nonmelanoma cancers, according to the results of a phase 2 study.
Further, vemurafenib (Zelboraf, Hoffmann-La Roche/Genentech) demonstrated activity in patients with non–small cell lung cancer, Erdheim–Chester disease (ECD) and Langerhans’-cell histiocytosis (LCH).
“Vemurafenib is a selective oral inhibitor of the BRAF V600 kinase and is associated with a response rate of approximately 50% and improved survival among patients with BRAF V600E mutation-positive metastatic melanoma,” José Baselga, MD, PhD, physician-in-chief and chief medical officer of Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Efforts by the Cancer Genome Atlas and other initiatives to characterize the genetic landscape of most tumor types have identified BRAF V600 mutations in nonmelanoma cancers, including colorectal cancer, NSCLC, papillary thyroid cancer, diffuse gliomas, cholangiocarcinoma, hairy-cell leukemia, multiple myeloma, Langerhans’-cell histiocytosis and Erdheim–Chester disease.”
Baselga and colleagues conducted a histology-independent phase 2 basket study of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers. The study included 122 patients enrolled in one of seven cancer cohorts: NSCLC (n = 20), colorectal cancer (n = 37), multiple myeloma (n = 5), cholangiocarcinoma (n = 8), ECD or LCH (n = 18), anaplastic thyroid cancer (n = 7) or other cancers (n = 27).
Patients with colorectal cancer received oral vemurafenib (960 mg twice daily) alone (n = 10) or with IV cetuximab (Erbitux; Bristol-Myers Squibb, Lilly) at a loading dose of 400 mg/m2, followed by a weekly 250-mg/m2 dose (n = 27).
All other patients received 960 mg vemurafenib twice daily alone.
Response rate served as the primary endpoint. Secondary endpoints included PFS, OS, duration of response and safety.
Patients with NSCLC demonstrated a response rate of 42% (95% CI, 20-67) and a median PFS of 7.3 months (95% CI, 3.5-10.8).
Forty-three percent (95% CI, 18-71) of patients with ECD or LCH achieved a response. After a median treatment duration of 5.9 months (range, 0.6-18.6), no patients in this cohort experienced disease progression during therapy.
Median OS had not been reached among patients with NSCLC, ECD or LCH, and median PFS had not been reached among patients with ECD or LCH.
Patients with colorectal cancer treated with combination vemurafenib and cetuximab achieved a median PFS of 3.7 months (95% CI, 1.8-5.1) and a median OS of 7.1 months (95% CI, 4.4-not reached).
Anecdotal responses also occurred in patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer and clear-cell carcinoma.
Safety data appeared comparable to previous studies of vemurafenib for melanoma. Rash (68%), fatigue (56%) and arthralgia (40%) occurred most frequently.
The researchers acknowledged the small patient population as a study limitation.
“Histology-independent, biomarker-selected basket studies are feasible and can serve as a tool for developing molecularly targeted cancer therapy,” Baselga and colleagues wrote. “Confirmation of promising activity identified in basket studies will often necessitate additional studies.” – by Cameron Kelsall
Disclosure: The study was funded by F. Hoffman-La Roche/Genentech. Please see the full study for a list of all researchers’ relevant financial disclosures.
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