Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

By P. Chapman, A. Hauschild, C. Robert, J. Haanen, P. Ascierto, J. Larkin, R. Dummer, C. Garbe, A. Testori, M. Maio and 18 more. New England Journal of Medicine, 2011

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Background Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. Methods We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. Results At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5b96c4802ae411feb7d9d7166656c0229ed724d0

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Citations in the corpus

Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, background): “Ipilimumab and vemurafenib, dabrafenib and trametinib have substantially improved response rates and/or survival of the patient population included in prospective randomized trials [25, 27, 29, 30].”
Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma (2015, neutral): “Stable disease 9 (12) 13 (35) 3 (13) 1 (10)”
Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, positive): “…PGC1a and oxidative n melanomas treated with BRAF-targeted therapy therefore combination with BRAF pathway inhibitors in vivo. the BRAF(V600E)mutation, leading to its approval as a treatment for patients with metastatic melanoma (Flaherty et al., 2010; Chapman et al., 2011; Sosman et al., 2012).”
Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells (2012, background): “For example, the use of drugs to target the protein product of the BCR – ABL translocation in chronic myeloid leukemia, or the BRAF gene in malignant melanoma, has transformed the treatment of these diseases and substantially improved survival rates (1,2).”
Glioma Subclassifications and Their Clinical Significance (2017, background): “Studies on BRAF mutant melanomas have found success with the BRAF inhibitors dabrafenib or vemurafenib [101].”