Vemurafenib (Zelboraf) nearly doubles the median overall survival (OS) in more than 50% of patients with BRAF V600
-mutated metastatic melanoma, according to a phase II trial published in the New England Journal of Medicine
In the multicenter phase II trial researchers enrolled a total of 132 patients with previously treated BRAF V600
-mutated metastatic melanoma. BRAF
mutations are found in more than 60% of all melanoma cases, and the V600
mutation is associated with the activation of the mitogen-activated protein kinase (MAPK) pathway, which promotes cell proliferation and prevents apoptosis or cell death. Vemurafenib is a BRAF inhibitor specifically designed to target this pathway.
The median OS of patients was 15.9 months (95% CI, 11.6-18.3). Historically, patients diagnosed with metastatic melanoma survive an average of 6-10 months, thereby suggesting that patients receiving vemurafenib experienced a significant improvement in OS.
Patients in the study were followed up for a median period of 12.9 months (range 0.6-20.1). The study found that 8 patients (6%) achieved a complete response and 62 patients (47%) achieved a partial response for an overall response rate of 53% (95% CI, 0.44 -0.62). The median duration of response achieved by patients was 6.7 months (95% CI, 5.6-8.6), and the median length of progression-free survival (PFS) was similar at 6.8 months (95%, 5.6-8.1). At the time of data cut-off, 33 of 132 patients (25%) had not progressed.
Jeffrey Sosman, MD
“This study confirms what we have discovered in our earlier trials,” said Jeffrey Sosman, MD, director of the Melanoma Program and co-leader of the Signal Transduction Program at Vanderbilt-Ingram Cancer Center in Nashville, TN, and one of the co-principal directors of the study, in a statement. “Many of our patients are exhibiting a strong, immediate response to this drug and some are living significantly longer, with manageable side effects. It was interesting to note that a few of the patients were treated with the drug for up to six months before showing convincing evidence of response.”
Patients in this study did not have favorable baseline characteristics compared to patients typically found in larger phase II or III melanoma trials. For example, 61% of patients had M1c disease and 49% of patients presented with an elevated LDH level. Some patients were placed on the immunotherapy ipilimumab post-progression but the addition of that drug did not affect the OS rate observed and the exclusion of those patients from the analysis did not change the median OS.
During the study, 34 patients (26%) developed cutaneous squamous-cell carcinoma or keratoacanthoma, with the median time to development of the first lesion associated with the disease being 8 weeks (range, 2-36). The most common events were arthralgia (59%), rash (52%), and photosensitivity (52%).
Developed by Plexxikon and Roche, vemurafenib has shown similar results in other studies. In the phase III BRIM3 study vemurafenib (960 mg bid orally) was compared with intravenous dacarbazine (1000 mg/m2 of body surface area) every 3 weeks as a monotherapy in 675 previously untreated patients with stage IIIC or IV melanoma.
After 6 months of treatment, vemurafenib demonstrated an OS of 84% compared with 64% in the dacarbazine group. In the interim analysis for OS and final analysis for PFS, vemurafenib demonstrated a 63% relative reduction in risk of death from melanoma compared with dacarbazine. Response rates were 48% for vemurafenib and 5% for dacarbazine (P
<.001). In addition, the risk of the composite endpoint, death, or disease progression was 74% lower in the vemurafenib group (P
The drug was approved by the FDA in August 2011 for the treatment of patients with unresectable or mestastaic melanoma in patients with the BRAF V600
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-14. doi:10.1056/NEJMoa1112302.