Vemurafenib for melanoma and other cancers
-ZELBORAF® (Genentech) is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
-Recommended dose is 960 mg orally twice daily. Administer ZELBORAF approximately 12 hours apart with or without a meal. ZELBORAF should be swallowed whole with a glass of water.
-Cutaneous squamous cell carcinomas (cuSCC) occurred in 24% of patients. Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage with excision and continue treatment without dose adjustment.
-Most common adverse reactions (≥ 30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.
-Advise patients to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.
One of the major cancer medicine success stories of 2011 was the FDA approval of vemurafenib (Zelboraf ®; Genentech/Daiichi Sankyo) for metastatic melanoma. For the first time in 30 years, vemurafenib, and an immunotherapeutic agent ipilimumab (Yervoy®, Bristol-Myers Squibb), showed significant survival benefit in the metastatic melanoma late-phase clinical trials and a possibility of improving the quality of life of patients. Vemurafenib was also profiled in the 2011 American Society of Clinical Oncology (ASCO)'s Annual Report on Progress Against Cancer,1 and is now a new standard of care for the melanoma patients carrying the BRAF V600E mutation.
Melanoma is a cancer of pigmented skin cells called melanocytes.2 In rare situations, melanoma can also occur in the other pigmented tissues, such as the eye (uvea), gastrointestinal track (including mouth and anal wall), and vaginal wall. Metastatic melanoma is one of the deadliest known cancers. It is estimated that 70,000 patients were diagnosed with melanoma last year, and there were close to 9,000 deaths.3 The incidence of melanoma increased in males by 4.7% from 1990 to 2007.3 Sadly, metastatic melanoma patients generally have a grim prognosis with a ten-year survival rate of only 10%.4 It remains to be seen if the widespread adoption of vemurafenib in metastatic melanoma management will increase the survival odds for these patients.5
Vemurafenib is a specific inhibitor of the BRAF V600E gene which is expressed in the majority of melanomas. BRAF V600E is an always-on mutant version of a cell signaling factor, B-RAF. First discovered in the early '80s as viral oncogenes, the RAF family of proteins are key components of the MAP kinase cell signaling pathway.
RAF proteins relay mitogenic signals originating at the cell surface receptor tyrosine kinases and lead to the activation of ERK transcription factors which are the genetic switches responsible for turning on the cell proliferation and survival genes in the nucleus. This RAS/RAF/MEK/ERK/MAP kinase signaling pathway is disregulated in numerous cancers with mutant oncogenic RAS and is found in nearly 15% of all human cancers.7
However, initial efforts to develop drugs targeting RAS or RAF-1 were futile, and it took another 10 years to discover activated B-RAF mutant forms in melanomas, colon carcinomas, and other cancers. In 2002, the scientists at the Wellcome Trust Sanger Institute analyzed over 500 cancer-cell lines and human tumor-derived cultures, and discovered that 80% of all melanomas, 12% of colon cancers, and 14% of ovarian cancers are driven by the BRAF V600E-mutant gene.7 In addition, this mutant gene was also discovered in glioma, sarcoma, lung, and breast cancer cell lines.7
After the discovery of the BRAF V600E cancer biomarker, it took just four years for the California-based Plexxikon, Inc., to discover a potent inhibitor of BRAF V600E, vemurafenib, and launch a clinical trial in metastatic melanoma patients. The results of the pivotal randomized multicenter clinical Phase III study BRIM3 (BRAF inhibitor in melanoma) trial, comparing vemurafenib with dacarbazine, the standard of care, in previously untreated metastatic melanoma patients, were presented at the ASCO 2011 meeting last May and were published one month later in the New England Journal of Medicine.8 Overall survival at six months was 84% (95% [CI], 78 to 89) in the vemurafenib group, and 64% (95% CI, 56 to 73) in the dacarbazine group. The interim analysis for overall survival and final analysis for progression-free survival showed that 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). The median progression-free survival was 5.3 months for vemurafenib and 1.6 months for dacarbazine. 8