ABSTRACT
Somatic point mutations in the BRAF gene have been found in approximately 50% of melanomas. BRAF (V600E), the most common mutation, results in the constitutive activation of BRAF (V600E) kinase, sustaining MAPK signaling and perpetuating cell growth. This groundbreaking discovery led to the clinical development of vemurafenib, a selective BRAF inhibitor. Vemurafenib has been approved for the treatment of patients with BRAF (V600E)-positive unresectable or metastatic melanoma based on survival benefit demonstrated in a randomized phase III study. The current approved dosing schedule of vemurafenib is 960 mg orally twice a day until disease progression or unacceptable toxicity. Vemurafenib is well tolerated, with the most common adverse effects including skin reactions, photosensitivity, headache, and arthralgia. Active research is ongoing to expand the utility of vemurafenib into the adjuvant setting and to circumvent rapid emergence of drug resistance.
ABSTRACT
Ipilimumab, a fully human anti-CTLA-4 antibody, has been approved for the treatment of unresectable or metastatic melanoma based on its survival benefit demonstrated in randomized phase III studies. The current approved dosing schedule of ipilimumab is 3 mg/kg as a 90-min intravenous infusion every 3 weeks for a total of 4 doses. The immune-mediated mechanism of action of ipilimumab can result in tumor response patterns that may differ from those observed with conventional chemotherapy; therefore, revised response criteria to fully capture the spectrum of responses have been developed and are being prospectively validated. The safety profile of ipilimumab also reflects its mechanism of action and is characterized by immune-related adverse events. Although most of these events are mild, tolerable and reversible, high-grade immune-related adverse events have been observed in 15% of patients and can be potentially life-threatening if not managed appropriately. Guidelines for the management of these events emphasize thorough patient education, vigilant monitoring and prompt intervention with corticosteroids when appropriate. Ongoing research, including evaluation of ipilimumab in the adjuvant setting, investigation of its use in combination with other agents and assessment of alternative doses, will help optimize and expand the use of this innovative treatment.
