BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Early phase studies
Vemurafenib (Zelboraf ®, PLX4032, RG7204, Roche/Genentech, Basel) was the first selective inhibitor of mutant BRAF developed. Pre-clinical studies demonstrated exquisite sensitivity of most cell lines harboring BRAFV600E mutations , leading to further clinical development. In the phase I trial, patients were initially treated with a crystalline formulation of vemurafenib, which was found to have minimal efficacy and poor bioavailability. The drug was reformulated to a microprecipitated bulk-powder formulation and dose escalation was performed, with a recommended phase two dose (RP2D) of 960 mg twice daily. An expansion cohort of 32 patients with BRAF mutant melanoma were treated at this dose, of which 24 (80%) experienced a partial response (investigator assessed, including both confirmed and unconfirmed), often with rapid and dramatic regression of disease. This trial demonstrated that almost all patients experience at least some disease regression with vemurafenib with the exception of two patients with primary disease progression (Fig. 4.1) . The median progression-free survival (PFS) was approximately 7 months; nearly all patients eventually developed disease progression. The drug was relatively well tolerated although 41% of patients required a dose reduction to 720 mg twice daily for chronic toxicity.
Fig. 4.1. Best overall response for 32 patients treated at the recommended phase II dose of vemurafenib in the phase I study (960 mg twice daily), measured as the change from baseline in the sum of the largest diameter of each target lesion
Phase II/III studies and subsequent experience
The follow-up non-randomized phase II study, BRIM-2, enrolled 132 patients with BRAFV600E mutant melanoma (BRAFV600K mutations were excluded). The overall response rate was 53% (6% with complete responses) with a median PFS of 6.7 months and a median overall survival (OS) of 15.9 months . These results were observed despite unfavorable baseline patient characteristics: 61% had AJCC stage M1c disease and nearly half had elevated lactate dehydrogenase (LDH). The most common toxicities observed were cutaneous, including rash (52%), pruritis (29%), skin papilloma (29%), skin cutaneous squamous cell carcinoma (cSCC; 26%), and palmar-plantar erythrodysesthesia (10%). Cutaneous SCCs were generally limited with one or two lesions managed with surgical resection although a few patients had multiple and recurrent SCCs eventually limiting therapy. Arthralgia was common but not severe (78%); elevated liver function tests were also observed (17%) and managed with dose reduction.
BRIM-3 was a randomized trial comparing vemurafenib with dacarbazine, enrolling 675 patients with a 1:1 randomization between arms. At the first interim analysis (3.8 months median follow up for the vemurafenib arm, performed soon after enrollment was completed) the OS and PFS endpoints had been met and patients on dacarbazine were allowed to cross over . Vemurafenib-treated patients had a decreased hazard of death (hazard ratio 0.37, 95% CI 0.26–0.55, p< 0.01), and progression (hazard ratio 0.26, 95% CI, 0.20–0.33; p< 0.001), and an overall response rate was 48% (Fig. 4.2). Toxicities were observed in similar incidence to BRIM-2; photosensitivity was also described in this trial which could be prevented with sunblock in many cases. Notably, 2.4% of patients also developed a second primary melanoma. Vemurafenib received regulatory approval in the United States for treatment of advanced melanoma in August of 2011 and is now widely used in first-line and previously treated advanced or metastatic melanoma.
Fig. 4.2. Kaplan-Meier estimates of survival in patients with BRAFV600E mutant melanoma treated with vemurafenib or dacarbazine in the phase III study of vemurafenib
Following approval, pre-clinical studies suggested that the intermittent administration of BRAF inhibitors delay the onset of acquired resistance . This has not yet been verified in the clinical setting, therefore this strategy should not be recommended for patients. However, when patients develop intolerable chronic toxicities, we prefer a strategy of intermittent dosing (i.e. 2 weeks on and 1 week off) over dose reduction below 720 mg twice daily. This approach has not yet been evaluated in a clinical trial.
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