Encorafenib
Encorafenib is a kinase inhibitor that inhibits BRAF activity along the RAF/MEK/ERK pathway.
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Preliminary data of a phase 2 trial evaluating encorafenib in combination with binimetinib showed that the regimen was well tolerated and had promising activity in patients with BRAF-mutant melanoma who were BRAF inhibitor treatment-naïve.4
The overall response rate and disease control rate was 74.5% and 96.4%, respectively. Furthermore, 7 of the 55 patients achieved a confirmed complete response and 34 had a confirmed partial response. Median progression-free survival was 11.3 months (95% CI, 7.4 – 14.6).
“The combination is quite active,” Dr Sullivan said. “The data that we presented at the 2015 ASCO Annual Meeting are impressive. The response rate was at the 70+% range, which is what you see with the other combination of dabrafenib/trametinib and vemurafenib/cobimetinib.”
Of note, the response rate and progression-free survival were consistent with other BRAF inhibitor/MEK inhibitor combinations like dabrafenib and trametinib; however, encorafenib/binimetinib was associated with lower rates of pyrexia and photosensitivity than dabrafenib/trametinib and vemurafenib/cobimetinib, respectively.4
”The toxicity profile is a little bit different than the toxicity profiles of the other 2 combinations, and that may be its distinguishing factor,” Dr Sullivan told Cancer Therapy Advisor.
“The combination of dabrafenib and trametinib is associated with a significant amount of fever syndrome, which can definitely be dose-limiting. The combination of vemurafenib and cobimetinib has a peculiar toxicity where patients are sensitive to light. Arthralgias are also common with vemurafenib/cobimetinib, but they are not seen with this novel combination,” he said.
However, Dr Sullivan noted that liver enzyme elevation was present in a significant minority of patients receiving encorafenib and binimetinib. These laboratory abnormalities may be the dominant toxicity if a lot of patients are treated with it.
“From a symptomatic standpoint, that combination is probably the best tolerated of the 3,” Dr Sullivan said.
The safety and efficacy of encorafenib plus binimetinib are being assessed in the multicenter, open-label, phase 3 trial, in which patients were randomly assigned 1:1:1 to receive encorafenib and binimetinib, encorafenib alone, or vemurafenib alone.4
Atezolizumab
The combination of vemurafenib and atezolizumab, an investigational PD-L1 inhibitor, resulted in durable responses in patients with previously untreated BRAF V600-mutant metastatic melanoma, according to findings of an ongoing phase 1b trial.5
“The data from the phase 1 trial of vemurafenib and atezolizumab presented at the Society for Melanoma Research 2015 Congress looked promising,” Dr Sullivan noted.
For the multicenter, open-label study, patients received the immunotherapy concurrently with the BRAF inhibitor or after a run-in period with vemurafenib alone for 56 or 28 days. Patients received atezolizumab at a dose of 20 or 15 mg/kg every 3 weeks or a fixed dose of 1200 mg and 960 mg of vemurafenib given orally twice daily during the run-in period or 720 mg twice daily when used in combination.
The study demonstrated an objective response rate of 76% (95% CI, 50.1 – 93.2), which included 3 complete responses and 10 partial responses among the 17 evaluable patients. With regard to safety, no dose-limiting toxicities or unexpected adverse events were observed with the combination.
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Atezolizumab plus vemurafenib is also being assessed in combination with cobimetinib for the treatment of the same patient population in a phase 1 trial.
