BRAF and MEK inhibitors rechallenge as effective treatment for patients with metastatic melanoma.

Despite considerable progress made in the treatment of patients with advanced melanoma, the majority of the patients treated with BRAF and mitogen-activated protein inhibitors (BRAFi and MEKi) experience a disease progression due to acquired resistance. Currently, ongoing studies explore the possibility to overcome or reverse this process. Our multicenter retrospective analysis included 51 patients with metastatic BRAF-mutated melanoma who had previously progressed on BRAFi/MEKi than had progressed on immunotherapy (anti-progression disease-1 or anti-cytotoxic T-lymphocyte-associated protein 4) and next were rechallenged with BRAFi/MEKi. Median age at BRAFi/MEKi rechallenge was 56 (range: 31-82 y/o). Median overall survival from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 29.7 and 9.3 months, respectively, whereas median progression-free survival was 10.5 and 5.9 months, respectively. Six-month, annual, and 2-year overall survival rates on both treatments were: 98% and 55%, 92% and 29%, and 69% and 2%, respectively. A response rate to treatment was higher in the group receiving BRAFi/MEKi for the first time as compared with the group receiving BRAFi/MEKi rechallenge and was overall response rate 72% and 27%; disease control rate 92% and 63%. Time interval between the end of the first BRAFi/MEKi treatment and the beginning of BRAFi/MEKi rechallenge did not influence median overall survival or progression-free survival. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. BRAFi/MEKi rechallenge treatment remains clinically important and is associated with the lower toxicity. BRAFi/MEKi rechallenge efficacy is higher in patients who are in good performance status, with normal lactate dehydrogenase, and without brain metastases.