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

Abstract

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.

Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting?

“…The correlation between duration of treatment break and clinical outcome is unclear. Valpione et al reported that the duration of treatment break (6.7-8.8 months) seems to be correlated with clinical outcome (14) while retrospective analyses and one prospective clinical trial did not confirm this finding (15)(16)(17). In our patients, the duration of the interval between treatments was more than 6 months for all cases but we observed mixed outcomes: two patients had long-term control of the disease (patient 1 and 2) and one patient (patient 3) had only a shortlived stabilization of symptoms (1 month) rapidly followed by a multi-site progression of disease.…”

“…Another recent multicenter retrospective analysis investigated the retreatment with BRAFi and MEKi combination in 51 patients with metastatic BRAF-mutated melanoma, previously progressed after receiving kinase inhibitors (BRAFi and MEKi or BRAFi alone) and immunotherapy (anti-PD-1 or anti-CTLA-4) (16). The median PFS and OS for the rechallenge combination treatment was 5.9 and 9.3 months, respectively.…”

“…We observed a stable response at first radiological evaluation in patient 4, but the follow-up was too short to address this issue, at the time of this report. Cybulska-Stopa et al reported adverse events in a greater number of patients during the first treatment with BRAFi with or without MEKi compared with rechallenge, demonstrating a lower toxicity, good tolerance of rechallenge and lack of toxicity accumulation of the treatments (16). The most frequent adverse events were mainly G1-2 (dermatological toxicity, pyrexia, diarrhea, increased levels of liver function enzymes), while the few G3 adverse events included rash, hepatotoxicity and skin cancer.…”

“…Rechallenge with the combination of BRAFi and MEKi after a previous treatment with the same class of inhibitors has been associated with limited activity; retrospective analyses and one prospective trial obtained re-induction of response in over 30% of patients and a median PFS of approximately 5 months (14)(15)(16). In this article, we describe four cases of patients with metastatic melanoma patients rechallenged with BRAFi and MEKi (dabrafenib and trametinib) after a previous line of treatment with BRAFi ± MEKi.…”

Clinical Implications of Acquired BRAF Inhibitors Resistance in Melanoma

“…However, the RR exceeds that obtainable with immunotherapy alone, suggesting the possible overcoming of the previously acquired resistance to BRAFi. More recently, a multicenter retrospective study [83] evaluated 51 patients with progressive disease after first line of treatment with BRAFi/MEKi and second line immunotherapy with anti PD1/PDL1 or anti CTLA4. Patients were rechallenged with BRAFi/MEKi, with an overall response rate of 27%.…”