The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma—A Retrospective, Real-World Cohort Study

SIMPLE SUMMARY: The clinical application of kinase inhibitors and immune-checkpoint inhibitors (CPI) has substantially improved the treatment landscape of melanoma. While BRAF/MEK inhibitors allow for rapid disease control, and CPI can evoke durable tumor responses, primary and secondary resistance frequently limit treatment efficacy. Observations from preclinical trials suggest that treatment with BRAF/MEK inhibitors may enhance susceptibility towards CPI therapy and thus improve long-term tumor control. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, real-world analysis, we analyzed the role of sequential treatment with BRAF/MEK inhibitors and CPI in 135 BRAF-mutant, metastatic melanoma patients. Our results demonstrate that front-line treatment with CPI is associated with favorable tumor control and overall survival in patients with BRAF-mutant melanoma. Further, our data indicate that patients who are refractory to front-line BRAF/MEKi therapy are at higher risk of rapid disease progression compared to patients with front-line CPI treatment. ABSTRACT: The advent of immune-checkpoint inhibitors (CPI) and BRAF/MEK-directed targeted therapy (TT) has improved the treatment landscape of patients with BRAFV600-mutant metastatic melanoma. While TT allows for rapid disease control, the development of secondary TT resistance limits the duration of responses. Responses to CPI have a slower onset but can be durable in a subset of patients. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, single-center, real-world analysis, we identified 135 patients with BRAF-mutated, metastatic melanoma who received consecutive treatment with TT followed by CPI, or vice versa, as first and second-line therapy, respectively. We collected data on clinical-pathological factors, treatment duration, best overall response, progression-free survival and overall survival (OS). Our data revealed that front-line treatment with CPI, followed by TT, showed a non-significant trend towards better OS compared to front-line TT (median OS: 35.0 vs. 18.0 months, p = 0.070). This association was confirmed in a subgroup of patients without systemic pre-treatments (median OS: 41.0 vs. 14.0 months, p = 0.02). Further, we observed significantly better objective response rates to second-line treatments for patients receiving front-line CPI (18.4 vs. 37.8%, p = 0.024). Last, our results indicated that rapid disease progression was less common in patients treated with front-line CPI (27.6% vs. 16.2%) and that subsequent treatment with TT resulted in favorable survival outcomes. Our real-world data indicate that sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in a subgroup of previously untreated BRAF-mutant metastatic melanoma patients.