The Impact of Drug–Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma

SIMPLE SUMMARY: Drug–drug interactions (DDIs) risk is quite common, potentially significant, and often underestimated. In this context, an advanced DDI detection software (Drug-PIN, V. 2/23) was used to assess the DDIs in a retrospective cohort of 177 patients with metastatic BRAF-mutated cutaneous melanoma treated with BRAF and MEK inhibitors. Furthermore, we evaluated the impact of DDIs on the toxicity profile. Here, we report that the median Drug-PIN score significantly increased when the target combination was added to the patient’s home therapy (p-value < 0.0001). Moreover, DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Both Drug-PIN score (p = 0.0291) and traffic light (p = 0.00821) were significant predictors of cardiotoxicity onset. Our results suggest evaluating DDIs in the clinical practice of melanoma patients treated with BRAF/MEK inhibitors to reduce potentially avoidable toxicities and improve treatment tolerability and patients’ quality of life. ABSTRACT: Background: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug–drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. Methods: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. Results: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient’s home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). Conclusions: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.