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.
背景：尽管治疗相关毒性显著，BRAF和MEK抑制仍是治疗BRAF突变黑色素瘤的有效策略。本研究分析了药物相互作用（DDI）对抗BRAF/抗MEK疗法毒性特征的影响。方法：在这项多中心、观察性、回顾性研究中，采用Drug-PIN软件（V 2/23）评估DDI，并分析Drug-PIN连续评分或Drug-PIN交通灯系统与治疗相关毒性及肿瘤学结局的关联性。结果：共纳入177例接受BRAF/MEK靶向治疗的晚期BRAF突变黑色素瘤患者。79%的患者出现各级别毒性反应，其中31例（17.5%）发生心血管毒性。94例（55.9%）患者存在需特定药物治疗的合并症。当靶向联合疗法加入患者基础治疗方案时，Drug-PIN评分中位数显著升高（p值<0.0001）。心血管毒性与Drug-PIN评分显著相关（p值=0.048）。Drug-PIN交通灯系统（p=0.00821）和Drug-PIN评分（p=0.0291）均是心脏毒性的显著预测因子。低级别与高级别DDI患者相比，总生存期（OS）（p=0.0045）和无进展生存期（PFS）（p=0.012）预后更佳。在发生心脏毒性亚组中，低级别DDI患者OS显著更优（p=0.0012），PFS亦呈现改善趋势（p=0.068）。结论：DDI是影响治疗相关心血管毒性风险的关键因素。本研究结果支持在接受BRAF/MEK抑制剂治疗的黑色素瘤患者中进行DDI评估的必要性。
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