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.
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 / Mezi, Silvia; Botticelli, Andrea; Scagnoli, Simone; Pomati, Giulia; Fiscon, Giulia; De Galitiis, Federica; Romana Di Pietro, Francesca; Verkhovskaia, Sofia; Amirhassankhani, Sasan; Pisegna, Simona; Gentile, Giovanna; Simmaco, Maurizio; Gohlke, Bjoern; Preissner, Robert; Marchetti, Paolo. - In: CANCERS. - ISSN 2072-6694. - 15:18(2023). [10.3390/cancers15184587]
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
Silvia MeziPrimo
;Andrea Botticelli;Simone Scagnoli
;Giulia Pomati;Giulia Fiscon;Simona Pisegna;Giovanna Gentile;Maurizio Simmaco;Paolo MarchettiUltimo
2023
Abstract
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.File | Dimensione | Formato | |
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