Comparative efficacy of combined CTLA-4 and PD-1 blockade vs. PD-1 monotherapy in metastatic melanoma: a real-world study

Background In light of the substantial toxicity associated with combined CTLA-4 and PD-1 blockade (ipilimumab and nivolumab), we assessed its efficacy and safety against anti-PD-1 monotherapy (nivolumab or pembrolizumab) in patients with metastatic melanoma under real-world conditions. Methods We conducted a retrospective observational study involving 962 patients with stage IV metastatic melanoma who initiated adjuvant treatment between January 2017 and December 2021 across outpatient clinics in the United States. We adjusted for variables such as age, sex, ECOG performance status, comorbidity index, social deprivation index, metastatic sites, BRAF mutation status, and year of treatment. Outcomes included overall survival (OS) and post-treatment hospitalizations, analyzed using propensity score adjustment and inverse probability of treatment weighted Kaplan–Meier estimators. Results After adjusting for all variables, no significant difference in OS was observed between treatment protocols in the overall cohort ( P = 0.417). In patients with multi-organ metastasis (involvement of more than two organ systems), combined CTLA-4 and PD-1 blockade was associated with improved OS ( P = 0.033). Conversely, monotherapy yielded significantly better OS in patients with oligo-organ metastasis (involvement of two or fewer organ systems; P = 0.008). Patients with oligo-organ metastasis also experienced higher hospitalization rates due to immune-related adverse events when treated with combination therapy (31.2% vs. 8.5%, P < 0.001). Conclusions Our real-world data indicate that combined CTLA-4 and PD-1 blockade is most beneficial for patients with multi-organ metastasis, while those with oligo-organ metastasis fare better with PD-1 monotherapy. The underlying reasons for these observations—whether they are due to differences in the characteristics of multi- and oligo-metastatic melanomas or the risk-benefit profile of the therapies—remain to be elucidated. These findings underscore the need for a nuanced approach to treatment regimens for stage IV melanoma patients.