Comparative efficacy and safety of prolgolimab + nurulimab and nivolumab + ipilimumab in the first-line therapy of metastatic or unresectable melanoma: A systematic review and matching-adjusted indirect comparison

Background. Metastatic and unresectable melanoma is considered as one of the most aggressive oncological diseases with a high mortality rate. In Russia, two first line immunotherapy combinations have been approved: nivolumab plus ipilimumab (NIVO+IPI) and prolgolimab plus nurulimab (PROLGO+NURU). Both regimens use dual immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). However, the lack of direct randomized comparisons between these regimens makes it difficult to choose the optimal first-line therapy.

Aim. This analysis evaluated the relative efficacy and safety of PROLGO+NURU versus NIVO 1 mg/kg + IPI 3 mg/kg (NIVO 1 + IPI 3) and NIVO 3 mg/kg + IPI 1 mg/kg (NIVO 3 + IPI 1) in patients with metastatic and unresectable melanoma using matching-adjusted indirect comparisons (MAICs).

Materials and methods. A systematic literature review was performed in Embase and PubMed databases. Three phase III randomized controlled trials (RCTs) were included: OCTAVA (PROLGO+NURU, n=135), CheckMate 067 (NIVO 1 mg/kg + IPI 3 mg/kg, n=314), and CheckMate 511 (two regimens: NIVO 1 mg/kg + IPI 3 mg/kg, n=178; NIVO 3 mg/kg + IPI 1 mg/kg, n=180). Individual patient data (IPD) on outcomes and baseline characteristics for PROLGO+NURU were obtained from the OCTAVA trial. For the NIVO + IPI arms, IPD on overall survival (OS) and progression-free survival (PFS) were reconstructed using Guyot’s algorithm from the published Kaplan–Meier curves, and aggregated baseline-characteristic data were extracted. Pairwise unanchored MAICs were performed, weighting on key prognostic factors and effect modifiers: baseline lactate dehydrogenase levels, TNM-defined presence of distant metastasis (M-stage), Eastern Cooperative Oncology Group (ECOG) performance status, BRAF-mutation status, PD-L1 expression <5%, age, and sum of longest diameters of target lesions. To address partial population non-overlap – specifically, the absence of mucosal melanoma and of asymptomatic central-nervous-system metastases (after local control) in OCTAVA – a simulation-based modelling was applied. Efficacy outcomes were analyzed with Cox proportional-hazards regression, and safety outcomes with logistic regression.

Results. OS was statistically significantly higher in the PROLGO+NURU arm than in either NIVO 1 + IPI 3 or NIVO 3 + IPI 1 arms: hazard ratio (HR) 0.69 (95% CI 0.47–0.96; p=0.026) in the CheckMate 067 population, HR 0.64 (0.42–0.91; p=0.011) and HR 0.63 (0.41–0.89; p=0.008) – in the CheckMate 511 population versus NIVO 1 + IPI 3 and NIVO 3 + IPI 1 regimens, respectively. Differences in PFS were statistically insignificant. The PROLGO+NURU regimen also demonstrated a more favorable safety profile, with a lower incidence of treatment-related adverse events, including Grade 3–4 events and events led to treatment discontinuation.

Conclusion. MAICs results showed that the PROLGO+NURU regimen achieved statistically significant superiority in OS compared with the approved NIVO+IPI regimens in Russia (as of 2025). The PROLGO+NURU combination also displayed a more favorable safety profile, with fewer treatment-related adverse events, including Grade 3–4 events and events led to treatment discontinuation. It should be emphasized that the comparison is indirect and the horizon of the comparison was limited (by about 50 months in CheckMate 511 population and 65 months in CheckMate 067 population). Consequently, the findings should be interpreted cautiously. Further updates incorporating data for the longer follow-up, including real-world data, are recommended.