Efficacy and safety of nivolumab-based therapies in first-line and Relapsed/Refractory Hodgkin lymphoma

Abstract Introduction: Despite being considered one of the most curable cancers, a sizable percentage of individuals with classic Hodgkin lymphoma (CHL) relapse or do not respond to first-line treatment. The emergence of immune checkpoint inhibitors, particularly nivolumab, an anti-PD-1 monoclonal antibody, has reshaped the therapeutic landscape in both treatment-naive and relapsed/refractory (R/R) settings. Combination regimens involving nivolumab with agents such as brentuximab vedotin (BV), AVD (adriamycin, vinblastine, dacarbazine) combination chemotherapy, and novel immunomodulators have shown promising activity. Despite this, the comparative efficacy and safety profiles of these combination therapies remain unclear. This meta-analysis synthesizes data from randomized controlled trials (RCTs) to assess the safety and effectiveness of n0ivolumab-based treatments in CHL. Methods: A systematic review was conducted following PRISMA guidelines. A comprehensive literature search of PubMed, Google Scholar, and ClinicalTrials.gov was done through July 2025. Randomized and non-randomized observational studies were screened. From 1,014 records initially identified from the bibliographic databases, 24 studies met the inclusion criteria. Studies enrolling patients with newly diagnosed or relapsed/refractory CHL treated with nivolumab, either as monotherapy or in combination with BV, combination chemotherapy, or other immunomodulators, were included. The primary outcomes included overall response rate (ORR), complete response (CR), 1-year, 2-year, and 3-year progression-free survival (PFS), as well as 1- year, 2-year, and 3-year overall survival (OS). Secondary outcomes evaluated were partial response (PR), progressive disease (PD), adverse events (AEs), and serious AEs (SAEs). Pooled proportions were estimated using random-effects models with Freeman-Tukey double arcsine transformation. Heterogeneity was assessed using τ² and I² statistics. Subgroup analyses were performed based on combination regimens, monotherapy, and treatment setting (first-line vs. relapsed/refractory). Results: The pooled analysis included 1,349 patients treated with nivolumab-based regimens across 24 studies. The overall response rate (ORR) across all nivolumab-based regimens was 2.25 [95% CI: 2.09–2.41]. Subgroup analysis by treatment setting showed a significantly higher pooled ORR in the first-line setting (2.71 [2.51–2.92]) compared to the relapsed/refractory (R/R) setting (2.17 [1.99–2.34]) (p < 0.001). Additionally, complete response (CR) rates were greater in the relapsed/refractory setting; among treatment-naïve patients, the pooled CR was 2.28 (95% CI: 2.09–2.47) compared to 2.22 (95% CI: 2.00–2.44). The projected progression-free survival (PFS) at 1 year was 1.96 [1.56–2.36], with no significant difference between first-line (2.07 [95% CI: 1.30–2.84]) and R/R cohorts (1.90 [95% CI: 1.41–2.38]) (p = 0.71). The 2-year and 3-year PFS rates were 1.99 [1.38–2.60] and 1.96 [1.56–2.36], respectively. When compared to nivolumab monotherapy, regimens that combined nivolumab with brentuximab vedotin (BV) or BV plus another drug/chemotherapy had higher PFS. Overall survival (OS) was high across all time points, with 1-year OS: 2.92 [2.43–3.41], 2-year OS: 2.93 [2.55–3.30], and 3-year OS: 2.81 [2.39–3.23], with no significant differences observed between treatment lines. In terms of safety, regimens that combined nivolumab with BV or other drugs had the highest rates of adverse events (AEs), with an incidence of 0.58 [0.42–0.75], with significant heterogeneity. Serious adverse events (SAEs) had a pooled rate of 0.58 [0.41–0.74], with similar rates across first-line and R/R settings (p = 0.71). Moderate to high (I² range: 78–91%) heterogeneity across pooled outcomes reflected variability in patient populations, treatment environments, and regimen composition. Conclusion: In relapsed or refractory CHL, nivolumab-based regimens are highly effective, producing durable responses and favorable survival outcomes, especially when combined with chemotherapy or antibody-drug conjugates such as BV. Although AEs are more common in multi-agent regimens, the safety profile remains acceptable. Nivolumab's role as a salvage or consolidation therapy is supported, given its relatively lower efficacy in the first-line therapeutic context.