Introduction: Relapsed or refractory (r/r) disease is seen in 20-30% patients with classic Hodgkin lymphoma (cHL), where 10-15% of patients with early-stage and 15-30% of patients with advanced-stage cHL will relapse, and 10-15% of all patients with cHL will have primary refractory disease. Management involves platinum/gemcitabine-based chemotherapy, brentuximab vedotin (BV), autologous stem cell transplant (ASCT), or PD-1 inhibitors that have led to improved outcomes in the past decade. PD-1 inhibitors are now indicated for patients with failed ASCT or in transplant-ineligible patients with r/r cHL and are increasingly used in frontline treatment. This systematic review and meta-analysis of clinical trials assesses the most recent evidence of the clinical efficacy and safety of the two most used PD-1 inhibitors: pembrolizumab and nivolumab, with emphasis on single-agent activity (compared to combination therapies) and prior exposure to BV.

Methods: Three major databases (PubMed, EBSCO Host, CENTRAL) were systematically screened for full-text publications in the English language of clinical trials investigating nivolumab or pembrolizumab for the management of patients with an established diagnosis of r/r cHL from inception to July 2025. Two co-authors independently evaluated titles, abstracts, and full-text articles, while discrepancies were resolved by a third co-author based on shared consensus. Pooled data analysis with 95% confidence intervals (CI) assessed complete response rate (CRR), overall response rate (ORR), 2-year overall survival (OS), 2-year progression-free survival (PFS), and grade ≥3 adverse events (AEs). For study heterogeneity, Cochran's Q test (p<0.05) and I² statistic (>50%) were used with a random-effects model (R software).

Results: A total of 15 trials with 19 treatment arms with 1,125 patients (mean age: 34 years old) were identified for the final analysis. Eleven trials included patients with prior exposure to ASCT (35% of all patients), and 13 trials had patients with prior exposure to BV (43% of all patients). Nivolumab and pembrolizumab monotherapies were investigated in 5 and 3 trials, respectively; BV with nivolumab was studied in 2 trials, the rest of the studies evaluated different combinations of immune-chemotherapies (n=2) or different immunotherapies (n=4), such as ipilimumab (±BV) and lirilumab. Consolidation with ASCT was used in 2 trials. With a median follow-up of 27.6 months, ORR was 74% (95%CI, 71-77%, n=17), CRR 40% (95%CI, 36-43%, n=18). Pooled incidence of AEs was 26% (95%CI, 23-29% n=16). Pooled 2-year OS was 89% (95%CI, 85-92%, n=5) and 2-year PFS was 44% (95%CI, 38-49%, n=4). In subgroup analyses, CRR were higher in patients treated with PD1 inhibition with ASCT (86%, 95%CI, 74-89%), BV plus nivolumab (66%, 95%CI, 57-74%), pembrolizumab with chemotherapy (95%CI, 80-95%) compared to pembrolizumab (26%, 95%CI, 22-31%) or nivolumab (95%CI, 27%, 22-32%) monotherapies. Likewise, ORR was better in patients who received BV with nivolumab (86%, 95%CI, 78-91%) and pembrolizumab with chemotherapy (98%, 95%CI, 90-100%) compared to those treated with pembrolizumab (68%, 95%CI, 63-73%) or nivolumab (74%, 95%CI, 69-78%) monotherapies. However, AEs were less common in pembrolizumab (95%CI, 16%, 13-20%) and nivolumab (22%, 95%CI, 18-27%) monotherapies compared to PD1 inhibitors with ASCT (48%, 95%CI, 38-58%) and pembrolizumab with chemotherapy (42%, 95%CI, 32-54%). No significant differences were seen in efficacy and safety between nivolumab and pembrolizumab monotherapies or between different combination therapies. Patients with prior exposure to BV had worse CRR (23%, 95%CI, 20-27% vs 54%, 95%CI, 48-60%) and 2-year PFS (36%, 95%CI, 31-42% vs 78%, 95%CI, 67-86%) compared to those without any exposure.

Conclusions: This meta-analysis confirms that both pembrolizumab and nivolumab in the treatment of r/r cHL similarly improve clinical outcomes with an acceptable safety profile. As the treatment landscape of r/r cHL evolves and with the introduction of PD-1 inhibitors in the frontline setting, the efficacy of these agents in combination with other treatment modalities, including emerging immunotherapeutic agents, should be investigated. Patients with multiple comorbidities, prior immunotherapy, the elderly, and HIV-associated HL are of special interest. The role of PD-1 inhibitors before and after ASCT should also be studied.

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2025
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