Background
Phase III, open-label RCT (KEYNOTE-204). 304 patients with relapsed or refractory classical Hodgkin lymphoma who had failed at least one prior line of therapy, were ineligible for ASCT, or had relapsed after ASCT. Patients with prior PD-1 blockade or prior BV were excluded. Stratified by ASCT status and disease response status.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV q3w (n=151)
Arm B: Brentuximab vedotin (BV) 1.8 mg/kg IV q3w (n=153)
Primary endpoint: PFS (investigator-assessed, ITT)
Median follow up: 24.9 months
Arm B: Brentuximab vedotin (BV) 1.8 mg/kg IV q3w (n=153)
Primary endpoint: PFS (investigator-assessed, ITT)
Median follow up: 24.9 months
Results
Median PFS (pembro vs. BV): 13.2 months vs. 8.3 months, HR 0.65 (95% CI 0.48–0.88), P=.0027
ORR (pembro vs. BV): 65.6% vs. 54.2%
CR rate (pembro vs. BV): 24.5% vs. 24.2% — comparable
OS: HR 1.16 (95% CI 0.76–1.79) — no significant difference
ORR (pembro vs. BV): 65.6% vs. 54.2%
CR rate (pembro vs. BV): 24.5% vs. 24.2% — comparable
OS: HR 1.16 (95% CI 0.76–1.79) — no significant difference
Adverse events
Pembrolizumab: grade ≥3 AEs 19.8%; immune-mediated AEs any grade 29.5% (hypothyroidism 13%, pneumonitis 4.9%, colitis 3.3%); discontinuations 13.4%
BV: grade ≥3 AEs 25.0%; peripheral neuropathy any grade 36%, grade ≥3 neuropathy 6.5%; neutropenia grade ≥3 14.5%
Deaths: treatment-related deaths 2 (pembrolizumab) vs. 1 (BV)
BV: grade ≥3 AEs 25.0%; peripheral neuropathy any grade 36%, grade ≥3 neuropathy 6.5%; neutropenia grade ≥3 14.5%
Deaths: treatment-related deaths 2 (pembrolizumab) vs. 1 (BV)
Conclusions
Pembrolizumab significantly improved PFS compared to brentuximab vedotin in R/R cHL (median 13.2 vs. 8.3 months; HR 0.65), establishing pembrolizumab as the preferred single-agent therapy for R/R cHL when PD-1 inhibitors have not been previously used. No significant OS difference was observed.
Key Limitations
No OS benefit despite superior PFS suggests effective cross-over salvage after progression, or that PFS improvement does not translate to survival advantage in this context. The trial population was heterogeneous (post-ASCT and ASCT-ineligible patients), limiting subgroup conclusions. CR rates were comparable between arms, so the PFS benefit reflects longer PR/stable disease duration rather than deeper responses. In the current era, pembrolizumab is primarily used as second-line monotherapy in the salvage-to-transplant pathway, where pembro-GVD combinations achieve high CR rates — making this monotherapy comparison somewhat less relevant for transplant-eligible patients.
Clinical Context
KEYNOTE-204 established pembrolizumab as preferred over BV for R/R cHL. However, the field has evolved beyond single-agent pembrolizumab: BV+nivolumab (Advani 2021, 85% ORR, 67% CR) and pembro-GVD (Moskowitz 2021, high CR rate, high ASCT bridge rate) are now preferred at major centers for transplant-eligible patients. Single-agent pembrolizumab is primarily used in patients ineligible for intensive salvage or as an intermediate step while planning transplant.