Background
Phase III, double-blind, placebo-controlled RCT. 617 patients with persistent, recurrent, or first-line metastatic cervical cancer with no prior chemotherapy for recurrent/metastatic disease. Patients with PD-L1 CPS ≥1 comprised ~88% of the enrolled population. Randomized 1:1.
Interventions and follow up
Arm A: Pembrolizumab 200 mg q3wk + cisplatin (50 mg/m²) or carboplatin (AUC 5) + paclitaxel (175 mg/m²) q3wk ± bevacizumab (15 mg/kg) × 6 cycles, then pembrolizumab maintenance
Arm B: Placebo + cisplatin or carboplatin + paclitaxel ± bevacizumab
Primary endpoint: PFS and OS in CPS ≥1 population and all-comers
mFollow up: 22 months
Arm B: Placebo + cisplatin or carboplatin + paclitaxel ± bevacizumab
Primary endpoint: PFS and OS in CPS ≥1 population and all-comers
mFollow up: 22 months
Results
mPFS (CPS ≥1): 10.4 vs 8.2 months (Arm A vs Arm B), HR 0.62, P<.001
mOS (CPS ≥1): 24.4 vs 16.5 months, HR 0.64, P<.001
mPFS (all): 10.4 vs 8.2 months, HR 0.65, P<.001
mOS (all): 24.4 vs 16.5 months, HR 0.67, P<.001
mOS (CPS ≥1): 24.4 vs 16.5 months, HR 0.64, P<.001
mPFS (all): 10.4 vs 8.2 months, HR 0.65, P<.001
mOS (all): 24.4 vs 16.5 months, HR 0.67, P<.001
Adverse events
Overall (Arm A vs Arm B): grade ≥3 AEs 81.8% vs 75.1%; bevacizumab-related hypertension and fistula rates similar between arms
Immune-mediated (Arm A vs Arm B): any-grade immune AEs 28.9% vs 14.0%; hypothyroidism 18.7% vs 8.0%; grade ≥3 colitis 2.7% vs 0.3%
Immune-mediated (Arm A vs Arm B): any-grade immune AEs 28.9% vs 14.0%; hypothyroidism 18.7% vs 8.0%; grade ≥3 colitis 2.7% vs 0.3%
Conclusions
Adding pembrolizumab to platinum-paclitaxel ± bevacizumab significantly improved both PFS and OS in persistent/recurrent/metastatic cervical cancer, with a 7.9-month OS benefit in CPS ≥1 patients. This was the first IO regimen to improve OS in cervical cancer.
Key Limitations
Benefit restricted to PD-L1 CPS ≥1 (~88% of patients); only ~12% have CPS <1 and benefit is unclear in this group. Bevacizumab use was optional, and imbalanced subgroups limit interpretation of the bevacizumab interaction. HPV-negative cervical cancer (rare, ~10%) may not benefit similarly. OS was still maturing at 22 months follow-up.
Clinical Context
FDA approved 2021; ESMO-MCBS score: A. Established pembrolizumab + platinum-paclitaxel ± bevacizumab as the new first-line standard of care for persistent/recurrent/metastatic cervical cancer in PD-L1 CPS ≥1, superseding the prior standard of cisplatin-paclitaxel-bevacizumab (GOG-240). BEATcc (atezolizumab) also showed benefit and provides an alternative for PD-L1-unselected patients.
References