Pembrolizumab Combo Practice-Changing in Advanced Cervical Cancer

The standard of care first-line therapy for persistent, recurrent, or metastatic cervical cancer is platinum-based chemotherapy ± bevacizumab. Although the addition of bevacizumab to platinum-based first-line chemotherapy has led to survival improvement (GOG 240), the prognosis for advanced cervical cancer remains poor, and there is a high unmet need for better therapies. Recently, immunotherapy with programmed cell death protein 1 (PD-1) inhibitors pembrolizumab (KEYNOTE-158 study) and cemiplimab (EMPOWER-Cervical 1) has shown impressive efficacy as monotherapy in previously treated advanced cervical cancer. The role of immunotherapy is currently being evaluated in multiple ongoing trials in the front-line setting.

At the 2021 ESMO Congress, Dr Nicoletta Colombo (European Institute of Oncology IRCCS and University of Milan-Bicocca, Milan, Italy) presented results from the first interim analysis of the double-blind, randomized, phase III KEYNOTE-826 trial, which evaluated the efficacy and safety of first-line pembrolizumab in combination with chemotherapy ± bevacizumab in cervical cancer. The results were published simultaneously in the New England Journal of Medicine. The trial enrolled 617 patients with advanced cervical cancer, who were randomized to receive either pembrolizumab or placebo, in addition to platinum-based chemotherapy ± bevacizumab (given at the investigator’s discretion). Patients were stratified according to planned bevacizumab therapy, metastatic disease at diagnosis, and PD-L1 combined positive score (CPS). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS). The median follow-up was 22 months.

At primary analysis, the superiority of adding pembrolizumab to chemotherapy ± bevacizumab for PFS and OS were tested sequentially in the CPS ≥1, intention to treat (ITT), and CPS ≥10 populations. Of note, 89% of patients had PD-L1-positive tumors, including approximately 50% with a CPS of ≥10. The addition of pembrolizumab to chemotherapy ± bevacizumab significantly improved PFS for all populations: patients with PD-L1 CPS ≥1 had a median PFS (mPFS) of 10.4 months in the pembrolizumab arm vs 8.2 months in the placebo arm (HR, 0.62; P<0.001); for the ITT population, mPFS was 10.4 months vs 8.2 months (HR, 0.65; P<0.001); and for those with CPS ≥10, mPFS was 10.4 months vs 8.1 months (HR, 0.58; P<0.001), respectively. Likewise, the addition of pembrolizumab significantly improved OS compared with placebo in all biomarker populations: for PD-L1 CPS ≥1, median OS (mOS) was not reached (NR) with pembrolizumab vs 16.3 months with placebo (HR, 0.64; P<0.001); for the ITT population, the mOS was 24.4 months vs 16.5 months (HR, 0.67; P<0.001); and for CPS ≥10 population, mOS was NR vs 16.4 months (HR, 0.61; P=0.001), respectively. The benefit of pembrolizumab for both PFS and OS was clear and generally consistent across all pre-specified subgroups, including those who received chemotherapy with or without bevacizumab. The addition of pembrolizumab to chemotherapy ± bevacizumab was also associated with higher objective response rates (ORR) that ranged from 66-70% (complete response [CR] 21-23%) in the pembrolizumab arm versus 49-51% (CR 11-13%) in the placebo arm. In addition, the median duration of response was approximately twice as long in the pembrolizumab arm. The safety profile of the pembrolizumab combination was manageable. Treatment-related adverse events (TRAEs) grade ≥3 were 68.4% in the pembrolizumab arm and 64.1% in the placebo arm. As expected, immune-mediated AEs were higher with pembrolizumab combination (33.9% vs 15.2%), and the most common were hypo- and hyper-thyroidism. Approximately one-third of patients in the pembrolizumab arm discontinued treatment due to TRAEs (31.3% vs 22.3%). TRAEs led to 2 deaths in the pembrolizumab arm and 4 deaths in the placebo arm. Importantly, the time to deterioration in the quality-of-life score was also significantly improved with addition of pembrolizumab (HR, 0.75).

Dr Colombo concluded that these results support the use of pembrolizumab combined with chemotherapy ± bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. A discussant of the trial, Dr Mansoor Raza Mirza (Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark), congratulated the investigators for the ‘’groundbreaking‘’ and “practice-changing” results. However, he also pointed out several questions that need to be answered in the future, including whether the combination of pembrolizumab with chemotherapy is effective in primary metastatic disease, in PD-L1-negative patients, in adenocarcinoma, and when given without bevacizumab.

Colombo N, et al. ESMO 2021; Abstract LBA2.
Colombo N, et al. N Engl J Med. 2021 Sep 18 [Online ahead of print].