Pembrolizumab plus chemotherapy for persistent, recurrent, or metastatic cervical cancer
The Keynote-826 trial was designed to assess whether adding pembrolizumab to platinum-based chemotherapy with or without bevacizumab could improve efficacy as compared to chemotherapy with or without bevacizumab as first-line therapy for persistent, recurrent, or metastatic cervical cancer. Results demonstrated that in this patient population both progression-free and overall survival were significantly longer with pembrolizumab than with placebo.
To date, standard treatment for persistent, recurrent, or metastatic cervical cancer is platinum-based chemotherapy. However, also the PD-1 inhibitors pembrolizumab and cemiplimab have shown efficacy as monotherapy in previously treated patients with cervical cancer. Thus far, no data for the addition of PD-1 inhibitors to chemotherapy with or without bevacizumab are available.
Keynote-826
Keynote-826 is a double-blind, phase III trial that randomly assigned patients with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy and, per investigator discretion, bevacizumab. Enrolled patients were not amenable to curative treatment and could not have received prior systemic chemotherapy (prior radiotherapy and chemoradiotherapy were permitted). The dual primary endpoints of the trial were progression-free survival (PFS) and overall survival (OS), each tested sequentially in patients with a PD-L1 combined positive score of 1 or more (PD-L1 CPS ≥1), in the intention-to-treat population, and in patients with a PD-L1 combined positive score of 10 or more (PD-L1 CPS ≥10).
Results
Baseline demographic and disease characteristics were generally well balanced between trial groups in all analysis populations. Bevacizumab was used by 63.6% of the patients in the pembrolizumab group and 62.5% of those in the placebo group. Overall, 72.3% of the patients had squamous-cell carcinoma and 19.8% had previously untreated metastatic disease at trial entry. Among the 548 patients with a PD-L1 CPS ≥1, a median PFS of 10.4 months was seen in the pembrolizumab group as compared to 8.2 months with placebo (HR[95%CI]: 0.62[0.50-0.77], p< 0.001). For the 617 patients in the intention-to-treat population, a median PFS of 10.4 and 8.2 months were reported, respectively (HR[95%CI]: 0.65[0.53-0.79], p< 0.001). In the 317 patients with a PD-L1 CPS ≥10, the corresponding median PFS was 10.4 months and 8.1 months, respectively (HR[95%CI]: 0.58[0.44-0.77], p< 0.001). In addition, also the percentage of patients who were alive without disease progression at 12 months favoured pembrolizumab in all populations. Overall survival at 24 months was 53.0% in the pembrolizumab group and 41.7% in the placebo group (HR[95%CI]: 0.64[0.50-0.81], p< 0.001), 50.4% and 40.4% (HR[95%CI]: 0.67[0.54-0.84], p< 0.001), and 54.4% and 44.6% (HR[95%CI]: 0.61[0.44-0.84], p= 0.001), respectively. The median overall survival was not reached in either PD-L1–selected population for pembrolizumab, it was 24.4 months in the intention-to-treat population for pembrolizumab, and it ranged from 16.3 to 16.5 months for placebo. The benefit of adding pembrolizumab to chemotherapy was generally consistent across all protocol-specified subgroups, including the with and without bevacizumab subgroups.
The percentage of patients with a confirmed response according to investigator review was higher in the pembrolizumab group than in the placebo group among those with a PD-L1 CPS ≥1 (68.1% vs. 50.2%), among those in the intention-to-treat population (65.9% vs. 50.8%), and among those with a PD-L1 CPS ≥10 (69.6% vs. 49.1%). More complete responses were noted in the pembrolizumab group than in the placebo group. Also the duration of response was longer with the addition of pembrolizumab (18.0 vs. 10.4 months, 18.0 vs. 10.4 months and 21.1 vs. 9.4 months for the PD-L1 ≥1, all comer and PD-L1 ≥10 subgroups, respectively). The median treatment duration was 10.0 months in the pembrolizumab group and 7.7 months in the placebo group. Grade 3 to 5 adverse events occurred in 81.8% of patients in the pembrolizumab group and in 75.1% of patients in the placebo group. The most common grade 3 to 5 adverse events were anaemia (30.3% in the pembrolizumab group and 26.9% in the placebo group) and neutropenia (12.4% and 9.7%, respectively). Potentially immune-mediated adverse events occurred in 33.9% of the patients in the pembrolizumab group and in 15.2% of those in the placebo group, including in 11.4% and 2.9%, respectively, who had grade 3 to 5 events. Finally, time to deterioration in the EQ-5D-5L VAS score was longer with pembrolizumab than with placebo (12-month estimate of patients free from deterioration, 58.2% vs. 44.8% (HR[95%CI]: 0.75[0.58-0.97]).
Conclusion
Adding pembrolizumab to chemotherapy with or without bevacizumab induces a statistically significant and clinically meaningful OS and PFS improvement in women with persistent, recurrent, or metastatic cervical cancer. In addition, the safety profile for this combination regimen was manageable. Therefore, pembrolizumab plus chemotherapy with or without bevacizumab may be a new standard of care for women with persistent, recurrent or metastatic cervical cancer.
Reference
Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study. Presented at ESMO 2021; Abstract LBA2_PR.
