The addition of pembrolizumab (Keytruda) to chemotherapy with or without bevacizumab (Avastin) resulted in significantly and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) in women with cervical cancer. The significant benefit occurred in all protocol-specified primary analysis populations and key subgroups in the phase 3 KEYNOTE-826 clinical trial, said Krishnansu Sujata Tewari, MD, Director, Division of Gynecologic Oncology, Obstetrics & Gynecology, University of California, Irvine, during a presentation at the 2022 American Society of Clinical Oncology Annual Meeting.
“These results provide further support for pembrolizumab plus chemotherapy, with or without bevacizumab, as a new standard of care for women with persistent, recurrent, or metastatic cervical cancer,” said Dr Tewari.
At a median follow-up of 22 months, pembrolizumab plus chemotherapy prolonged PFS and OS versus placebo and chemotherapy in all subgroups defined by bevacizumab use, histology, platinum use, and previous chemoradiation therapy (CRT) evaluated in the all-comer population, with a benefit similar to that in the broader KEYNOTE-826 population, he said. The primary results from KEYNOTE-826 showed an improvement in median OS from 16.5 months to 24.4 months with the addition of pembrolizumab to chemotherapy with or without bevacizumab (hazard ratio [HR], 0.67; P <.001) and an improvement in median PFS from 8.2 to 10.4 months (HR, 0.65; P <.001).
KEYNOTE-826 was a randomized, double-blind study evaluating pembrolizumab in combination with platinum-based chemotherapy (paclitaxel [Taxol] plus cisplatin or paclitaxel plus carboplatin) with or without bevacizumab compared with placebo in combination with the same platinum-based chemotherapy regimens with or without bevacizumab as first-line treatment. The trial enrolled 617 women with persistent, recurrent, or metastatic squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix who had not been treated with systemic chemotherapy and who were no longer amenable to curative treatment (ie, surgery and/or radiation).
Patients were randomized to receive 200 mg of pembrolizumab once every 3 weeks for up to 35 cycles and paclitaxel plus cisplatin or carboplatin once every 3 weeks, with or without 15 mg/kg of bevacizumab once every 3 weeks, or placebo once every 3 weeks and paclitaxel plus cisplatin or carboplatin once every 3 weeks, with or without 15 mg/kg of bevacizumab once every 3 weeks.
The median follow-up was 22 months at the data cut-off of May 3, 2021. In all subgroups of the population, the use of pembrolizumab with chemotherapy and bevacizumab resulted in longer PFS and OS when compared with placebo.
In the subgroup of patients who received bevacizumab, the median PFS was 15.2 months with pembrolizumab versus 10.2 months with placebo (HR, 0.61; 95% confidence interval [CI], 0.47-0.79) and median OS was not reached versus 24.7 months, respectively (HR, 0.63; 95% CI, 0.47-0.87). In those who did not receive bevacizumab, median PFS was 6.3 months with pembrolizumab versus 6.2 months with placebo (HR, 0.74; 95% CI, 0.54-1.01) and median OS was 16.8 months versus 12.6 months, respectively (HR, 0.74; 95% CI, 0.53-1.04).
In the subgroup of patients with squamous histology, median PFS was 10.4 months with pembrolizumab versus 6.9 months with placebo (HR, 0.63; 95% CI, 0.50-0.80) and median OS was 23.5 months versus 14.2 months, respectively (HR, 0.61; 95% CI, 0.47-0.80). In patients with nonsquamous histology, median PFS was 11.6 months with pembrolizumab versus 8.4 months with placebo (HR, 0.66; 95% CI, 0.43-1.00) and median OS was not reached versus 21.3 months, respectively (HR, 0.76; 95% CI, 0.47-1.23).
In the subgroup of patients who received carboplatin, median PFS was 10.2 months versus 7.4 months with placebo (HR, 0.69; 95% CI, 0.55-0.86) and median OS was 21.4 months versus 15.9 months (HR, 0.69; 95% CI, 0.54-0.89). In patients who received cisplatin, the median PFS with pembrolizumab was 15.2 months versus 8.4 months (HR, 0.47; 95% CI, 0.28-0.77) and median OS was not reached versus 21.3 months, respectively (HR, 0.59; 95% CI, 0.32-1.09).
Among patients who received previous CRT, the median PFS was 10.3 months with pembrolizumab versus 6.3 months with placebo (HR, 0.62; 95% CI, 0.45-0.86) and median OS was 21.3 months versus 12.6 months, respectively (HR, 0.64; 95% CI, 0.45-0.91).
Discussant Ritu Salani, MD, MBA, Director, Gynecologic Oncology, and Professor, Obstetrics and Gynecology, University of California, Los Angeles, noted the superior outcomes with the addition of pembrolizumab in groups with squamous-cell carcinoma and in those with adenocarcinoma. “I think this helps us understand that immunotherapy can play a role regardless of the histologic type,” she said.
Dr Salani questioned whether bevacizumab should be withheld in patients with previous CRT based on the 14.5% rate of fistula in patients receiving bevacizumab in the GOG 240 study, all of which occurred in the CRT group. The fistula rate was not reported in KEYNOTE-826.
She also pointed to the limited access to bevacizumab in the study. “I will not argue that the 4-drug regimen has the best outcome, but as [Dr Tewari] highlighted, some places did not give bevacizumab because there was no access to it, and access to pembrolizumab is going to be challenging,” Dr Salani said. “Even in places where cervical cancer is highest, access to chemotherapy will be a challenge. There are some cost associations along with that, even in places that do have access.”