Final OS Analysis Confirms Benefit of Pembrolizumab/Chemotherapy With or Without Bevacizumab in Frontline Cervical Cancer

Bradley J. Monk, MD, FACS, FACOG

The final overall survival analysis of KEYNOTE-826 (NCT03635567) demonstrated the benefit of pembrolizumab (Keytruda) in combination with chemotherapy with or without the addition of bevacizumab (Avastin) vs placebo for patients with persistent, recurrent, or metastatic cervical cancer.^1,2 The data were presented in a press briefing ahead of the 2023 ASCO Annual Meeting.

At a median follow-up of 39.1 months, patients in the pembrolizumab arm (n = 308) experienced a median OS of 26.4 months (95% CI, 21.3-32.5) compared with 16.8 months (95% CI, 14.6-19.4) for those in the placebo arm (n = 309; HR, 0.63; 95% CI, 0.52-0.77; nominal P < .0001). The 12- and 24-month OS rates in the pembrolizumab group were 74.9% (95% CI, 69.7%-79.4%) and 52.1% (95% CI, 46.4%-57.5%), respectively. In the placebo group, those rates were 63.7% (95% CI, 58.1%-68.8%) and 38.7% (95% CI, 33.2%-44.1%), respectively.

Notably, 88.8% of enrolled patients had a PD-L1 combined positive score CPS of at least 1. Among this subgroup, pembrolizumab plus chemotherapy with or without bevacizumab elicited a median OS of 28.6 months (95% CI, 22.1-38.0) vs 16.5 months (95% CI, 14.5-20.0) for placebo plus chemotherapy with or without bevacizumab (HR, 0.60; 95% CI, 0.49-0.74; nominal P < .0001).

The 12- and 24-month OS rates for patients with a PD-L1 CPS of at least 1 in the pembrolizumab arm were 75.5% (95% CI, 69.9%-80.1%) and 53.5% (95% CI, 47.4%-59.2%), respectively. Those rates were 63.2% (95% CI, 57.2%-68.6%) and 39.4% (95% CI, 33.6%-45.2%), respectively, in patients with a PD-L1 CPS of at least 1 treated with the placebo regimen.

“Before KEYNOTE-826, the standard of care was a platinum-based paclitaxel chemotherapy combination with or without bevacizumab treatment for people with this diagnosis,” lead study author Bradley J. Monk, MD, FACS, FACOG, a professor in the Division of Gynecologic Oncology at Creighton University School of Medicine, HonorHealth Research Institute in Phoenix, Arizona, stated in a news release. “This study demonstrates that giving immunotherapy earlier provides a substantial OS benefit compared with the second-line setting. Our results also show a survival benefit of pembrolizumab in patients who are not eligible for bevacizumab, offering a therapeutic option in this population of patients with a high unmet need.”

In October 2021, the FDA approved pembrolizumab for use in combination with chemotherapy, with or without bevacizumab, in patients with persistent, recurrent, or metastatic cervical cancer whose tumors have a PD-L1 CPS of 1 or higher, as determined by an FDA-approved test, based on prior data from KEYNOTE-826.3

The randomized, double-blind trial enrolled patients with persistent, recurrent, or metastatic cervical cancer that was not amenable to curative treatment. No prior systemic chemotherapy was permitted, although previous radiotherapy or chemoradiotherapy was allowed. Patients also needed to have an ECOG performance status of 0 or 1.1,2

Patients were randomly assigned 1:1 to receive 200 mg of intravenous pembrolizumab or matching placebo once every 3 weeks for up to 35 cycles in combination with chemotherapy with or without bevacizumab.

Chemotherapy in both arms consisted of 175 mg/m2 of paclitaxel plus 50 mg/m2 of cisplatin or area under the curve 5 of carboplatin once every 3 weeks for up to 6 cycles. Patients who received bevacizumab were given 15 mg/kg doses once every 3 weeks.

Stratification factors included metastatic disease at diagnosis (yes vs no), PD-L1 CPS (<1 vs 1 to <10 vs ≥10), and planned bevacizumab use (yes vs no).

Investigator-assessed OS and PFS per RECIST v1.1 criteria served as the trial’s co-primary end points. Secondary end points included overall response rate, duration of response, 12-month PFS rate, and safety.

Additional data showed that the pembrolizumab regimen also produced an OS benefit vs the placebo regimen in patients with a PD-L1 CPS of at least 10 (HR, 0.58). In this subgroup, the pembrolizumab regimen generated a median OS of 29.6 months compared with 17.4 months for the placebo regimen.

The final analysis also demonstrated that pembrolizumab plus chemotherapy with or without bevacizumab elicited a PFS benefit in the all-comer population (10.4 months vs 8.2 months; HR, 0.61), the PD-L1 CPS of at least 1 subgroup (HR, 0.58), and PD-L1 CPS of at least 10 subgroup (HR, 0.52). Survival benefits were observed in the subgroups of patients who did and did not receive bevacizumab.

The pembrolizumab regimen also led to a higher ORR and longer DOR compared with the placebo regimen.

Regarding safety, pembrolizumab plus chemotherapy with or without bevacizumab was manageable, and adverse effects (AEs) were consistent with the known toxicity profiles of the individual agents. Long-term follow-up did not reveal any new safety signals.

In the pembrolizumab group, 82.4% of patients experienced grade 3 or higher AEs compared with 75.4% of patients in the placebo group. The most common grade 3 or higher AEs in the pembrolizumab group vs the placebo arm included anemia (30.3% vs 27.8%), neutropenia (12.4% vs 9.7%), and hypertension (10.4% vs 11.7%).

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” Merry Jennifer Markham, MD, FACP, FASCO, a professor of medicine in the Division of Hematology and Oncology in the Department of Medicine and associate director for medical affairs at the University of Florida Health Cancer Center, said in a news release.3

References

1. Monk BJ, Colombo N, Tewari K, et al. Pembrolizumab + chemotherapy versus placebo + chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. J Clin Oncol. 2023;41(suppl 16):5500. doi:10.1200/JCO.2023.41.16_suppl.5500
2. Adding pembrolizumab to chemotherapy improves survival in people with advanced cervical cancer. News release. ASCO. May 25, 2023. Accessed May 25, 2023. https://old-prod.asco.org/about-asco/press-center/news-releases/adding-pembrolizumab-chemotherapy-improves-survival-people
3. FDA approves pembrolizumab combination for the first-line treatment of cervical cancer. News release. FDA. October 13, 2021. Accessed May 25, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-combination-first-line-treatment-cervical-cancer