The Benefit and Risk of Addition of PD-1/PD-L1 Inhibitors to Chemotherapy for Advanced Cervical Cancer: a Phase 3 Randomized Controlled Trials Based Meta-analysis

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2025 Mar 13

PMID 40075324

Authors

Deping Luo

Ying Yu

Qi Wang

Tao Peng

Chan Li

Wenxiong Zhang

Jing Huang

Affiliations

Soon will be listed here.

Abstract

Background: Chemotherapy has been confirmed as an effective treatment for advanced cervical cancer. However, whether combining PD-1/PD-L1 inhibitors with chemotherapy (PIC) offers superior efficacy remains a subject of debate. This meta-analysis aims to compare the antitumor effects and safety profile of PIC versus chemotherapy.

Methods: We conducted a comprehensive search across six databases to identify eligible randomized controlled trials (RCTs). The primary outcomes assessed were overall survival (OS) and progression-free survival (PFS), while the secondary endpoints included response rates and adverse events (AEs).

Results: Four RCTs (BEATcc, CALLA, KEYNOTE-826, and KEYNOTE-A18) analyzing 2,857 patients were included. The PIC regimen notably enhanced OS (hazard ratio [HR]: 0.70 [0.61, 0.80], P < 0.00001), PFS (HR: 0.69 [0.61, 0.77], P < 0.00001), objective response rate (ORR) (risk ratio [RR]: 1.11 [1.02, 1.22], P = 0.02), and disease control rate (DCR) (RR: 1.05 [1.01, 1.08], P = 0.004). Improvements in OS and PFS for the PIC group were evident across nearly all subgroups. Moreover, the survival benefit for the PIC group increased with longer patient survival and elevated PD-L1 expression. The PIC group encountered higher rates of grade 3-5 AEs, and serious AEs. The top 5 grade 3-5 AEs were anemia (19.47%), hypertension (12.65%), decreased white blood cell count (11.76%), decreased neutrophil count (11.38%), and neutropenia (10.99%).

Conclusions: The PIC regimen appears superior to chemotherapy alone for advanced cervical cancer (metastatic/recurrent or locally advanced), demonstrating improved survival and response rates. However, the associated increase in AEs warrants careful consideration in its clinical application.

References

Oaknin A, Gladieff L, Martinez-Garcia J, Villacampa G, Takekuma M, De Giorgi U . Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2023; 403(10421):31-43. DOI: 10.1016/S0140-6736(23)02405-4. View

Jadad A, Moore R, Carroll D, Jenkinson C, Reynolds D, Gavaghan D . Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996; 17(1):1-12. DOI: 10.1016/0197-2456(95)00134-4. View

Rodrigues M, Vanoni G, Loap P, Dubot C, Timperi E, Minsat M . Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial. Nat Commun. 2023; 14(1):3698. PMC: 10287640. DOI: 10.1038/s41467-023-39383-8. View

Yang S, Wang P, Liu H, Chang C, Chang W, Lee W . Cervical cancer: Part II the landscape of treatment for persistent, recurrent and metastatic diseases (I). Taiwan J Obstet Gynecol. 2024; 63(5):637-650. DOI: 10.1016/j.tjog.2024.08.001. View

Manso L, Ramchandani-Vaswani A, Romero I, Sanchez-Lorenzo L, Bermejo-Perez M, Estevez-Garcia P . SEOM-GEICO Clinical Guidelines on cervical cancer (2023). Clin Transl Oncol. 2024; 26(11):2771-2782. PMC: 11466906. DOI: 10.1007/s12094-024-03604-3. View

Siegel R, Giaquinto A, Jemal A . Cancer statistics, 2024. CA Cancer J Clin. 2024; 74(1):12-49. DOI: 10.3322/caac.21820. View

Wang Y, Zhang Y, Liang X, Liu J, Zhao Y, Su Q . The Impact of Frailty on the Toxic Reaction of Chemotherapy in Patients With Cervical Cancer: A Longitudinal Study. Cancer Nurs. 2024; . DOI: 10.1097/NCC.0000000000001404. View

Sun T, Li M, Zhang Z, Wang J, Xing Y, Ri M . Usnic acid suppresses cervical cancer cell proliferation by inhibiting PD-L1 expression and enhancing T-lymphocyte tumor-killing activity. Phytother Res. 2021; 35(7):3916-3935. DOI: 10.1002/ptr.7103. View

Liang Y, Wang W, Zhu X, Yu M, Zhou C . Inhibition of myeloid-derived suppressive cell function with all-trans retinoic acid enhanced anti-PD-L1 efficacy in cervical cancer. Sci Rep. 2022; 12(1):9619. PMC: 9187659. DOI: 10.1038/s41598-022-13855-1. View

10.

Higgins J, Altman D, Gotzsche P, Juni P, Moher D, Oxman A . The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. PMC: 3196245. DOI: 10.1136/bmj.d5928. View

11.

Tuninetti V, Virano E, Salutari V, Ricotti A, Pisano C, Ducceschi M . Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study. Eur J Cancer. 2024; 203:114039. DOI: 10.1016/j.ejca.2024.114039. View

12.

Nishio S, Yonemori K, Usami T, Minobe S, Yunokawa M, Iwata T . Pembrolizumab plus chemotherapy in Japanese patients with persistent, recurrent or metastatic cervical cancer: Results from KEYNOTE-826. Cancer Sci. 2022; 113(11):3877-3887. PMC: 9633308. DOI: 10.1111/cas.15479. View

13.

Wang Z, Wang B, Feng Y, Ye J, Mao Z, Zhang T . Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer. J Immunother Cancer. 2024; 12(8). PMC: 11308911. DOI: 10.1136/jitc-2024-009024. View

14.

Tewari K, Colombo N, Monk B, Dubot C, Caceres M, Hasegawa K . Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer: Subgroup Analyses From the KEYNOTE-826 Randomized Clinical Trial. JAMA Oncol. 2023; 10(2):185-192. PMC: 10722390. DOI: 10.1001/jamaoncol.2023.5410. View

15.

Feng X, Meng X, Tang D, Guo S, Liao Q, Chen J . Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer. Cancer Pathog Ther. 2024; 2(1):38-49. PMC: 10846320. DOI: 10.1016/j.cpt.2023.07.003. View

16.

Wang Y, Wang J, Du J, Tang X, Xiao J . Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review. Front Immunol. 2024; 15:1305810. PMC: 10847356. DOI: 10.3389/fimmu.2024.1305810. View

17.

Oaknin A, Monk B, Vergote I, de Melo A, Kim Y, Lisyanskaya A . EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022; 174:299-309. DOI: 10.1016/j.ejca.2022.03.016. View

18.

Monk B, Tewari K, Dubot C, Caceres M, Hasegawa K, Shapira-Frommer R . Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023; 24(4):392-402. DOI: 10.1016/S1470-2045(23)00052-9. View

19.

Wu Y, Jiang P, Chen Z, Li W, Dong B, Zhang Y . Efficacy and safety of different chemotherapy regimens concurrent with radiotherapy in the treatment of locally advanced cervical cancer. BMC Cancer. 2024; 24(1):589. PMC: 11094845. DOI: 10.1186/s12885-024-12358-8. View

20.

Abu-Rustum N, Yashar C, Arend R, Barber E, Bradley K, Brooks R . NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024. J Natl Compr Canc Netw. 2023; 21(12):1224-1233. DOI: 10.6004/jnccn.2023.0062. View