Combined pembrolizumab and bevacizumab therapy in heavily treated recurrent ovarian cancer

Background: Recurrence in epithelial ovarian cancer (EOC), especially in the late stage, remains a significant challenge, with a five-year survival rate of approximately 40% in advanced-stage disease. A recent phase 2 trial evaluating the combination of pembrolizumab, bevacizumab and oral cyclophosphamide in recurrent EOC demonstrated an objective response rate (ORR) of 47.5%. However, severe adverse events, primarily attributed to cyclophosphamide, were observed in 32.5% of patients. Methods: This retrospective study reviewed the therapeutic response and adverse effects in EOC patients who had received two to three prior lines of chemotherapy and were subsequently treated with pembrolizumab and bevacizumab between 2018 and 2021. Their response rates were assessed using the Gynecological Cancer Intergroup (GCIG) criteria based on serum cancer antigen 125 (CA-125) levels (categorized as response with normalization, response, non-response or progression) or the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) if baseline CA-125 levels were within the normal range. Results: A total of 12 patients were included, comprising six (50.0%) with high-grade serous carcinoma, three (25.0%) with clear cell carcinoma, one (8.3%) with mucinous carcinoma, one (8.3%) with endometrioid carcinoma, and one (8.3%) with mixed histology. Among them, one patient (8.3%) exhibited a response with normalization of CA-125, four (33.3%) demonstrated a response, four (33.3%) showed no response, and three (25.0%) experienced disease progression. The ORR was 41.7%, with a higher response rate observed in clear cell carcinoma (66.7%), including the patient with response and CA-125 normalization. Notably, no severe adverse effects were reported during treatment. Conclusions: This study differs from prior trials incorporating cyclophosphamide by evaluating pembrolizumab and bevacizumab as a two-drug regimen, potentially offering a less toxic alternative for recurrent ovarian cancer. However, the retrospective design and small sample size necessitate cautious interpretations of the findings, and larger prospective trials are warranted to further investigate the efficacy of this combination.

Epithelial ovarian cancer; Ovarian clear cell carcinoma; Angiogenesis inhibitor; Checkpoint inhibitor

[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2024; 74: 229–263.

[2] National Cancer Institute: Surveillance E, and End Results Program. Cancer stat facts: ovarian cancer. 2022. Available at: https://seer.cancer.gov/statfacts/html/ovary.html (Accessed: 01 March 2025).

[3] Lawrie TA, Winter-Roach BA, Heus P, Kitchener HC. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews. 2015; 2015: CD004706.

[4] Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nature Reviews Disease Primers. 2016; 2: 16061.

[5] Cannistra SA. Cancer of the ovary. The New England Journal of Medicine. 2004; 351: 2519–2529.

[6] Lin H, Wu CH, Fu HC, Ou YC. Evolving treatment paradigms for platinum-resistant ovarian cancer: an update narrative review. Taiwanese Journal of Obstetrics and Gynecology. 2024; 63: 471–478.

[7] Na JR, Liu Y, Fang K, Tan Y, Liang PP, Yan M, et al. Unraveling the potential biomarkers of immune checkpoint inhibitors in advanced ovarian cancer: a comprehensive review. Investigational New Drugs. 2024; 42: 728–738.

[8] Boudreau JE. Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors. Journal of Clinical Investigation. 2024; 134: e184790.

[9] Zhang T, Zheng S, Liu Y, Li X, Wu J, Sun Y, et al. DNA damage response and PD-1/PD-L1 pathway in ovarian cancer. DNA Repair. 2021; 102: 103112.

[10] Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Annals of Oncology. 2019; 30: 1080–1087.

[11] Kokkotou E, Grapsa D, Papadopoulou A, Gaitanakis S, Bakakos P, Poulakou G, et al. Soluble PD-L1 and serum vascular endothelial growth factor-B may independently predict prognosis in patients with advanced non-small cell lung cancer treated with pembrolizumab. Cancers. 2025; 17: 421.

[12] Zsiros E, Lynam S, Attwood KM, Wang C, Chilakapati S, Gomez EC, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncology. 2021; 7: 78–85.

[13] Andrikopoulou A, Liontos M, Skafida E, Koutsoukos K, Apostolidou K, Kaparelou M, et al. Pembrolizumab in combination with bevacizumab and oral cyclophosphamide in heavily pre-treated platinum-resistant ovarian cancer. International Journal of Gynecological Cancer. 2023; 33: 571–576.

[14] Glynn SM, Gaillard S, Stone RL, Fader AN, Beavis AL. Pembrolizumab with bevacizumab and cyclophosphamide for the treatment of recurrent ovarian clear cell carcinoma: a case series. Gynecologic Oncology Reports. 2024; 53: 101374.

[15] Michels J, Ghiringhelli F, Frenel JS, Brard C, You B, Floquet A, et al. Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer. Journal of Clinical Oncology. 2021; 39: 5522.

[16] Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). International Journal of Gynecological Cancer. 2011; 21: 419–423.

[17] Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. Immune-modified response evaluation criteria in solid tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy. Journal of Clinical Oncology. 2018; 36: 850–858.

[18] Hillmann J, Maass N, Bauerschlag DO, Flörkemeier I. Promising new drugs and therapeutic approaches for treatment of ovarian cancer-targeting the hallmarks of cancer. BMC Medicine. 2025; 23: 10.

[19] Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. 2017; 18: 779–791.

[20] Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study. Journal of Clinical Oncology. 2007; 25: 5165–5171.

[21] Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. Journal of Clinical Oncology. 2007; 25: 5180–5186.

[22] Peng H, He X, Wang Q. Immune checkpoint blockades in gynecological cancers: a review of clinical trials. Acta Obstetricia et Gynecologica Scandinavica. 2022; 101: 941–951.

[23] Nishio S, Matsumoto K, Takehara K, Kawamura N, Hasegawa K, Takeshima N, et al. Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: subgroup analysis from the KEYNOTE-100. Cancer Science. 2020; 111: 1324–1332.

[24] Lin YC, Wen KC, Sung PL, Chou YT, Liew PL, Chen LY, et al. Complete remission of heavily treated ovarian clear cell carcinoma with ARID1A mutations after pembrolizumab and bevacizumab combination therapy: a case report. Journal of Ovarian Research. 2020; 13: 143.

[25] Liu Z, Jing C, Kong F. From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer. Journal of Ovarian Research. 2024; 17: 39.

[26] Tong A, Di X, Zhao X, Liang X. Review the progression of ovarian clear cell carcinoma from the perspective of genomics and epigenomics. Frontiers in Genetics. 2023; 14: 952379.

[27] Mandal J, Mandal P, Wang TL, Shih IM. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response. Journal of Biomedical Science. 2022; 29: 71.

[28] Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nature Medicine. 2018; 24: 556–562.

[29] Okamura R, Kato S, Lee S, Jimenez RE, Sicklick JK, Kurzrock R. ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy. The Journal for ImmunoTherapy of Cancer. 2020; 8: e000438.

[30] Alatise KL, Gardner S, Alexander-Bryant A. Mechanisms of drug resistance in ovarian cancer and associated gene targets. Cancers. 2022; 14: 6246.

[31] Bound NT, Vandenberg CJ, Kartikasari AER, Plebanski M, Scott CL. Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: a focus on the immune system. Frontiers in Genetics. 2022; 13: 886170.

[32] Oura K, Morishita A, Tadokoro T, Fujita K, Tani J, Kobara H. Immune microenvironment and the effect of vascular endothelial growth factor inhibition in hepatocellular carcinoma. International Journal of Molecular Sciences. 2024; 25: 13590.

[33] Xiao F, Wang Z, Qiao L, Zhang X, Wu N, Wang J, et al. Application of PARP inhibitors combined with immune checkpoint inhibitors in ovarian cancer. Journal of Translational Medicine. 2024; 22: 778.

[34] Herrera FG, Ronet C, Ochoa de Olza M, Barras D, Crespo I, Andreatta M, et al. Low-dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy. Cancer Discovery. 2022; 12: 108–133.

[35] Zhang Z, Liu X, Chen D, Yu J. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduction and Targeted Therapy. 2022; 7: 258.