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Balstilimab and other immunotherapy for recurrent and metastatic cervical cancer

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Abstract

Recurrent and metastatic cervical cancer is generally treated by cisplatin, paclitaxel, and bevacizumab with limited benefit this constituting an unmet need. Immune checkpoint inhibitors, namely the inhibitors of programmed death 1 and programmed death ligand 1 have been proved to be efficacious in the treatment of patients with advanced cervical cancer. Recently, a PD-1 inhibitor, pembrolizumab was approved for such cancer. However, there is much scope of improvement of current outcome. Dual blockade of cytotoxic T lymphocyte-associated protein 4 and PD-1 is an attractive therapeutic approach. It is used in other cancers and is currently proposed for cancer cervix also. Search is on for single or combined regimen showing efficacy in multiple pathological conditions of cancer cervix irrespective presence of PD-L1 in malignant tissue. An effort to meet such unmet need has culminated in inventing new immune checkpoint inhibitors namely PD-1 inhibitor, AGEN2034 (Balstilimab) and CTLA-4 inhibitor, AGEN1884 (Zalifrelimab).They have shown meaningful and durable activity as single-agent therapy in previously treated patients with persistent R/M CC in a large phase II trial (NCT03104699) in PD-L1 + and PD-L1- tumour. Responses were found both in squamous cell carcinoma & adenocarcinoma cell types. Balstilimab plus zalifrelimab combination (NCT03495882) produced improved clinical benefit over monotherapy as evidenced by higher relative response rates and longer response duration, as well as a manageable safety profile. Interesting development of this combination and other immunotherapies in R/M CC are discussed in this ensuing review.

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References

  1. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, Bray F. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020 Feb;8(2):e191-e203. https://doi.org/10.1016/S2214-109X(19)30482-6. Epub 2019 Dec 4. Erratum in: Lancet Glob Health. 2022 Jan;10(1):e41. PMID: 31812369; PMCID: PMC7025157.

  2. Cohen AC, Roane BM, Leath CA 3rd. Novel therapeutics for recurrent cervical cancer: moving towards personalized therapy. Drugs. 2020;80(3):217–27. https://doi.org/10.1007/s40265-019-01249-z.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Breous-Nystrom E, Schultze K, Meier M, Flueck L, Holzer C, Boll M, Seibert V, Schuster A, Blanusa M, Schaefer V, Grawunder U, Martin-Parras L, van Dijk MA. Retrocyte display® technology: generation and screening of a high diversity cellular antibody library. Methods. 2014;65(1):57–67. https://doi.org/10.1016/j.ymeth.2013.09.003 (Epub 2013 Sep 12 PMID: 24036249).

    Article  CAS  PubMed  Google Scholar 

  4. Chand D, Savitsky D, Gonzalez A, Manrique M, et al. AGEN2034, a novel anti-PD-1 antibody that combines effectively with CTLA-4 pathway blockade to enhance T cell activity Poster: #P312 SITC Annual Meeting Washington,DC,USA November 9–12,2017.

  5. Gombos RB, Gonzalez A, Manrique M, Chand D, Savitsky D, Morin B, Breous-Nystrom E, Dupont C, Ward RA, Mundt C, Duckless B, Tang H, Findeis MA, Schuster A, Waight JD, Underwood D, Clarke C, Ritter G, Merghoub T, Schaer D, Wolchok JD, van Dijk M, Buell JS, Cuillerot JM, Stein R, Drouin EE, Wilson NS. Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody. PLoS One. 2018 Apr 4;13(4):e0191926. https://doi.org/10.1371/journal.pone.0191926. PMID: 29617360; PMCID: PMC5884502. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884502/#!po=77.9070

  6. Completion of balstilimab BLA filing extended to 1h2021.News release. Agenus, Inc. December 4, 2020. Accessed 4 Dec 2020. https://bit.ly/2VDlc26

  7. O’Malley DM, Oaknin A, Monk B, et al. Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): Preliminary results of two independent phase II trials. Presented at: 2020 ESMO Congress; September 19–21, 2020; Virtual. Abstract LBA34

  8. Drescher C, Moore KN, J.F. Liu JF, et al. Phase I/II, open-label, multiple ascending dose trial of AGEN2034, an anti-PD-1 monoclonal antibody, in advancedsolid malignancies: Results of dose escalation inadvanced cancer and expansion cohorts in subjects with relapsed/refractory cervical cancer. Ann. Oncol. 29 (2018) viii412–viii413.

  9. O'Malley DM, Oaknin A, Monk BJ, et al. Phase II study of the safety and efficacy of the anti- PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer. GynecolOncol. 2021 Aug 24:S0090-8258(21)01316-0. 10.1016/j.ygyno.2021.08.018. Epub ahead of print. PMID: 34452745 (NCT03104699).

  10. Joyce C, et al. Differentiated Activity Profile for the PD-1 Inhibitor Balstilimab. American Society of Clinical Oncology (ASCO) June 3–7, 2021

  11. O'Malley, et al. Balstilimab (anti-PD-1) in Combination with Zalifrelimab (anti-CTLA-4): Final Results from a Phase 2 Study in Patients (pts) with Recurrent/metastatic (R/M) Cervical Cancer (CC). European Society for Medical Oncology (ESMO) Virtual Sept 16–21, 2021

  12. Randall LM, O'Malley DM, Jackson CG et al. Balstilimab alone or in combination with zalifrelimab as second- line treatment for patients with previously treated recurrent/metastatic cervical cancer: a randomized, placebo-controlled phase II trial (RaPiDS/GOG-3028) ESMO Congress 2021, September 16–21, 2021

  13. O’Malley DM, Randall LM, Jackson CG, et al. RaPiDS (GOG-3028): randomized Phase II study of balstilimab alone or in combination with zalifrelimab in cervical cancer. Future Oncol. 2021;17(26):3433–43. https://doi.org/10.2217/fon-2021-0529 (Epub 2021 Aug 19 PMID: 34409858).

    Article  CAS  PubMed  Google Scholar 

  14. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet 393(10167), 169–182 (2019). Canfell K. Towards the global elimination of cervical cancer. Papillomavirus Res. 8, 100170 (2019).

  15. Tewari KS, Sill MW, et al. Long HJ 3rd Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734–43.

    Article  CAS  Google Scholar 

  16. Gyawali B, Iddawela M. Bevacizumab in advanced cervical cancer: issues and challenges for low-and middle-income countries. J Glob Oncol. 2017;3(2):93–7.

    Article  Google Scholar 

  17. Eskander RN, Tewari KS. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. ClinTher. 2015;37(1):20–38. https://doi.org/10.1016/j.clinthera.2014.11.010 (PMID: 25592089).

    Article  CAS  Google Scholar 

  18. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733–41.

    Article  CAS  Google Scholar 

  19. Longoria TC, Tewari KS. Pharmacologic management of advanced cervical cancer: antiangiogenesis therapy and immunotherapeutic considerations. Drugs. 2015;75(16):1853–65. https://doi.org/10.1007/s40265-015-0481-z.PMID:26474780;PMCID:PMC5061500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Boussios S, Seraj E, Zarkavelis G, et al. Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: where do we stand? a literature review. Crit Rev Oncol Hematol. 2016;108:164–74.

    Article  Google Scholar 

  21. Chung HC, Ros W, Delord JP et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the Phase II KEYNOTE-158 study. J. Clin. Oncol. 37(17), 1470–1478 (2019). • Clinical trial that led to the accelerated approval of pembrolizumab for second-line treatment of patients with programmed death ligand 1-positive, recurrent/metastatic cervical cancer.

  22. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, et al. Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23–34. doi: https://doi.org/10.1056/NEJMoa1504030. Epub 2015 May 31. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. PMID: 26027431; PMCID: PMC5698905.

  23. LiuY,WuL,TongRet al. PD-1/PD-L1 inhibitors in cervical cancer. Front. Pharmacol. 10, 65 (2019). • Summarizes the clinical status and application of targeted programmed death 1/programmed death ligand 1 inhibitors in cervical cancer.

  24. Kagabu M, Nagasawa T, Fukagawa D, et al. Immunotherapy for uterine cervical cancer. Healthcare (Basel). 2019;7(3):108.

    Article  Google Scholar 

  25. Wei SC, Levine JH, Cogdill AP, et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell. 2017;170(6):1120-1133 e1117.

    Article  CAS  Google Scholar 

  26. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98–106.

    Article  CAS  Google Scholar 

  27. ZurHausen H. Papillomaviruses in the causation of human cancers: a brief historical account. Virology. 2009;384(2):260–5.

    Article  CAS  Google Scholar 

  28. Samstein RM, Lee CH, Shoushtari AN et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51(2), 202–206 (2019). • Largemulticenter analysis investigating the association between tumor mutational burden and clinical response to immune checkpoint inhibitors.

  29. WangJ, Li Z, Gao A, Wen Q, Sun Y. The prognostic landscape of tumor-infiltrating immune cells in cervical cancer. Biomed. Pharmacother. 120, 109444 (2019).

  30. Burk RD, Chen Z, Saller C, et al. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84.

    Article  CAS  Google Scholar 

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Correspondence to Chinmoy K. Bose.

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Bose, C.K. Balstilimab and other immunotherapy for recurrent and metastatic cervical cancer. Med Oncol 39, 47 (2022). https://doi.org/10.1007/s12032-022-01646-7

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