The evolving role of immune checkpoint inhibitors in cervical and endometrial cancer

Abstract

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for numerous tumor types, including cervical and endometrial cancers. Multiple ICIs against programmed cell death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have demonstrated encouraging outcomes in controlled clinical studies for advanced cervical and endometrial cancers. For advanced cervical cancer, approved ICIs as second-line treatment include cemiplimab, nivolumab, and pembrolizumab as single agents. In the first-line treatment setting, options include pembrolizumab alone or in combination with bevacizumab, as well as atezolizumab combined with a backbone platinum-based chemotherapy plus bevacizumab. Additionally, for locally advanced cervical cancer, pembrolizumab is recommended alongside concurrent chemoradiotherapy. For endometrial cancer, pembrolizumab monotherapy, pembrolizumab in combination with lenvatinib, and dostarlimab are currently approved as second-line treatment options. Moreover, either dostarlimab or pembrolizumab can be added to first-line platinum-based chemotherapy for mismatch repair deficient malignancies. Although the inclusion of these agents in clinical practice has led to improved overall response rates and survival outcomes, many patients still lack benefits, possibly due to multiple intrinsic and adaptive resistance mechanisms to immunotherapy. This review aims to highlight the rationale for utilizing ICIs and their current role, while also delineating the proposed mechanisms of resistance to ICIs in cervical and endometrial cancer.

Keywords

Immunotherapy / cervical cancer / endometrial cancer / immune checkpoint inhibitors

References

[1] Wolchok JD,Gonzalez R.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med2017;377:1345-56 PMCID:PMC5706778

[2] Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90. PMCID:PMC5972549

[3] Maude SL,Buechner J.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med2018;378:439-48 PMCID:PMC5996391

[4] Nishio H,Aoki D.Current status of cancer immunotherapy for gynecologic malignancies.Jpn J Clin Oncol2021;51:167-72

[5] Levinson K,Rubin K.Immunotherapy in gynecologic cancers: what we know now and where we are headed.Am Soc Clin Oncol Educ Book2019;39:e126-40

[6] Wei SC,Cogdill AP.Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade.Cell2017;170:1120-33.e17 PMCID:PMC5591072

[7] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer2012;12:252-64 PMCID:PMC4856023

[8] Roberts K,Lwin Z,Hughes BG.Immune checkpoint inhibitors: navigating a new paradigm of treatment toxicities.Asia Pac J Clin Oncol2017;13:277-88

[9] Le DT,Smith KN.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science2017;357:409-13 PMCID:PMC5576142

[10] Marabelle A,Ascierto PA.Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study.J Clin Oncol2020;38:1-10 PMCID:PMC8184060

[11] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[12] Siegel RL,Fuchs HE.Cancer statistics, 2022.CA Cancer J Clin2022;72:7-33

[13] Bedell SL,Goldstein AR.Cervical cancer screening: past, present, and future.Sex Med Rev2020;8:28-37

[14] Münger K.Human papillomavirus immortalization and transformation functions.Virus Res2002;89:213-28

[15] Hu Z.The precision prevention and therapy of HPV-related cervical cancer: new concepts and clinical implications.Cancer Med2018;7:5217-36 PMCID:PMC6198240

[16] Allemani C, Weir HK, Carreira H, et al; CONCORD Working Group. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2015;385:977-1010. PMCID:PMC4588097

[17] Ojesina AI,Freeman SS.Landscape of genomic alterations in cervical carcinomas.Nature2014;506:371-5 PMCID:PMC4161954

[18] Otter SJ,Stewart AJ.The role of biomarkers for the prediction of response to checkpoint immunotherapy and the rationale for the use of checkpoint immunotherapy in cervical cancer.Clin Oncol2019;31:834-43

[19] Enwere EK,Dean M.Expression of PD-L1 and presence of CD8-positive T cells in pre-treatment specimens of locally advanced cervical cancer.Mod Pathol2017;30:577-86

[20] Chung H,Perets R.Pembrolizumab treatment of advanced cervical cancer: updated results from the phase II KEYNOTE-158 study.Gynecol Oncol2021;162:S27

[21] Chung HC,Delord JP.Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.J Clin Oncol2019;37:1470-8

[22] Tewari KS, Monk BJ, Vergote I, et al; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with cemiplimab in recurrent cervical cancer. N Engl J Med 2022;386:544-55.

[23] Oaknin A,Meyer T.Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.Lancet Oncol2024;25:588-602

[24] Oaknin A,Meyer T.520MO Safety and efficacy of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic cervical cancer (R/M Cx Ca) in checkmate 358.Ann Oncol2022;33:S782

[25] National Comprehensive Cancer Network. Cervical cancer (Version 3.2024). Available from: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. [Last accessed on 7 Jun 2024]

[26] O’Malley DM,Monk BJ.Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase II study.J Clin Oncol2022;40:762-71 PMCID:PMC8887945

[27] Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 2021;385:1856-67.

[28] Monk BJ, Colombo N, Tewari KS, et al; KEYNOTE-826 Investigators. First-line pembrolizumab + chemotherapy versus placebo + chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. J Clin Oncol 2023;41:5505-11.

[29] Oaknin A, Gladieff L, Martínez-García J, et al; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 2024;403:31-43.

[30] Monk B,Wu X.O001/#504 Durvalumab, in combination with and following chemoradiotherapy, in locally advanced cervical cancer: results from the phase 3 international, randomized, double-blind, placebo-controlled calla trial.Int J Gynecol Cancer2022;32:A2-3

[31] Lorusso D, Xiang Y, Hasegawa K, et al; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet 2024;403:1341-50.

[32] Garcia-Duran C,Villacampa G.ATOMICC trial: a randomized, open-label, phase II trial of anti-PD1, dostarlimab, as maintenance therapy for patients with high-risk locally advanced cervical cancer after chemoradiation.Int J Gynecol Cancer2022;32:1196-200

[33] National Cancer Institute. Cancer stat facts: uterine cancer. Available from: https://seer.cancer.gov/statfacts/html/corp.html. [Last accessed on 7 Jun 2024]

[34] Miller DS,Mannel RS.Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG oncology/GOG0209).J Clin Oncol2020;38:3841-50 PMCID:PMC7676887

[35] Levine DA; The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73. PMCID:PMC3704730

[36] Howitt BE,Sholl LM.Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1.JAMA Oncol2015;1:1319-23

[37] Eggink FA,Leary A.Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.Oncoimmunology2016;6:e1264565 PMCID:PMC5353925

[38] O’Malley DM,Cassier PA.Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study.J Clin Oncol2022;40:752-61 PMCID:PMC8887941

[39] Oaknin A,Gilbert L.Safety, efficacy, and biomarker analyses of dostarlimab in patients with endometrial cancer: interim results of the phase I GARNET study.Clin Cancer Res2023;29:4564-74 PMCID:PMC10643997

[40] Soumerai TE,Bandlamudi C.Clinical utility of prospective molecular characterization in advanced endometrial cancer.Clin Cancer Res2018;24:5939-47 PMCID:PMC6279519

[41] Oaknin A,Gilbert L.Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): the GARNET study.J Clin Oncol2022;40:5509

[42] Ott PA,Berton-Rigaud D.Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study.J Clin Oncol2017;35:2535-41

[43] Mahecha AM.The influence of vascular endothelial growth factor-A and matrix metalloproteinase-2 and -9 in angiogenesis, metastasis, and prognosis of endometrial cancer.Onco Targets Ther2017;10:4617-24 PMCID:PMC5614795

[44] Hack SP,Wang Y.Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities.Front Immunol2020;11:598877 PMCID:PMC7674951

[45] Makker V,Aghajanian C.Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer.J Clin Oncol2020;38:2981-92 PMCID:PMC7479759

[46] Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 2022;386:437-48.

[47] Makker V,Casado Herráez A.Lenvatinib plus pembrolizumab in previously treated advanced endometrial cancer: updated efficacy and safety from the randomized phase III study 309/KEYNOTE-775.J Clin Oncol2023;41:2904-10 PMCID:PMC10414727

[48] Pantelidou C,De Oliveria Taveira M.PARP inhibitor efficacy depends on CD8⁺ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer.Cancer Discov2019;9:722-37 PMCID:PMC6548644

[49] Post CCB,Boere IA.Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial).Gynecol Oncol2022;165:223-9

[50] Konstantinopoulos PA,Xiong N.Evaluation of treatment with talazoparib and avelumab in patients with recurrent mismatch repair proficient endometrial cancer.JAMA Oncol2022;8:1317-22 PMCID:PMC9335244

[51] Mirza MR, Chase DM, Slomovitz BM, et al; RUBY Investigators. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med 2023;388:2145-58.

[52] Mirza M,Herrstedt J.740MO Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): analysis of progression free survival (PFS) and overall survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial.Ann Oncol2023;34:S507

[53] Powell M. Overall survival in patients with primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy in Part 1 of the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. In: Presented at the SGO 2024 Annual Meeting; San Diego, California; 2024. Available from: https://www.onclive.com/view/overall-survival-in-patients-with-primary-advanced-or-recurrent-endometrial-cancer-treated-with-dostarlimab-plus-chemotherapy-in-part-1-of-the-engot-en6-nsgo-gog-3031-ruby-trial. [Last accessed on 7 Jun 2024]

[54] Eskander RN,Beffa L.Pembrolizumab plus chemotherapy in advanced endometrial cancer.N Engl J Med2023;388:2159-70 PMCID:PMC10351614

[55] Colombo N,Hudson E.LBA40 phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma.Ann Oncol2023;34:S1281-2

[56] Marth C,Bidzinski M.#88 Lenvatinib plus pembrolizumab versus chemotherapy as first-line therapy for advanced or recurrent endometrial cancer: primary results of the phase 3 ENGOT-en9/LEAP-001 study.Int J Gynecol Cancer2024;34:A570.2-1

[57] Westin SN, Moore K, Chon HS, et al; DUO-E Investigators. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol 2024;42:283-99. PMCID:PMC10824389

[58] Mirza MR,Hanker LC. Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib maintenance therapy in patients with primary-advanced or recurrent endometrial cancer in the ENGOT-EN6-NSGO/GOG-3031/RUBY Trial. In: Presented at the SGO 2024 Annual Meeting. San Diego, California.

[59] Lheureux S,Konstantinopoulos PA.Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer.J Immunother Cancer2022;10:e004233 PMCID:PMC8921950

[60] Slomovitz B,Lortholary A.ENGOT-en11/GOG-3053/KEYNOTE-B21: a phase 3 study of pembrolizumab or placebo in combination with adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed high-risk endometrial cancer (570).Gynecol Oncol2022;166:S278

[61] RAINBO Research Consortium. Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program.Int J Gynecol Cancer2022;33:109-17 PMCID:PMC9811074

[62] Ge Y,Zhao KN.Emerging therapeutic strategies of different immunotherapy approaches combined with PD-1/PD-L1 blockade in cervical cancer.Drug Des Devel Ther2022;16:3055-70 PMCID:PMC9470119

[63] Le DT,Wang H.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[64] Li B,Chen P.Immune checkpoint inhibitors: basics and challenges.Curr Med Chem2019;26:3009-25

[65] Lei Q,Sun K,Zhang Y.Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors.Front Cell Dev Biol2020;8:672 PMCID:PMC7385189

[66] Koyama S,Li YY.Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.Nat Commun2016;7:10501 PMCID:PMC4757784

[67] Chitsike L.The potential of immune checkpoint blockade in cervical cancer: can combinatorial regimens maximize response? A review of the literature.Curr Treat Options Oncol2020;21:95

[68] Hung AL,Theodros D.TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM.Oncoimmunology2018;7:e1466769 PMCID:PMC6136875

[69] Popovic A,Zaidi N.Emerging strategies for combination checkpoint modulators in cancer immunotherapy.J Clin Invest2018;128:3209-18 PMCID:PMC6063475

[70] Buchbinder EI.CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition.Am J Clin Oncol2016;39:98-106 PMCID:PMC4892769

[71] Liu L,Liu X.Blocking TIGIT/CD155 signalling reverses CD8⁺ T cell exhaustion and enhances the antitumor activity in cervical cancer.J Transl Med2022;20:280 PMCID:PMC9210727

[72] Cao W,Fischer JV,Kong B.Immunotherapy in endometrial cancer: rationale, practice and perspectives.Biomark Res2021;9:49 PMCID:PMC8207707

[73] Friedrich M,Lazaridou MF.Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy.Cancer Immunol Immunother2019;68:1689-700 PMCID:PMC11028168

[74] Friedman LA,Sloan EA,Mills AM.MHC class I loss in endometrial carcinoma: a potential resistance mechanism to immune checkpoint inhibition.Mod Pathol2021;34:627-36

[75] Wang J,Datar I.Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3.Cell2019;176:334-47.e12 PMCID:PMC6365968

[76] Kouo T,Pucsek AB.Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells.Cancer Immunol Res2015;3:412-23 PMCID:PMC4390508

[77] Zhang Y,Xu C.Analysis of the immune checkpoint lymphocyte activation gene-3 (LAG-3) in endometrial cancer: an emerging target for immunotherapy.Pathol Res Pract2022;236:153990

[78] He Y,Zhao C,Zhou C.TIM-3, a promising target for cancer immunotherapy.Onco Targets Ther2018;11:7005-9 PMCID:PMC6198883

[79] Sauer N,Szlasa W.TIM-3 as a promising target for cancer immunotherapy in a wide range of tumors.Cancer Immunol Immunother2023;72:3405-25 PMCID:PMC10576709

[80] Tang R,Subramanian A.Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function.Sci Immunol2022;7:eabm0631 PMCID:PMC9273260

[81] Moore M,Mills AM.TIM-3 in endometrial carcinomas: an immunotherapeutic target expressed by mismatch repair-deficient and intact cancers.Mod Pathol2019;32:1168-79

[82] Thomas SJ,Zeidler MP.The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours.Br J Cancer2015;113:365-71 PMCID:PMC4522639

[83] Ren Y,Liu RZ.JAK1 truncating mutations in gynecologic cancer define new role of cancer-associated protein tyrosine kinase aberrations.Sci Rep2013;3:3042 PMCID:PMC3807107

[84] Vesely MD,Schreiber RD.Natural innate and adaptive immunity to cancer.Annu Rev Immunol2011;29:235-71

[85] Albacker LA,Smith P.Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion.PLoS One2017;12:e0176181 PMCID:PMC5679612

[86] Stelloo E,Nijman HW.Microsatellite instability derived JAK1 frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer.Oncotarget2016;7:39885-93 PMCID:PMC5129978

[87] Dou Y, Kawaler EA, Cui Zhou D, et al; Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterization of endometrial carcinoma. Cell 2020;180:729-48.e26. PMCID:PMC7233456

[88] Pakish JB,Chen Z.Immune microenvironment in microsatellite-instable endometrial cancers: hereditary or sporadic origin matters.Clin Cancer Res2017;23:4473-81 PMCID:PMC5540763

[89] Bellone S,Siegel ER.A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.Cancer2022;128:1206-18 PMCID:PMC9465822

[90] Tinker AV,Gravina A.2022-RA-1198-ESGO Post hoc analysis of objective response rate by mismatch repair protein dimer loss/mutation status in patients with mismatch repair deficient endometrial cancer treated with dostarlimab.Int J Gynecol Cancer2022;32:A414.1-4

[91] Eskander RN,Miller A.LBA43 Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial.Ann Oncol2023;34:S1284