Immune checkpoint inhibitors in women with gynecologic cancers: Practical considerations


      • Currently, there are approved indications for immune checkpoint inhibitors in endometrial cancer and cervical cancer.
      • Pembrolizumab is approved for tumors with high microsatellite instability regardless of site of origin.
      • Toxicity of immune checkpoint inhibition are often autoimmune in nature, can occur early or late, and require vigilance.


      Immune checkpoint inhibitors are an exciting new class of cancer therapeutics. Recently, a PD-1 inhibitor has been approved by the Food and Drug Administration for several indications that are relevant to patients with gynecologic malignancies. In this review, we explore the clinical considerations for the use of checkpoint inhibitor therapy in this population. Specifically, we will discuss the approved indications, recommended dosing, clinical monitoring while on treatment, common adverse events, and treatment of adverse events should they arise. Additionally, we will review mechanisms of resistance and other challenges associated with the use of checkpoint inhibitors. We will conclude with a discussion of possible future directions for immunotherapy in women with gynecologic cancers.


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        • Koebel C.M.
        • Vermi W.
        • Swann J.B.
        • Zerafa N.
        • Rodig S.J.
        • Old L.J.
        • et al.
        Adaptive immunity maintains occult cancer in an equilibrium state.
        Nature. 2007; 450: 903-907
        • Shankaran V.
        • Ikeda H.
        • Bruce A.T.
        • White J.M.
        • Swanson P.E.
        • Old L.J.
        • et al.
        IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.
        Nature. 2001; 410: 1107-1111
        • Piersma S.J.
        • Jordanova E.S.
        • van Poelgeest M.I.
        • Kwappenberg K.M.
        • van der Hulst J.M.
        • Drijfhout J.W.
        • et al.
        High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer.
        Cancer Res. 2007; 67: 354-361
        • Ino K.
        • Yamamoto E.
        • Shibata K.
        • Kajiyama H.
        • Yoshida N.
        • Terauchi M.
        • et al.
        Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival.
        Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 2008; 14: 2310-2317
        • Zhang L.
        • Conejo-Garcia J.R.
        • Katsaros D.
        • Gimotty P.A.
        • Massobrio M.
        • Regnani G.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N. Engl. J. Med. 2003; 348: 203-213
        • Gao Q.
        • Qiu S.J.
        • Fan J.
        • Zhou J.
        • Wang X.Y.
        • Xiao Y.S.
        • et al.
        Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.
        Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2007; 25: 2586-2593
        • Pages F.
        • Berger A.
        • Camus M.
        • Sanchez-Cabo F.
        • Costes A.
        • Molidor R.
        • et al.
        Effector memory T cells, early metastasis, and survival in colorectal cancer.
        N. Engl. J. Med. 2005; 353: 2654-2666
        • Pardoll D.M.
        The blockade of immune checkpoints in cancer immunotherapy.
        Nat. Rev. Cancer. 2012; 12: 252-264
        • Chung H.C.
        • Ros W.
        • Delord J.P.
        • Perets R.
        • Italiano A.
        • Shapira-Frommer R.
        • et al.
        Efficacy and safety of Pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.
        Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2019; 37: 1470-1478
        • Le D.T.
        • Durham J.N.
        • Smith K.N.
        • Wang H.
        • Bartlett B.R.
        • Aulakh L.K.
        • et al.
        Mismatch-Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade.
        Science (New York, NY2017
        • Marabelle A.
        • Le D.T.
        • Ascierto P.A.
        • Di Giacomo A.M.
        • De Jesus-Acosta A.
        • Delord J.P.
        • et al.
        Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient Cancer: results from the phase II KEYNOTE-158 study.
        Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2020; 38: 1-10
        • Hause R.J.
        • Pritchard C.C.
        • Shendure J.
        • Salipante S.J.
        Classification and characterization of microsatellite instability across 18 cancer types.
        Nat. Med. 2016; 22: 1342-1350
        • Bruegl A.S.
        • Ring K.L.
        • Daniels M.
        • Fellman B.M.
        • Urbauer D.L.
        • Broaddus R.R.
        Clinical challenges associated with universal screening for lynch syndrome-associated endometrial cancer.
        Cancer Prev. Res. (Phila.). 2017; 10: 108-115
        • Makker V.
        • Taylor M.H.
        • Aghajanian C.
        • Oaknin A.
        • Mier J.
        • Cohn A.L.
        • et al.
        Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer.
        Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2020; (online, ahead of print) (Jco1902627)
        • Lee J.S.
        • Ruppin E.
        Multiomics prediction of response rates to therapies to inhibit programmed cell death 1 and programmed cell death 1 Ligand 1.
        JAMA Oncol. 2019; (online, ahead of print)
        • Wang Q.
        • Wu X.
        Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment.
        Int. Immunopharmacol. 2017; 46: 210-219
        • Rimm D.L.
        • Han G.
        • Taube J.M.
        • Yi E.S.
        • Bridge J.A.
        • Flieder D.B.
        • et al.
        A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer.
        JAMA Oncology. 2017; 3: 1051-1058
        • Rimm D.L.
        • Han G.
        • Taube J.M.
        • Yi E.S.
        • Bridge J.A.
        • Flieder D.B.
        • et al.
        Reanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer.
        Breast Cancer Res. 2019; 21: 72
        • Disis M.L.
        • Taylor M.H.
        • Kelly K.
        • Beck J.T.
        • Gordon M.
        • Moore K.M.
        • et al.
        Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial.
        JAMA Oncol. 2019; 5: 393-401
        • Ott P.A.
        • Bang Y.J.
        • Berton-Rigaud D.
        • Elez E.
        • Pishvaian M.J.
        • Rugo H.S.
        • et al.
        Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study.
        Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2017; 35 (Jco2017725952): 2535-2541
        • Wang Y.
        • Zhou S.
        • Yang F.
        • Qi X.
        • Wang X.
        • Guan X.
        • et al.
        Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis.
        JAMA Oncol. 2019; 5: 1008-1019
        • Topalian S.L.
        • Hodi F.S.
        • Brahmer J.R.
        • Gettinger S.N.
        • Smith D.C.
        • McDermott D.F.
        • et al.
        Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
        N. Engl. J. Med. 2012; 366: 2443-2454
        • Institute NIoHNNC
        Common Terminology Criteria for Adverse Events (CTCAE).
      1. Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ (Clinical research ed). 2018;363:k4226.

        • Wang D.Y.
        • Salem J.E.
        • Cohen J.V.
        • Chandra S.
        • Menzer C.
        • Ye F.
        • et al.
        Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.
        JAMA Oncology. 2018; 4: 1721-1728
        • Nagai H.
        • Muto M.
        Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update.
        Int. J. Clin. Oncol. 2018; 23: 410-420
        • Braaten T.J.
        • Brahmer J.R.
        • Forde P.M.
        • Le D.
        • Lipson E.J.
        • Naidoo J.
        • et al.
        Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation.
        Ann. Rheum. Dis. 2019; 79: 332-338
        • Vergote I.
        • Teneriello M.
        • Powell M.A.
        • Miller D.S.
        • Garcia A.A.
        • Mikheeva O.N.
        • et al.
        A Phase II Trial of Lenvatinib in Patients with Advanced or Recurrent Endometrial Cancer: Angiopoietin-2 as a Predictive Marker for Clinical Outcomes.
        American Society of Clinical Oncology, 2013
        • Nakamura Y.
        Biomarkers for immune checkpoint inhibitor-mediated tumor response and adverse events.
        Frontiers in Medicine. 2019; 6: 119
        • Manson G.
        • Norwood J.
        • Marabelle A.
        • Kohrt H.
        • Houot R.
        Biomarkers associated with checkpoint inhibitors.
        Ann. Oncol. 2016; 27: 1199-1206
        • Hasan Ali O.
        • Berner F.
        • Bomze D.
        • Fassler M.
        • Diem S.
        • Cozzio A.
        • et al.
        Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors.
        Eur. J. Cancer. 2019; 107: 8-14
        • Cappelli L.C.
        • Dorak M.T.
        • Bettinotti M.P.
        • Bingham C.O.
        • Shah A.A.
        Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis.
        Rheumatology (Oxford). 2019; 58: 476-480
        • Puzanov I.
        • Diab A.
        • Abdallah K.
        • Bingham 3rd, C.O.
        • Brogdon C.
        • Dadu R.
        • et al.
        Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group.
        J Immunother Cancer. 2017; 5: 95
        • Brahmer J.R.
        • Lacchetti C.
        • Schneider B.J.
        • Atkins M.B.
        • Brassil K.J.
        • Caterino J.M.
        • et al.
        Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.
        J. Clin. Oncol. 2018; 36: 1714-1768
        • Haanen J.
        • Carbonnel F.
        • Robert C.
        • Kerr K.M.
        • Peters S.
        • Larkin J.
        • et al.
        Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann. Oncol. 2017; 28 (iv119-iv42)
        • Menzies A.M.
        • Johnson D.B.
        • Ramanujam S.
        • Atkinson V.G.
        • Wong A.N.M.
        • Park J.J.
        • et al.
        Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.
        Ann. Oncol. 2017; 28: 368-376
        • Tison A.
        • Quere G.
        • Misery L.
        • Funck-Brentano E.
        • Danlos F.X.
        • Routier E.
        • et al.
        Safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune disease: a nationwide.
        Multicenter Cohort Study. Arthritis Rheumatol. 2019; 71: 2100-2111
        • Horvat T.Z.
        • Adel N.G.
        • Dang TO
        • Momtaz P.
        • Postow M.A.
        • Callahan M.K.
        • et al.
        Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer center.
        Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015; 33: 3193-3198
        • Tazdait M.
        • Mezquita L.
        • Lahmar J.
        • Ferrara R.
        • Bidault F.
        • Ammari S.
        • et al.
        Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: comparison of RECIST 1.1, irRECIST and iRECIST criteria.
        European Journal of Cancer (Oxford, England : 1990). 2018; 88: 38-47
        • Chiou V.L.
        • Burotto M.
        Pseudoprogression and immune-related response in solid tumors.
        Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015; 33: 3541-3543
        • Teulings H.E.
        • Limpens J.
        • Jansen S.N.
        • Zwinderman A.H.
        • Reitsma J.B.
        • Spuls P.I.
        • et al.
        Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.
        Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015; 33: 773-781
        • Freeman-Keller M.
        • Kim Y.
        • Cronin H.
        • Richards A.
        • Gibney G.
        • Weber J.S.
        Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes.
        Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2016; 22: 886-894
        • Haratani K.
        • Hayashi H.
        • Chiba Y.
        • Kudo K.
        • Yonesaka K.
        • Kato R.
        • et al.
        Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer.
        JAMA Oncology. 2018; 4: 374-378
        • Trujillo J.A.
        • Luke J.J.
        • Zha Y.
        • Segal J.P.
        • Ritterhouse L.L.
        • Spranger S.
        • et al.
        Secondary resistance to immunotherapy associated with beta-catenin pathway activation or PTEN loss in metastatic melanoma.
        J Immunother Cancer. 2019; 7: 295
        • Spranger S.
        • Gajewski T.F.
        Impact of oncogenic pathways on evasion of antitumour immune responses.
        Nat. Rev. Cancer. 2018; 18: 139-147
        • Galluzzi L.
        • Chan T.A.
        • Kroemer G.
        • Wolchok J.D.
        • Lopez-Soto A.
        The hallmarks of successful anticancer immunotherapy.
        Sci. Transl. Med. 2018; 10
        • Luke J.J.
        • Bao R.
        • Sweis R.F.
        • Spranger S.
        • Gajewski T.F.
        WNT/beta-catenin pathway activation correlates with immune exclusion across human cancers.
        Clin. Cancer Res. 2019; 25: 3074-3083
        • Matulonis U.A.
        • Shapira-Frommer R.
        • Santin A.D.
        • Lisyanskaya A.S.
        • 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 : Official Journal of the European Society for Medical Oncology / ESMO. 2019; 30: 1080-1087
        • Zamarin D.
        • Burger R.A.
        • Sill M.W.
        • Powell Jr., D.J.
        • Lankes H.A.
        • Feldman M.D.
        • et al.
        Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study.
        Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2020; 38 (Jco1902059): 1814-1823
        • Cristescu R.
        • Mogg R.
        • Ayers M.
        • Albright A.
        • Murphy E.
        • Yearley J.
        • et al.
        Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
        Science (New York, N.Y.). 2018; 362
        • Anagnostou V.
        • Smith K.N.
        • Forde P.M.
        • Niknafs N.
        • Bhattacharya R.
        • White J.
        • et al.
        Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer.
        Cancer Discov. 2017; 7: 264-276
        • Zaretsky J.M.
        • Garcia-Diaz A.
        • Shin D.S.
        • Escuin-Ordinas H.
        • Hugo W.
        • Hu-Lieskovan S.
        • et al.
        Mutations associated with acquired resistance to PD-1 blockade in melanoma.
        N. Engl. J. Med. 2016; 375: 819-829
        • Seidel J.A.
        • Otsuka A.
        • Kabashima K.
        Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations.
        Front. Oncol. 2018; 8: 86
        • Hu Z.I.
        • Hellmann M.D.
        • Wolchok J.D.
        • Vyas M.
        • Shia J.
        • Stadler Z.K.
        • et al.
        Acquired resistance to immunotherapy in MMR-D pancreatic cancer.
        J Immunother Cancer. 2018; 6: 127
        • Gettinger S.N.
        • Wurtz A.
        • Goldberg S.B.
        • Rimm D.
        • Schalper K.
        • Kaech S.
        • et al.
        Clinical features and management of acquired resistance to PD-1 Axis inhibitors in 26 patients with advanced non-small cell lung cancer.
        J. Thorac. Oncol. 2018; 13: 831-839
        • George S.
        • Miao D.
        • Demetri G.D.
        • Adeegbe D.
        • Rodig S.J.
        • Shukla S.
        • et al.
        Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma.
        Immunity. 2017; 46: 197-204