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Checkpoint Inhibitors in Gynecological Malignancies: Are we There Yet?

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Abstract

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the field of oncology. For many cancer types, treatment paradigms have changed, as immunotherapy is increasingly being integrated into frontline standard-of-care treatments and producing meaningful and prolonged responses. This has inspired an avalanche of clinical trials studying ICIs in all types of malignancies, including gynecological cancers. Ovarian and endometrial cancers are characterized by DNA damage repair defects, either via disruption of the homologous recombination DNA repair mechanism in the former or via defects in the mismatch repair (MMR) pathway in the latter, which lead to a high load of neoantigens in both. Cervical cancer is dependent on the expression of human papillomavirus (HPV) proteins, which induce an immune response. Regardless, clinical trials testing ICIs in gynecological malignancies have initially led to disappointing results. Despite durable responses in some patients, overall response rates have been dismal. Nevertheless, in recent years, with the development of better predictive tumor biomarkers, such as microsatellite instability for endometrial cancer and programmed death ligand 1 for cervical cancer, ICIs have found their way into routine treatments for patients with advanced-stage disease. ICI-based combinations, although adding toxicity, have further improved response rates, and new combinations are currently being tested in clinical trials, as are other immunotherapy modalities, such as adoptive cell transfer and HPV-based vaccines. This review summarizes current clinical evidence supporting the use of immunotherapy in gynecological malignancies and describes studies in progress, with a focus on ICIs and predictive response biomarkers.

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References

  1. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8(9):1069–86. https://doi.org/10.1158/2159-8290.CD-18-0367.

    Article  PubMed  Google Scholar 

  2. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. https://doi.org/10.1056/NEJMoa1510665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bellmunt J, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26. https://doi.org/10.1056/NEJMoa1613683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Socinski MA, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. https://doi.org/10.1056/NEJMoa1716948.

    Article  CAS  PubMed  Google Scholar 

  6. Hodi FS, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–92. https://doi.org/10.1016/S1470-2045(18)30700-9.

    Article  CAS  PubMed  Google Scholar 

  7. Motzer RJ, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90. https://doi.org/10.1056/NEJMoa1712126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schmid P, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21. https://doi.org/10.1056/NEJMoa1809615.

    Article  CAS  PubMed  Google Scholar 

  9. Eggermont AMM, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–801. https://doi.org/10.1056/NEJMoa1802357.

    Article  CAS  PubMed  Google Scholar 

  10. Antonia SJ, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29. https://doi.org/10.1056/NEJMoa1709937.

    Article  CAS  PubMed  Google Scholar 

  11. Oiseth SJ, Aziz MS. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. JCMT. 2017;3(10):250. https://doi.org/10.20517/2394-4722.2017.41.

    Article  CAS  Google Scholar 

  12. Ribas A, et al. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist. 2007;12(7):873–83. https://doi.org/10.1634/theoncologist.12-7-873.

    Article  CAS  PubMed  Google Scholar 

  13. Perets R, et al. Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): updated interim results from a phase I study. JCO. 2019;37(15_suppl):2558. https://doi.org/10.1200/JCO.2019.37.15_suppl.2558.

    Article  Google Scholar 

  14. Keir ME, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203(4):883–95. https://doi.org/10.1084/jem.20051776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Horn L, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–9. https://doi.org/10.1056/NEJMoa1809064.

    Article  CAS  PubMed  Google Scholar 

  16. Gandhi L, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–92. https://doi.org/10.1056/NEJMoa1801005.

    Article  CAS  PubMed  Google Scholar 

  17. Stenger M. First-line atezolizumab plus platinum-based chemotherapy vs chemotherapy alone in advanced urothelial cancer—the ASCO post; 2020. https://ascopost.com/issues/june-25-2020/first-line-atezolizumab-plus-platinum-based-chemotherapy-vs-chemotherapy-alone-in-advanced-urothelial-cancer/. Accessed 13 Sep 2020.

  18. Slater H. Phase III KEYNOTE-361 trial fails to meet primary end points. Cancer Network; 2020. https://www.cancernetwork.com/view/phase-iii-keynote-361-trial-fails-to-meet-primary-end-points. Accessed 13 Sep 2020.

  19. Rini BI, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–27. https://doi.org/10.1056/NEJMoa1816714.

    Article  CAS  PubMed  Google Scholar 

  20. Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774.

    Article  CAS  PubMed  Google Scholar 

  21. Langer CJ, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–508. https://doi.org/10.1016/S1470-2045(16)30498-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mok TSK, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–30. https://doi.org/10.1016/S0140-6736(18)32409-7.

    Article  CAS  PubMed  Google Scholar 

  23. Paz-Ares L, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929–39. https://doi.org/10.1016/S0140-6736(19)32222-6.

    Article  CAS  PubMed  Google Scholar 

  24. Schachter J, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390(10105):1853–62. https://doi.org/10.1016/S0140-6736(17)31601-X.

    Article  CAS  PubMed  Google Scholar 

  25. Fuchs CS, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. https://doi.org/10.1001/jamaoncol.2018.0013.

    Article  PubMed  PubMed Central  Google Scholar 

  26. El-Khoueiry AB, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502. https://doi.org/10.1016/S0140-6736(17)31046-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. O’Neil BH, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS ONE. 2017;12(12):e0189848. https://doi.org/10.1371/journal.pone.0189848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Antonarakis ES, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. JCO. 2020;38(5):395–405. https://doi.org/10.1200/JCO.19.01638.

    Article  CAS  Google Scholar 

  29. Hodi FS, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci. 2008;105(8):3005–10. https://doi.org/10.1073/pnas.0712237105.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Marabelle A, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. JCO. 2020;38(1):1–10. https://doi.org/10.1200/JCO.19.02105.

    Article  CAS  Google Scholar 

  31. Liu JF, et al. Safety, clinical activity and biomarker assessments of atezolizumab from a phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol. 2019a;154(2):314–22. https://doi.org/10.1016/j.ygyno.2019.05.021.

    Article  CAS  PubMed  Google Scholar 

  32. Chung HC, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(17):1470–8. https://doi.org/10.1200/JCO.18.01265.

    Article  CAS  PubMed  Google Scholar 

  33. Hellmann MD, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. https://doi.org/10.1056/NEJMoa1910231.

    Article  CAS  PubMed  Google Scholar 

  34. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25(13):3753–8. https://doi.org/10.1158/1078-0432.CCR-18-4070.

    Article  CAS  PubMed  Google Scholar 

  35. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.

    Article  PubMed  Google Scholar 

  36. Bast RC, et al. Critical questions in ovarian cancer research and treatment: report of an American Association for Cancer Research Special Conference. Cancer. 2019;125(12):1963–72. https://doi.org/10.1002/cncr.32004.

    Article  PubMed  Google Scholar 

  37. Schlienger K, et al. TRANCE- and CD40 ligand-matured dendritic cells reveal MHC class I-restricted T cells specific for autologous tumor in late-stage ovarian cancer patients. Clin Cancer Res. 2003;9(4):1517–27.

    CAS  PubMed  Google Scholar 

  38. Zhang L, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13. https://doi.org/10.1056/NEJMoa020177.

    Article  CAS  PubMed  Google Scholar 

  39. Hwang W-T, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124(2):192–8. https://doi.org/10.1016/j.ygyno.2011.09.039.

    Article  PubMed  Google Scholar 

  40. Bachmayr-Heyda A, et al. Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients—a study of the OVCAD consortium. BMC Cancer. 2013;13:422. https://doi.org/10.1186/1471-2407-13-422.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Adams SF, et al. Intraepithelial T cells and tumor proliferation: impact on the benefit from surgical cytoreduction in advanced serous ovarian cancer. Cancer. 2009;115(13):2891–902. https://doi.org/10.1002/cncr.24317.

    Article  PubMed  Google Scholar 

  42. Sato E, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102(51):18538–43. https://doi.org/10.1073/pnas.0509182102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. https://doi.org/10.1038/nature10166.

    Article  CAS  Google Scholar 

  44. Strickland KC, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7(12):13587–98. https://doi.org/10.18632/oncotarget.7277.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Morse CB, et al. Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma. Gynecol Oncol. 2019;153(2):217–22. https://doi.org/10.1016/j.ygyno.2019.02.011.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Matulonis UA, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080–7. https://doi.org/10.1093/annonc/mdz135.

    Article  CAS  PubMed  Google Scholar 

  47. Hamanishi J, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. JCO. 2015;33(34):4015–22. https://doi.org/10.1200/JCO.2015.62.3397.

    Article  CAS  Google Scholar 

  48. Disis ML, 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(3):393. https://doi.org/10.1001/jamaoncol.2018.6258.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zamarin D, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. JCO. 2020. https://doi.org/10.1200/JCO.19.02059.

    Article  Google Scholar 

  50. Alexandrov LB, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. https://doi.org/10.1038/nature12477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cristescu R, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362(6411):eaar3593. https://doi.org/10.1126/science.aar3593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Feinberg J, Elvin JA, Bellone S, Santin AD. Identification of ovarian cancer patients for immunotherapy by concurrent assessment of tumor mutation burden (TMB), microsatellite instability (MSI) status, and targetable genomic alterations (GA). Gynecol Oncol. 2018;149:36. https://doi.org/10.1016/j.ygyno.2018.04.081.

    Article  Google Scholar 

  53. Konstantinopoulos PA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019a;5(8):1141. https://doi.org/10.1001/jamaoncol.2019.1048.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Drew Y, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCA m) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gynecol Oncol. 2018;149:246–7. https://doi.org/10.1016/j.ygyno.2018.04.555.

    Article  Google Scholar 

  55. Mirza MR, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64. https://doi.org/10.1056/NEJMoa1611310.

    Article  CAS  PubMed  Google Scholar 

  56. Gelmon KA, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852–61. https://doi.org/10.1016/S1470-2045(11)70214-5.

    Article  CAS  PubMed  Google Scholar 

  57. Sandhu SK, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882–92. https://doi.org/10.1016/S1470-2045(13)70240-7.

    Article  CAS  PubMed  Google Scholar 

  58. Home—ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed 27 Apr 2020.

  59. Liu JF, et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: a phase 2 clinical trial. JAMA Oncol. 2019b. https://doi.org/10.1001/jamaoncol.2019.3343.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Martin-Lluesma S, Graciotti M, Grimm AJ, Boudousquié C, Chiang CL, Kandalaft LE. Are dendritic cells the most appropriate therapeutic vaccine for patients with ovarian cancer? Curr Opin Biotechnol. 2020;65:190–6. https://doi.org/10.1016/j.copbio.2020.03.003.

    Article  CAS  PubMed  Google Scholar 

  61. Phase II study of ipilimumab monotherapy in recurrent platinum-sensitive ovarian cancer—study results—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/results/NCT01611558. Accessed 25 Apr 2020.

  62. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370(9590):890–907. https://doi.org/10.1016/S0140-6736(07)61416-0.

    Article  CAS  PubMed  Google Scholar 

  63. Zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342–50. https://doi.org/10.1038/nrc798.

    Article  CAS  PubMed  Google Scholar 

  64. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  65. Borysiewicz LK, et al. A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer. Lancet. 1996;347(9014):1523–7. https://doi.org/10.1016/s0140-6736(96)90674-1.

    Article  CAS  PubMed  Google Scholar 

  66. Sharma RK, et al. Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4–1BB ligand eradicates established tumors. Cancer Res. 2009;69(10):4319–26. https://doi.org/10.1158/0008-5472.CAN-08-3141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Alvarez RD, et al. A pilot study of pNGVL4a-CRT/E7(detox) for the treatment of patients with HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3). Gynecol Oncol. 2016;140(2):245–52. https://doi.org/10.1016/j.ygyno.2015.11.026.

    Article  CAS  PubMed  Google Scholar 

  68. Basu P, et al. A randomized phase 2 study of ADXS11-001 listeria monocytogenes–listeriolysin O immunotherapy with or without cisplatin in treatment of advanced cervical cancer. Int J Gynecol Cancer. 2018;28(4):764–72. https://doi.org/10.1097/IGC.0000000000001235.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Massarelli E, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5(1):67–73. https://doi.org/10.1001/jamaoncol.2018.4051.

    Article  PubMed  Google Scholar 

  70. Frenel J-S, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;35(36):4035–41. https://doi.org/10.1200/JCO.2017.74.5471.

    Article  CAS  PubMed  Google Scholar 

  71. Naumann RW, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. JCO. 2019a;37(31):2825–34. https://doi.org/10.1200/JCO.19.00739.

    Article  CAS  Google Scholar 

  72. Santin AD, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020;157(1):161–6. https://doi.org/10.1016/j.ygyno.2019.12.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Migden MR, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–51. https://doi.org/10.1056/NEJMoa1805131.

    Article  CAS  PubMed  Google Scholar 

  74. Papadopoulos KP, et al. First-in-human study of cemiplimab alone or in combination with radiotherapy and/or low-dose cyclophosphamide in patients with advanced malignancies. Clin Cancer Res. 2020;26(5):1025–33. https://doi.org/10.1158/1078-0432.CCR-19-2609.

    Article  CAS  PubMed  Google Scholar 

  75. Naumann RW, et al. Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: results from CheckMate 358. Ann Oncol. 2019b;30:v898–9. https://doi.org/10.1093/annonc/mdz394.059.

    Article  Google Scholar 

  76. Stevanović S, et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers. Clin Cancer Res. 2019;25(5):1486–93. https://doi.org/10.1158/1078-0432.CCR-18-2722.

    Article  PubMed  Google Scholar 

  77. Lheureux S, et al. Association of ipilimumab with safety and antitumor activity in women with metastatic or recurrent human papillomavirus-related cervical carcinoma. JAMA Oncol. 2018;4(7):e173776. https://doi.org/10.1001/jamaoncol.2017.3776.

    Article  PubMed  Google Scholar 

  78. Charo LM, Plaxe SC. Recent advances in endometrial cancer: a review of key clinical trials from 2015 to 2019. F1000Res. 2019;8:849. https://doi.org/10.12688/f1000research.17408.1.

    Article  Google Scholar 

  79. Suarez AA, Felix AS, Cohn DE. Bokhman Redux: endometrial cancer ‘types’ in the 21st century. Gynecol Oncol. 2017;144(2):243–9. https://doi.org/10.1016/j.ygyno.2016.12.010.

    Article  PubMed  Google Scholar 

  80. Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73. https://doi.org/10.1038/nature12113.

    Article  CAS  Google Scholar 

  81. Rayner E, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16(2):71–81. https://doi.org/10.1038/nrc.2015.12.

    Article  CAS  PubMed  Google Scholar 

  82. Wang F, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.2963.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Prendergast EN, et al. Comprehensive genomic profiling of recurrent endometrial cancer: implications for selection of systemic therapy. Gynecol Oncol. 2019;154(3):461–6. https://doi.org/10.1016/j.ygyno.2019.06.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Soumerai TE, et al. Clinical utility of prospective molecular characterization in advanced endometrial cancer. Clin Cancer Res. 2018;24(23):5939–47. https://doi.org/10.1158/1078-0432.CCR-18-0412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Oaknin A, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti-PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-h and MSS endometrial cancer. Gynecol Oncol. 2019;154:17. https://doi.org/10.1016/j.ygyno.2019.04.044.

    Article  Google Scholar 

  86. Hasegawa K, et al. “Efficacy and safety of nivolumab (Nivo) in patients (pts) with advanced or recurrent uterine cervical or corpus cancers. JCO. 2018;36(15_suppl):5594–5594. https://doi.org/10.1200/JCO.2018.36.15_suppl.5594.

    Article  Google Scholar 

  87. Konstantinopoulos PA, et al. Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. J Clin Oncol. 2019b;37(30):2786–94. https://doi.org/10.1200/JCO.19.01021.

    Article  CAS  PubMed  Google Scholar 

  88. Antill YC, et al. “Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status: the phase II PHAEDRA trial (ANZGOG1601). JCO. 2019;37(15_suppl):5501–5501. https://doi.org/10.1200/JCO.2019.37.15_suppl.5501.

    Article  Google Scholar 

  89. Ott PA, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J Clin Oncol. 2017a;35(22):2535–41. https://doi.org/10.1200/JCO.2017.72.5952.

    Article  CAS  PubMed  Google Scholar 

  90. Makker V, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):711–8. https://doi.org/10.1016/S1470-2045(19)30020-8.

    Article  CAS  PubMed  Google Scholar 

  91. Makker V, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.19.02627.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Fleming GF, et al. Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC). JCO. 2017;35(15_suppl):5585–5585. https://doi.org/10.1200/JCO.2017.35.15_suppl.5585.

    Article  Google Scholar 

  93. Ott PA, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1–positive endometrial cancer: results from the KEYNOTE-028 study. JCO. 2017b;35(22):2535–41. https://doi.org/10.1200/JCO.2017.72.5952.

    Article  CAS  Google Scholar 

  94. Fader AN, et al. Preliminary results of a phase II study: PD-1 blockade in mismatch repair–deficient, recurrent or persistent endometrial cancer. Gynecol Oncol. 2016;141:206–7. https://doi.org/10.1016/j.ygyno.2016.04.532.

    Article  Google Scholar 

  95. Mollica V, et al. Immunotherapy and radiation therapy in renal cell carcinoma. CDT. 2020. https://doi.org/10.2174/1389450121666200311121540.

    Article  Google Scholar 

  96. Fife K, Bang A. Combined radiotherapy and new systemic therapies—have we moved beyond palliation? Clin Oncol. 2020. https://doi.org/10.1016/j.clon.2020.07.021.

    Article  Google Scholar 

  97. Neijt JP, et al. Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. JCO. 2000;18(17):3084–92. https://doi.org/10.1200/JCO.2000.18.17.3084.

    Article  CAS  Google Scholar 

  98. Pectasides D, et al. Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol. 2008;109(2):250–4. https://doi.org/10.1016/j.ygyno.2008.01.028.

    Article  CAS  PubMed  Google Scholar 

  99. Miller D, et al. Late-breaking abstract 1: randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurrent endometrial carcinoma: a gynecologic oncology group study. Gynecol Oncol. 2012;125(3):771. https://doi.org/10.1016/j.ygyno.2012.03.034.

    Article  Google Scholar 

  100. Haanen JBAG, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–42. https://doi.org/10.1093/annonc/mdx225.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Steve Spencer for English editing of this manuscript.

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Authors and Affiliations

  1. Division of Oncology, Rambam Health Care Campus, Haifa, Israel

    Tarek Taha & Ruth Perets

  2. Division of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa, Israel

    Ari Reiss & Amnon Amit

  3. Technion, Israel Institute of Technology, Haifa, Israel

    Amnon Amit & Ruth Perets

  4. Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa, Israel

    Ruth Perets

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  1. Tarek Taha
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  2. Ari Reiss
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  3. Amnon Amit
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  4. Ruth Perets
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Correspondence to Ruth Perets.

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This manuscript was funded by the women’s health grant at Rambam.

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AR served on an advisory board for MSD, the manufacturer of pembrolizumab, and has no other conflicts of interest. TT, AA, and RP have no conflicts of interest that might be relevant to the contents of this manuscript.

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TT and RP wrote the first draft of the manuscript. All of the authors participated in the conceptual design and writing of the manuscript, as well as critical revisions of important intellectual content, while RP supervised the writing of the manuscript.

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Taha, T., Reiss, A., Amit, A. et al. Checkpoint Inhibitors in Gynecological Malignancies: Are we There Yet?. BioDrugs 34, 749–762 (2020). https://doi.org/10.1007/s40259-020-00450-x

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