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Integration of immunotherapy into treatment of cervical cancer: Recent data and ongoing trials

Open AccessPublished:April 01, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102385

      Highlights

      • Two immunotherapies for recurrent/metastatic cervical cancer were approved in 2021.
      • Several trials are anticipated in recurrent/metastatic and locally advanced disease.
      • Some cases of difficult-to-treat adenocarcinoma or PD-L1-negative tumors responded.
      • Immunotherapy will become a new standard in the treatment of cervical cancer.

      Abstract

      Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab combined with chemotherapy ± bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immunotherapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new biomarkers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low- and middle-income countries are anticipated.

      Keywords

      Introduction

      Cervical cancer is preventable and treatable, yet remains a significant global health burden. In 2020, it was the fourth most diagnosed cancer and the fourth leading cause of cancer-related deaths in women [
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      Figure thumbnail gr1
      Fig. 1FIGO 2018 staging system for cervical cancer. *Early-stage cervical cancer includes stage IA1-IB2 and IIA1, and locally advanced disease includes stages IB3 and IIA2–IVA. Adapted from in Bhatla et al, 2018
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      For patients with recurrent or metastatic cervical cancer (r/mCC) who cannot receive curative intent surgery or radiotherapy, platinum-based chemotherapy with bevacizumab, if not contraindicated, is standard [
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      ]. This regimen provides a median overall survival (OS) of 14.3–18.3 months [
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      ], and, until recently, there was little benefit with second-line systemic therapies.
      Patients with LACC treated with curative intent have a better prognosis than those with r/mCC. Chemoradiotherapy (CRT) became the standard of care for LACC in 1999, providing significant improvement in disease-free survival (DFS) and OS over radiotherapy alone [

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      ]; intracavitary brachytherapy following CRT further improved outcomes and is considered a critical component of CRT [
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      ]. Recent attempts to enhance CRT have experienced setback; addition of adjuvant chemotherapy to CRT did not improve survival in the phase III OUTBACK trial [
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      ].
      Immunotherapy is a promising emerging option supported by multiple findings. First, nearly all cases of cervical cancer arise after persistent infection with a high-risk HPV subtype [
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      ]. Integration of HPV E6 and E7 viral oncoproteins into the cellular genome allows for their unregulated expression, creating a conducive environment for further genetic mutations related to tumor cell survival and immune escape [
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      ]. This immune system suppression is a key step in development of cervical cancer. Second, programmed cell death ligand-1 (PD-L1) is widely expressed in the tumor microenvironment [
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      ]. Third, the presence or absence of tumor-infiltrating immune cells has prognostic significance in cervical cancer [
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      ]. Finally, with respect to treatment for LACC, radiotherapy increases antigen generation and presentation, T-cell priming, dendritic activation, as well as levels of pro-inflammatory cytokines [
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      ], and small clinical trials of radiotherapy-based treatment combined with immunotherapy show promise [
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      ].
      Immunotherapies that directly target cervical cancer and provide innate antitumor effects as well as those that function to reactivate the immune system against cervical tumors are under investigation. In June 2018, pembrolizumab was the first immunotherapy to receive US Food and Drug Administration (FDA) accelerated approval as second-line treatment for patients with PD-L1-positive persistent or r/mCC. In 2021, two additional FDA approvals were granted: tisotumab vedotin for second-line r/mCC and pembrolizumab combined with chemotherapy ± bevacizumab for first-line PD-L1-positive persistent or r/mCC. With at least 2 dozen additional immunotherapies in clinical trials (Table 1) [
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      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      ,
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      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ,
      • Duska L.R.
      • Scalici J.M.
      • Temkin S.M.
      • Schwarz J.K.
      • Crane E.K.
      • Moxley K.M.
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      Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.
      ,
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..
      ,
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      ,
      • Qu Y.-Y.
      • Guo H.
      • Luo H.
      • Zou Q.
      • Xing N.
      • Sun Z.
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      Camrelizumab plus famitinib malate in patients with advanced renal cell cancer and unresectable urothelial carcinoma: A multicenter, open-label, single-arm, phase II trial..
      ,
      • Tewari K.S.
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      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
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      Survival with cemiplimab in recurrent cervical cancer.
      ,
      • Tjulandin S.
      • Demidov L.
      • Moiseyenko V.
      • Protsenko S.
      • Semiglazova T.
      • Odintsova S.
      • et al.
      Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice.
      ,

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      ], the treatment landscape for cervical cancer is on the verge of a paradigm shift. Multiple compounds are in various stages of development that examine the potential for improvement in efficacy and safety in different treatment lines and cervical cancer stages. With many of these in early stages, specific advantages and risks for these treatments remain to be seen. Here we review pivotal trials of immunotherapies that were recently approved or have the potential for regulatory consideration through 2024 (Fig. 2) [

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      ,

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      ] and discuss biomarkers and histologic type in relation to immunotherapy, as well as anticipated challenges.
      Table 1Risks and benefits of selected therapies under investigation for treatment of locally advanced cervical cancer.
      TherapyClass/Target Mechanism of actionCervical Cancer StagePrevious TherapiesClinical PhaseAdditional Insights
      BalstimabPD-1r/m SCC, AC, or ASC cervical cancerFailed prior platinum-based chemotherapyIITargets PD-1/PD-L1 CTLA-4 axis

      Hypothyroidism, diarrhea, fatigue most common trAEs
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.


      CadonilimabPD-1 and CTLA-4r/m SCC or ASC cervical cancerUp to 2 prior systemic therapiesIITargets PD-1/PD-L1 CTLA-4 axis

      Bispecific antibody may affect toxicity



      Anemia, hypothyroidism, alanine aminotransferase increase most common trAEs

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      CamrelizumabPD-1r/m SCC, AC, or ASC cervical cancerRelapsed after platinum-based chemotherapy regimenIITargets PD-1/PD-L1 CTLA-4 axis

      CemiplimabPD-1r/m or persistent SCC, AC, or ASC cervical cancerPrior platinum-based regimenIIITargets PD-1/PD-L1 CTLA-4 axis

      Fatigue, nausea, anemia, asthenia, and decreased appetite most common trAEs
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      GepatanolimabPD-1r/m PD-L1-positive cervical cancerProgressed or had recurrence after platinum-based chemotherapyIITargets PD-1/PD-L1 CTLA-4 axis
      NivolumabPD-1Virus-associated cancers (including r/m SCC cervical cancer with HPV status positive or unknown)Progressed after up to 2 prior systemic therapiesI/IITargets PD-1/PD-L1 CTLA-4 axis
      PembrolizumabPD-1r/m or persistent SCC, AC, or ASC cervical cancerUntreatedIIITargets PD-1/PD-L1 CTLA-4 axis

      AEs included hypothyroidism and decreased white cell count in treatment arm
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      High-risk SCC, AC, or ASC cervical cancer, FIGO 2014 stage IB2-IIB node positive or stage III-IVA any node statusUntreatedIII

      Common trAEs of concern were diarrhea, nausea, and vomiting
      • Duska L.R.
      • Scalici J.M.
      • Temkin S.M.
      • Schwarz J.K.
      • Crane E.K.
      • Moxley K.M.
      • et al.
      Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.
      ProlgolimabPD-1 with FC silencing LALA mutationr/m or persistent SCC cervical cancerUntreatedIIITargets PD-1/PD-L1 CTLA-4 axis

      LALA mutation may reduce FcγRI, IIa, IIIa binding, and improve efficacy
      • Tjulandin S.
      • Demidov L.
      • Moiseyenko V.
      • Protsenko S.
      • Semiglazova T.
      • Odintsova S.
      • et al.
      Novel PD-1 inhibitor prolgolimab: expanding non-resectable/metastatic melanoma therapy choice.
      SintilimabPD-1r/m cervical cancerRelapsed after platinum-based chemotherapy regimenIITargets PD-1/PD-L1 CTLA-4 axis
      ZimberelimabPD-1PD-L1-positive r/m cervical cancerProgressed on ≥ 1 chemotherapy or are resistant to chemotherapyIITargets PD-1/PD-L1 CTLA-4 axis
      AtezolizumabPD-L1PD-L1-positive r/m or persistent SCC, AC, or ASC cervical cancerProgressed after 1–2 prior systemic chemotherapy regimensIITargets PD-1/PD-L1 CTLA-4 axis
      r/m or persistent SCC, AC, or ASC cervical cancerUntreatedIII
      DurvalumabPD-L1SCC, AC, or ASC cervical cancer, FIGO 2009 Stage IB2-IIB node positive or IIIA-IVA any node statusUntreatedIIITargets PD-1/PD-L1 CTLA-4 axis
      IBI-310CTLA-4r/m cervical cancerRelapsed after platinum-based chemotherapy regimenIITargets PD-1/PD-L1 CTLA-4 axis
      IpilimumabCTLA-4Virus-associated cancers (including r/m SCC cervical cancer with HPV status positive or unknownProgressed after up to 2 prior systemic therapiesI/IITargets PD-1/PD-L1 CTLA-4 axis
      ZafrelimabCTLA-4r/m SCC, AC, or ASC cervical cancerFailed a prior platinum-based chemotherapy regimenIITargets PD-1/PD-L1 CTLA-4 axis

      Hypothyroidism, diarrhea, fatigue most common trAEs
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      FamitinibVEGFR-2, PDGFR, c-kit, FGFR (small molecule rTKIrTKI) (list targets)
      • Qu Y.-Y.
      • Guo H.
      • Luo H.
      • Zou Q.
      • Xing N.
      • Sun Z.
      • et al.
      Camrelizumab plus famitinib malate in patients with advanced renal cell cancer and unresectable urothelial carcinoma: A multicenter, open-label, single-arm, phase II trial..
      r/m SCC, AC, or ASC cervical cancerRelapsed after platinum-based chemotherapy regimenIIUnique targets

      Multiple targets and lack of specificity may cause off-target or unanticipated effects
      LifileucelAutologous tumor infiltrating lymphocytesr/m, or persistent SCC, AC, or ASC cervical cancer≥1 prior systemic therapyIIUnique mechanism of action

      Most common grade 3/4 AEs included anemia, thrombocytopenia, neutropenia, and febrile neutropenia
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..




      TiragolumabTIGITPD-L1-positive r/m or persistent SCC, AC, or ASC cervical cancerProgressed after 1–2 prior systemic chemotherapy regimensIIUnique target
      Tisotumab vetodinAntibody drug conjugate targeting tissue factor, with tubulin inhibitor payloadr/m SCC, AC, or ASC cervical cancerup to 2 prior systemic treatments, which included platinum-based chemotherapy +/- bevacizumabIIUnique target and mechanism Most common trAEs include alopecia, epistaxis, nausea, conjunctivitis, fatigue, dry eye
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      Z-100Immunomodulator (bacterial extract)SCC cervical cancer, FIGO 2008 Stage IIIBUntreatedIIIUnique mechanism
      AC, adenocarcinoma; ASC, adenosquamous carcinoma; c-kit, stem cell factor receptor; CRT, chemoradiotherapy; FcγR, FC gamma receptor; FGFR, fibroblast growth factor receptor; FIGO, International Federation of Gynecology and Obstetrics; PDGFR, platelet-derived growth factor receptor; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; r/m, recurrent/metastatic; SCC, squamous cell carcinoma; rTKI, receptor tyrosine kinase inhibitor; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; trAEs, treatment-related adverse events; VEGFR-2, vascular endothelial growth factor receptor 2.
      Figure thumbnail gr2
      Fig. 2Health authority decisions and anticipated pivotal trial data for cervical cancer immunotherapies 2021–2024. *The cadonilimab primary endpoint data were released in an Akesobio investor presentation
      [

      Akesobio. 2021 Interim Results Presentation, August 2021. 2021. https://www.akesobio.com/media/1525/akeso-2021-ir-presentation-20210901_final_sj.pdf. accessed October 6, 2021.

      ]
      and were presented at an academic congress
      [

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      ]
      . Tistumab vedotin monotherapy was given accelerated approval for treatment of adult patients with r/m cervical cancer that progressed on or after chemotherapy. §Final primary endpoint data have not been disclosed by the study sponsor nor presented at an academic congress or published in a peer-reviewed journal. Pembrolizumab in combination with chemotherapy and with or without bevacizumab was approved for patients with untreated r/m or persistent cervical cancer that expresses PD-L1 (CPS ≥ 1%). BLA, biologic license application; CPS, combined positive score; FDA, United States Food and Drug Administration; PD-L1, programmed cell death ligand-1; r/m, recurrent/metastatic.

      Key clinical trials of immunotherapy for cervical cancer

      Second-line therapies for recurrent or metastatic cervical cancer

      Numerous immunotherapies or immunotherapy combinations are under evaluation for second-line or greater treatment of r/mCC, with one antibody-drug conjugate FDA-approved in September 2021 (Table 2) [
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      ,
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..
      ,
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ,

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      ,
      • Naumann R.W.
      • Hollebecque A.
      • Meyer T.
      • Devlin M.-J.
      • Oaknin A.
      • Kerger J.
      • 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.
      ,
      • Naumann R.W.
      • Oaknin A.
      • Meyer T.
      • Lopez-Picazo J.M.
      • Lao C.
      • Bang Y.-J.
      • et al.
      Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358.
      ,

      Regeneron. Regeneron and Sanofi Provide Regulatory Update on Libtayo® (cemiplimab-rwlc) in Advanced Cervical Cancer. 2022. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-regulatory-update-libtayor. accessed February 2, 2022.

      ,

      US Food and Drug Administration. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer accessed October 7, 2021.

      ,
      • Wu X.
      • Xia L.
      • Zhou Q.
      • Zhu J.
      • Wang K.
      • Chen J.
      • et al.
      357 GLS-010 (zimberelimab), a novel fully human anti-PD-1 mAb in chinese patients with recurrent/metastatic cervical cancer: results from a multicenter, open-label, single-arm phase II trial.
      ].
      Table 2Selected therapies under investigation for second-line or later treatment of recurrent/metastatic cervical cancer.
      TherapyMechanism of actionCervical cancer-related health authority designations/decisionsPivotal trial name/IDsStudy designPatient populationTreatment armsPrimary endpoint(s)Primary endpoint completion dateAvailable pivotal trial

      efficacy data
      Tisotumab vedotinAntibody drug conjugate targeting tissue factor, with tubulin inhibitor payloadFDA accelerated approval September 2021

      US Food and Drug Administration. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer accessed October 7, 2021.

      innovaTV 204/ GOG-3023/ ENGOT-cx6



      NCT03438396
      Phase II

      Open-label

      Single Arm
      Adults with r/m SCC, AC, or ASC cervical cancer who had up to 2 prior systemic treatments, which included platinum-based chemotherapy +/- bevacizumabTisotumab vedotin monotherapy

      2.0 mg/kg IV Q3W
      ORR by IRC per RECIST v1.1June 2020Coleman, et al 2021:
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.


      (N = 101)

      Median 10.0 months F/U

      ORR, 24%

      DCR, 72%
      CemiplimabAnti-PD-1 antibodyFDA BLA voluntarily withdrawn January 2022

      Regeneron. Regeneron and Sanofi Provide Regulatory Update on Libtayo® (cemiplimab-rwlc) in Advanced Cervical Cancer. 2022. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-regulatory-update-libtayor. accessed February 2, 2022.

      EMPOWER-CERVICAL 1/ GOG-3016/ ENGOT-cs9



      NCT03257267
      Phase III

      Open-label



      Randomized 1:1

      Adults with r/m or persistent SCC, AC, or ASC cervical cancer who had a prior platinum-based regimenExperimental arm:

      Cemiplimab monotherapy

      350 mg IV Q3W



      Comparator arm:

      Investigator’s choice chemotherapy (IC)
      OS in SCC population



      OS in overall population
      January 2021Tewari, et al 2022:
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.




      SCC population

      (N = 477)

      Cemiplimab arm OS, 11.1 months

      IC arm OS, 8.8 months

      HR 0.73; P = 0.006



      Overall population

      (N = 608)

      Cemiplimab arm OS, 12.0 months

      IC arm OS, 8.5 months

      HR, 0.69; P < 0.001
      Cadonilimab (AK104)Anti-PD-1/CTLA-4 bi-specific antibodyFDA fast-track therapy 2020; China NMPA breakthrough therapy 2020;

      FDA orphan drug 2021



      NDA submitted to China NMPA September 2021, with priority review
      AK104-201-AU



      NCT04380805
      Phase II

      Open-label

      Single Arm
      Adults with r/m SCC, AC or ASC cervical cancer who had up to 2 prior systemic therapiesCadonilimab monotherapy

      6 mg/kg IV Q2W
      ORR by IRCAugust 2021SGO 2022

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.





      Overall population

      (N = 100)

      ORR, 33%

      CR, 12%



      PD-L1 + population

      (N = 64)

      ORR 44%

      Nivolumab + ipilimumabAnti-PD-1 antibody and an anti-CTLA-4 antibodyNoneCheckMate358



      NCT02488759
      Phase I/II

      Open-label

      Multiple cohort

      Randomized
      Adults with virus-associated cancers (including r/m SCC cervical cancer with HPV status positive or unknown that progressed after up to 2 prior systemic therapies)
      • Naumann R.W.
      • Hollebecque A.
      • Meyer T.
      • Devlin M.-J.
      • Oaknin A.
      • Kerger J.
      • 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.
      Combo A:

      Nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W



      Combo B:

      Nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W for 4 doses, then nivolumab 240 mg Q2W
      ORR by investigator assessmentExpected September 2021

      ESMO 2019:
      • Naumann R.W.
      • Oaknin A.
      • Meyer T.
      • Lopez-Picazo J.M.
      • Lao C.
      • Bang Y.-J.
      • et al.
      Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358.




      No PST

      Combo A (n = 19); ORR, 32%

      Combo B (n = 24); ORR, 46%



      With PST

      Combo A (n = 26); ORR, 23%

      Combo B (n = 22); ORR, 36%
      Geptanolimab (GB226)Anti-PD-1 antibodyNoneGxplore-008



      NCT03808857
      Phase II

      Open-label

      Single Arm

      Adults with r/m PD-L1-positive cervical cancer who progressed or had recurrence after platinum-based chemotherapyGeptanolimab monotherapy

      3 mg/kg infusion Q2W
      ORRExpected December 2021None
      Lifileucel

      (LN-145)
      Autologous tumor infiltrating lymphocytesFDA orphan drug 2018; FDA breakthrough therapy 2019innovaTIL-04



      NCT03108495
      Phase II

      Open-label

      Multiple cohorts

      Nonrandomized
      Adults with r/m, or persistent SCC, AC, or ASC cervical cancer who had ≥ 1 prior systemic therapy



      Cohort 1:

      PD with 1–3 prior chemotherapies +/- bevacizumab



      Cohort 2:

      Same as Cohort 1, plus must have received prior ICI therapy



      Cohort 3 (US only):

      Only received prior CRT or surgery for locoregional disease; not treated with prior immunotherapy



      Cohort 4: Did not meet criteria for Cohorts 1 and 2



      Cohort 5: Pts progressed on previous LN-145 treatment
      Adoptive cell transfer of autologous TILs



      Cohort 1, 2, 4: After non-myeloablative lymphodepletion (NMA), pts receive LN-145, then IL-2



      Cohort 3: Pembro, then NMA, then pts receive LN-145 followed by IL-2; pembro ∼ 3 wks after IL-2, for up to 24 months



      Cohort 5: pts receive a second treatment with LN-145
      Cohort 1 and 2:

      ORR by IRC per RECIST v1.1



      Cohort 3: Safety of pembro combo



      Cohort 4:

      Efficacy and safety



      Cohort 5:

      Efficacy and safety

      Expected December 2021ASCO 2019:*
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..


      (N = 27)

      Median F/U 7.4 months

      ORR, 44%

      DCR, 85%
      Camrelizumab + famitinibAnti–PD-1 antibody and a small molecule rTKIChina NMPA breakthrough therapy 2020

      SHR-1210-II-217



      NCT04680988
      Phase II

      Open-label

      Multiple arms Randomized
      Adults with r/m SCC, AC, or ASC cervical cancer who relapsed after platinum-based chemotherapy regimenArm 1: Camrelizumab IV Q3W + famitinib orally once daily



      Arm 2:

      Camrelizumab IV Q3W



      Arm 3 (active comparator):

      Investigator’s choice of: albumin-bound paclitaxel, pemetrexed, or gemcitabine
      PFS per RECIST v1.1 of Arm 1 vs Arm 2



      OS of Arm 1 vs Arm 3
      Expected

      April 2022
      None
      Zimberelimab (GLS-010)Anti-PD-1 antibodyChina NMPA breakthrough therapy 2021YH-S001-05



      NCT03972722
      Phase II

      Open-label

      Single arm
      Adults with PD-L1-positive r/m cervical cancer who progressed on ≥ 1 chemotherapy or are resistant to chemotherapyZimberelimab monotherapy 240 mg Q2WORR by IRC per RECIST v1.1Expected May 2022IGCS 2020:
      • Wu X.
      • Xia L.
      • Zhou Q.
      • Zhu J.
      • Wang K.
      • Chen J.
      • et al.
      357 GLS-010 (zimberelimab), a novel fully human anti-PD-1 mAb in chinese patients with recurrent/metastatic cervical cancer: results from a multicenter, open-label, single-arm phase II trial.


      (N = 41)

      Median 5.2 months F/U

      ORR, 27%

      DCR, 54%
      Balstilimab + zalifrelimabAnti-PD-1 antibody and an anti-CTLA-4 antibodyFDA fast-track therapy 2020RaPiDS



      NCT03894215
      Phase II

      Blinded

      Noncomparative

      Randomized 1:1
      Adults with r/m SCC, AC, or ASC cervical cancer who failed a prior platinum-based chemotherapy regimenArm 1:

      Balstilimab 300 mg Q3W + placebo



      Arm 2:

      Balstilimab 300 mg Q3W + zalifrelimab 1 mg/kg Q6W
      ORR by IRC per RECIST v1.1Expected December 2022None
      Tiragolumab + atezolizumabAnti-TIGIT antibody and an anti-PD-L1 antibodyNoneSKYSCRAPER-04



      NCT04300647
      Phase II

      Open-label

      Parallel-cohort

      Randomized 3:1
      Adults with PD-L1-positive r/m or persistent SCC, AC, or ASC cervical cancer who progressed after 1–2 prior systemic chemotherapy regimensArm 1: Tiragolumab 600 mg IV Q3W + atezolizumab 1200 mg IV Q3W



      Arm 2:

      Atezolizumab monotherapy

      1200 mg IV Q3W
      ORR by IRCExpected July 2023None
      Sintilimab +

      IBI-310
      Anti–PD-1 antibody and an anti-CTLA-4 antibodyNoneCIBI310E201



      NCT04590599
      Phase II

      Double-blind

      Parallel-cohort

      Randomized
      Adults with r/m cervical cancer who relapsed after platinum-based chemotherapy regimenArm 1:

      Sintilimab 200 mg + placebo



      Arm 2:

      Sintilimab 200 mg + IBI-310
      ORR by IRC per RECIST v1.1Expected November 2023None



      *Cohorts were not specified in the ASCO poster or abstract; however, there were 4 patients who received prior anti-PD-1/PD-L1 therapy, suggesting a mix of cohorts is represented.
      Trial design and anticipated primary endpoint completion dates were obtained from the respective clinicaltrials.gov webpages. Therapies are listed in order of primary endpoint completion date.
      AC, adenocarcinoma; ASC, adenosquamous carcinoma; ASCO, American Society of Clinical Oncology; BLA, biologic license application; CRT, chemoradiation; CR, complete response; DCR, disease control rate; ESMO, European Society for Medical Oncology; FDA, United States Food and Drug Administration; ICI, immune checkpoint inhibitor; IGCS, International Gynecologic Cancer Society; IRC, independent review committee; NMPA, China's National Medical Products Administration; ORR, objective response rate; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PST, prior systemic therapies; pts, patients; RECIST, Response Evaluation Criteria in Solid Tumors; rTKI, receptor tyrosine kinase inhibitor; SCC, squamous cell carcinoma; SGO, Society of Gynecologic Oncology; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains.

      Cadonilimab

      Cadonilimab (AK104) is a first-in-class anti-programmed cell death-1 (PD-1)/cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) bispecific monoclonal antibody being studied as monotherapy for patients with r/mCC after failed platinum-based chemotherapy. It received FDA fast-track and orphan drug designation as well as China's National Medical Products Administration (NMPA) breakthrough therapy designation [

      Akesobio. Cadonilimab (PD-1/CTLA-4 Bispecific Antibody) Obtained Orphan Drug Designation from FDA of the United States for Treating Cervical Cancer. 2021. https://www.akesobio.com/en/media/akeso-news/2021-3-3/. accessed July 6, 2021.

      ]. The pivotal trial is a phase II, single arm study of cadonilimab monotherapy in patients with previously treated r/mCC. Results showed 33.0% objective response rate (ORR) in 100 patients treated with cadonilimab (12.0% complete response) [

      Wu X. Efficacy and safety of cadonilimab, an anti-PD-1/CTLA4 bi-specific antibody, in previously treated recurrent or metastatic (R/M) cervical cancer: a multicenter, open-label, single-arm, phase II trial. Presented at: Society of Gynecologic Oncology Annual Meeting on Womens' Cancer; March 19, 2022; Phoenix, AZ.

      ]. Patients considered PD-L1-positive (n = 64) had an ORR of 43.8%. Unpublished results from an August 2021 Akesobio investor meeting [

      Akesobio. 2021 Interim Results Presentation, August 2021. 2021. https://www.akesobio.com/media/1525/akeso-2021-ir-presentation-20210901_final_sj.pdf. accessed October 6, 2021.

      ] were submitted in a new drug application to the China NMPA in September 2021 [

      Akesobio. New drug application for cadonilimab (PD-1/CTLA-4 bi-specific antibody) for the treatment of relapsed or metastatic cervical cancer accepted by NMPA. 2021. https://portalvhds1fxb0jchzgjph.blob.core.windows.net/press-releases-attachments/1338370/HKEX-EPS_20210924_9946859_0.PDF. accessed October 6, 2021.

      ]. A second registrational trial in China (NCT04868708) is anticipated to complete its primary endpoint in April 2022 and a phase III trial in China of cadonilimab versus placebo combined with platinum-based chemotherapy ± bevacizumab for first-line persistent or r/mCC started in July 2021 (NCT04982237).

      Cemiplimab

      Cemiplimab is a high-affinity, hinge-stabilized, human anti-PD-1 IgG4 monoclonal antibody [
      • Rischin D.
      • Gil-Martin M.
      • González-Martin A.
      • Braña I.
      • Hou J.Y.
      • Cho D.
      • et al.
      PD-1 blockade in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer.
      ]. EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is a phase III, open-label, randomized study of cemiplimab versus investigator’s choice chemotherapy in 608 patients with r/mCC that progressed after first-line platinum-based treatment. The trial stopped early due to the significant benefit of cemiplimab therapy. After discussions with the FDA regarding additional post-marketing studies, cemiplimab company sponsors voluntarily withdrew an FDA biologic license application in January 2022, though regulatory submissions outside of the US are being considered [

      Regeneron. Regeneron and Sanofi Provide Regulatory Update on Libtayo® (cemiplimab-rwlc) in Advanced Cervical Cancer. 2022. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-regulatory-update-libtayor. accessed February 2, 2022.

      ].
      Median OS in the overall population (N = 304 for both arms) was 12.0 months with cemiplimab vs 8.5 months with chemotherapy (hazard ratio [HR], 0.69; P < 0.001) and ORR was 16.4% cemiplimab vs 6.3% chemotherapy [
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ]. Progression-free survival (PFS) in the overall and squamous cell carcinoma (SCC) populations also favored cemiplimab (2.8 vs 2.9 months for both populations; overall: HR, 0.75, P < 0.001; SCC: HR, 0.71, P < 0.001). Prespecified subgroup analysis favored cemiplimab over chemotherapy regardless of histology or Eastern Cooperative Oncology Group status, as well as for patients from Asia or regions other than North America, for those who had prior bevacizumab, or who received 1 prior line of therapy for r/mCC.
      Treatment-related adverse events (AEs) occurred in 56.7% of patients receiving cemiplimab (n = 300) vs 81.4% receiving chemotherapy (n = 290), and no new toxicities were observed [
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ]. While the rate of treatment-related AEs of ≥ grade 3 was lower for cemiplimab (14.7% vs 40.3%), discontinuations due to any grade treatment-related AEs were more frequent (5.7% vs 3.4%). In both overall and SCC populations, treatment with cemiplimab resulted in statistically significant improvement in patient-reported global health status/quality of life and physical functioning scores versus chemotherapy, as well as clinically meaningful benefit in role functioning, pain, and appetite loss [
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ].

      Geptanolimab

      Geptanolimab (GB226) is an anti-PD-1 monoclonal antibody. The ongoing phase II pivotal trial, Gxplore-008, is evaluating the efficacy, safety, and immunogenicity of geptanolimab for second-line or later treatment of patients with PD-L1-positive r/mCC. Approximately 80 patients from China will be enrolled. The primary endpoint is ORR, which is estimated for completion in December 2021.

      Zimberelimab

      Zimberelimab (GLS-010) is a novel, fully-human anti-PD-1 monoclonal antibody being investigated as monotherapy for patients with PD-L1-positive (combined positive score [CPS] ≥ 1) r/mCC that failed ≥ 1 prior chemotherapy regimen. It received China’s NMPA breakthrough therapy designation in March 2021 [

      Ligand’s partner Gloria Biosciences receives approval in China for zimberelimab for the treatment of recurrent or refractory classical Hodgkin’s lymphoma. 2021. Available at: https://www.businesswire.com/news/home/20210830005543/en/Ligand%E2%80%99s-Partner-Gloria-Biosciences-Receives-Approval-in-China-for-Zimberelimab-for-the-Treatment-of-Recurrent-or-Refractory-Classical-Hodgkin%E2%80%99s-Lymphoma. [accessed December 9, 2021].

      ]. The phase II registrational trial is enrolling approximately 89 patients, and primary endpoint (ORR) completion is expected in May 2022. In an interim analysis of 41 evaluable patients (April 2, 2020; median follow-up 5.2 months), investigator-assessed ORR was 27% and median DoR was not reached [
      • Wu X.
      • Xia L.
      • Zhou Q.
      • Zhu J.
      • Wang K.
      • Chen J.
      • et al.
      357 GLS-010 (zimberelimab), a novel fully human anti-PD-1 mAb in chinese patients with recurrent/metastatic cervical cancer: results from a multicenter, open-label, single-arm phase II trial.
      ]. Treatment-related AEs ≥ grade 3 were experienced by 17 of 45 patients (38%), and 1 patient discontinued due to an AE [
      • Wu X.
      • Xia L.
      • Zhou Q.
      • Zhu J.
      • Wang K.
      • Chen J.
      • et al.
      357 GLS-010 (zimberelimab), a novel fully human anti-PD-1 mAb in chinese patients with recurrent/metastatic cervical cancer: results from a multicenter, open-label, single-arm phase II trial.
      ].

      Balstilimab + zalifrelimab

      Balstilimab (bal) is a fully-human anti-PD-1 antibody. Zalifrelimab (zal) is a fully-human anti-CTLA-4 antibody. The bal + zal combination received FDA fast-track designation for r/mCC in March 2020. In final results from the phase II study, C-550–01, the ORR and median DoR were 25.6% and not reached for 125 patients who relapsed after one prior platinum-based treatment for r/mCC [
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      ]. At a median follow up of 21.0 months, median PFS and OS were 2.7 and 12.8 months. Hypothyroidism (16.8%), diarrhea (14.2%), and fatigue (11.6%) were the most frequent treatment-related AEs, and 20% of patients experienced ≥ grade 3 treatment-related AEs. Toxicities were manageable as only 12.3% and 7.7% of patients had a treatment-related AE resulting in dose interruption or discontinuation.
      RaPiDS is the ongoing pivotal, phase II randomized trial assessing the safety and efficacy of second-line bal monotherapy and bal + zal in patients with previously treated r/mCC. Approximately 200 patients from the United States, Mexico, Korea, Taiwan, and Thailand will be enrolled, and the trial is expected to complete in December 2022. The primary endpoint is ORR.

      Nivolumab + ipilimumab

      Combination therapy with anti-PD-1 antibody nivolumab, and anti-CTLA-4 antibody ipilimumab, is approved for treatment of several solid tumors [

      Opdivo (nivolumab injection). US Prescribing information. Bristol Myers Squibb; September 2021. Accessed January 4, 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394.

      ]. In the Checkmate 358 study, nivolumab was tested alone and in combination with other anticancer agents for treatment of virus-associated tumors. Interim results were presented at ESMO 2019 for 2 regimens of nivolumab + ipilimumab (combo A: nivolumab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q6W; combo B: nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3W (four doses), then nivolumab 240 mg Q2W) in 91 patients with HPV + or HPV status unknown r/mCC who were untreated or had failed up to two prior systemic therapies [
      • Naumann R.W.
      • Oaknin A.
      • Meyer T.
      • Lopez-Picazo J.M.
      • Lao C.
      • Bang Y.-J.
      • et al.
      Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358.
      ]. Patients who were not previously treated had numerically higher ORRs with both regimens (combo A and B untreated: 32% and 46%; previously treated: 23% and 36%). This trend was also evident with median PFS and OS (PFS combo A and B untreated: 13.8 and 8.5 months; previously treated: 3.6 and 5.8 months; OS untreated: not reached for both; previously treated: 10.3 and 25.4 months). The safety profile of both combinations was consistent with other indications. Primary endpoint completion was expected September 2021, but the results have not yet been published.

      Sintilimab + IBI-310

      Sintilimab is a fully-human anti-PD-1 IgG4 monoclonal antibody. IBI-310 is a biosimilar of ipilimumab. The ongoing phase II pivotal, randomized, double-blind trial is evaluating efficacy and safety of sintilimab + IBI-310 versus sintilimab + placebo in patients with r/mCC who failed prior platinum-based chemotherapy. Approximately 174 patients from China will be enrolled with completion expected in November 2023. The primary endpoint is ORR.

      Camrelizumab + famitinib

      Camrelizumab is a humanized anti-PD-1 IgG4 monoclonal antibody. Famitinib is a receptor tyrosine kinase inhibitor targeting c-Kit, vascular endothelial growth factor receptor-2 and -3, platelet-derived growth factor receptor, FMS-like tyrosine kinase-3 receptor, and Ret [
      • Xie C.
      • Zhou J.
      • Guo Z.
      • Diao X.
      • Gao Z.
      • Zhong D.
      • et al.
      Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients.
      ,
      • Zhou A.
      • Zhang W.
      • Chang C.
      • Chen X.
      • Zhong D.
      • Qin Q.
      • et al.
      Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib.
      ]. The combination received China's NMPA breakthrough therapy designation [

      Hengrui. Hengrui Medicine's camrelizumab + famitinib malate combination therapy is included in the public announcement of the type of breakthrough treatment [Translated]. 2020. https://mp.weixin.qq.com/s/HTmMrJVkHaksBaW3Wk3BCw. accessed October 18, 2021.

      ]. The ongoing phase II, pivotal, randomized trial (SHR-1210-II-217) is evaluating the efficacy and safety of camrelizumab alone or in combination with famitinib versus chemotherapy in patients with r/mCC who failed prior platinum-based treatment. Approximately 250 patients from China will be enrolled. The dual primary endpoints are PFS for camrelizumab + famitinib versus camrelizumab alone and OS for camrelizumab + famitinib versus chemotherapy. Primary endpoint completion is estimated for April 2022.

      Tiragolumab + atezolizumab

      The inhibitory receptor, TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), is involved in dampening adaptive and innate immune responses to tumors and is being pursued as an immunotherapy target for multiple solid tumors [
      • Chauvin J.-M.
      • Zarour H.M.
      TIGIT in cancer immunotherapy.
      ]. Its expression has been observed in cervical cancer tumor infiltrating lymphocytes (TILs) [
      • Li X.i.
      • Wang R.
      • Fan P.
      • Yao X.
      • Qin L.
      • Peng Y.
      • et al.
      A comprehensive analysis of key immune checkpoint receptors on tumor-infiltrating T cells from multiple types of cancer.
      ]. In the ongoing phase II, international SKYSCRAPER-04 study, the safety and efficacy of the combination of tiragolumab (anti-TIGIT antibody), with atezolizumab (anti-PD-L1 antibody), or atezolizumab monotherapy is being evaluated in patients with PD-L1-positive r/mCC that progressed after ≥ 1 chemotherapy regimen. Enrollment completed in July 2021 with 172 patients. The primary endpoint of ORR is expected in July 2023.

      Lifileucel

      Lifileucel (LN-145) is an adoptive cell therapy, whereby TILs are harvested from the patient, expanded ex vivo, then infused after nonmyeloablative lymphodepletion. Lifileucel received FDA breakthrough designation in 2019 [

      Broderick JM. FDA Grants LN-145 Breakthrough Designation for Cervical Cancer [press release]. 2019. https://www.onclive.com/view/fda-grants-ln145-breakthrough-designation-for-cervical-cancer. accessed September 28, 2021.

      ] based on interim data from the ongoing phase II innovaTIL-04 (C-145–04) trial, which evaluated the efficacy and safety of lifileucel in 27 patients with persistent or r/mCC who had at least one prior line of chemotherapy [
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..
      ,

      Broderick JM. FDA Grants LN-145 Breakthrough Designation for Cervical Cancer [press release]. 2019. https://www.onclive.com/view/fda-grants-ln145-breakthrough-designation-for-cervical-cancer. accessed September 28, 2021.

      ]. At median follow-up of 7.4 months, ORR was 44.4%, disease control rate (DCR) was 85.2%, and the median DoR was not reached. Adverse events were consistent with the underlying advanced disease, lymphodepletion, and IL-2 regimens. The most common grade 3/4 AEs included anemia (55.6%), thrombocytopenia (44.4%), neutropenia (29.6%), and febrile neutropenia (29.6%). AE frequency was highest within ∼ 12 days of receiving treatment, and was fairly infrequent afterward [
      • Jazaeri A.A.
      • Zsiros E.
      • Amaria R.N.
      • Artz A.S.
      • Edwards R.P.
      • Wenham R.M.
      • et al.
      Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma..
      ]. Primary endpoint completion is expected in December 2021.

      Tisotumab vedotin

      Tisotumab vedotin (TV) is a tissue factor-directed antibody-drug conjugate that releases the microtubule-disrupting agent monomethyl auristatin E (MMAE) after internalization into the target cell, which leads to cell cycle arrest and apoptotic cell death. MMAE may also leave the target cell and enter and kill neighboring tumor cells, known as bystander cytotoxicity [
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      ]. In September 2021, TV was granted FDA accelerated approval to treat patients with r/mCC with disease progression on or after chemotherapy [

      US Food and Drug Administration. FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tisotumab-vedotin-tftv-recurrent-or-metastatic-cervical-cancer accessed October 7, 2021.

      ]. This is the first approved antibody-drug conjugate for cervical cancer. Approval was based on the pivotal phase II, single arm innovaTV 204/GOG-3023/ENGOT-cx6 trial [
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      ]. After 10 months’ median follow-up of 101 women with previously treated r/mCC, the confirmed ORR was 24% and median duration of response (DoR) was 8.3 months. The most common treatment-related adverse events included alopecia, epistaxis, nausea, conjunctivitis, fatigue, and dry eye. Treatment-related serious and grade ≥ 3 AEs occurred for 13% and 28% of patients, respectively. A confirmatory phase III trial of TV versus chemotherapy for second- or third-line r/mCC was initiated in February 2021 (NCT04697628).
      TV is also under investigation in combination with pembrolizumab for previously-treated r/mCC in a phase II study (innovaTV 205/ENGOT-cx8/GOG-3024) [
      • Vergote I.B.
      • Monk B.J.
      • O’Cearbhaill R.E.
      • Westermann A.M.
      • Banerjee S.
      • Collins D.C.
      • et al.
      723MO - Tisotumab vedotin (TV) + carboplatin (Carbo) in first-line (1L) or + pembrolizumab (Pembro) in previously treated (2L/3L) recurrent or metastatic cervical cancer (r/mCC): interim results of ENGOT-Cx8/GOG-3024/innovaTV 205 study.
      ]. After median follow-up of 13 months, confirmed response rate was 38% and median DoR was 13.8 months. Forty-six percent of patients who received TV + pembrolizumab reported TV-related ≥ grade 3 AEs.

      First-line therapies for recurrent and metastatic cervical cancer

      Three immune checkpoint inhibitors (ICIs) are being tested in combination with chemotherapy regimens ± bevacizumab in phase III trials, with pembrolizumab approved in October 2021 for first-line treatment of PD-L1-positive disease (Table 3) [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ,

      Merck. FDA approves Merck’s KEYTRUDA® (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). 2021. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-with-or-without-bevacizumab-as-treatment-for-patients-with-persistent-recurrent-or-metastatic-cervical-cancer-whose-tum/. accessed October 18, 2021.

      ].
      Table 3Selected therapies under investigation for first-line treatment of recurrent/metastatic cervical cancer.
      TherapyMechanism of actionCervical cancer-related health authority designations/decisionsPivotal trial name/IDsStudy designPatient populationTreatment armsPrimary endpoint(s)Primary endpoint completion dateAvailable pivotal trial

      efficacy data
      PembrolizumabAnti-PD-1 antibodyFDA approval October 2021:

      in combination with chemotherapy in patients with PD-L1 positive tumors (CPS ≥ 1)

      Merck. FDA approves Merck’s KEYTRUDA® (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). 2021. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-with-or-without-bevacizumab-as-treatment-for-patients-with-persistent-recurrent-or-metastatic-cervical-cancer-whose-tum/. accessed October 18, 2021.

      KEYNOTE-826



      NCT03635567
      Phase III,

      double-blind,

      randomized 1:1
      Adults with r/m or persistent SCC, AC, or ASC cervical cancer not previously treated;

      known PD-L1 status prior to randomization
      Experimental arm:

      Pembrolizumab 200 mg IV + investigator choice of platinum-based chemotherapy regimen (IC) on day 1 per 21-day cycle



      Control arm:

      Placebo + IC on day 1 per 21-day cycle
      PFS by ICR per RECIST v1.1



      OS
      November 2022Colombo et al. 2021
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.




      ITT population (N = 617)

      Median PFS

      Pembro arm 10.4 months

      Placebo arm 8.2 months

      HR, 0.65; P < 0.001

      24-month OS

      Pembro arm 50.4%

      Placebo arm 40.4%

      HR, 0.67; P < 0.001



      PD-L1 CPS ≥ 1 (N = 548)

      Median PFS

      Pembro arm 10.4 months

      Placebo arm 8.2 months

      HR, 0.62; P < 0.001

      24-month OS

      Pembro arm 53%

      Placebo arm 41.7%

      HR, 0.64; P < 0.001
      AtezolizumabAnti-PD-L1 antibodyNoneBEATcc/ ENGOT-cx10



      NCT03556839
      Phase III,

      open-label,

      randomized 1:1
      Adults with r/m or persistent SCC, AC, or ASC cervical cancer not previously treatedExperimental arm:

      atezolizumab 1200 mg + chemotherapy (cisplatin 50 mg/m2 or carboplatin AUC 5 + paclitaxel 175 mg/m2) + bevacizumab 15 mg/kg IV on day 1 per 21-day cycle



      Control arm:

      chemotherapy + bevacizumab 15 mg/kg IV on day 1 per 21-day cycle
      OSExpected March 2023None
      Prolgolimab (BCD-100)Anti-PD-1 antibodyNoneFERMATA/ ENGOT-cx13



      NCT03912415
      Phase III,

      double-blind

      randomized 1:1
      Adults with r/m or persistent SCC cervical cancer not previously treated;

      known PD-L1 status prior to randomization
      Experimental arm:

      prolgolimab 3 mg/kg IV Q3W + chemotherapy (cisplatin or carboplatin + paclitaxel) +/- bevacizumab



      Control arm:

      placebo + chemotherapy +/- bevacizumab
      OSExpected December 2024None
      Trial design and anticipated primary endpoint completion dates were obtained from the respective clinicaltrials.gov webpages. Therapies are listed in order of primary endpoint completion date.
      AC, adenocarcinoma; ASC, adenosquamous carcinoma; ICR, independent central review; IV, intravenous; OS, overall survival; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SCC, squamous cell carcinoma.

      Pembrolizumab

      Pembrolizumab is an anti-PD-1 antibody approved for treatment of many malignancies, including for PD-L1-positive (CPS ≥ 1) r/mCC that progressed on or after chemotherapy [

      Keytruda (pembrolizumab). US Prescribing information. Merck Sharp & Dohme Corp.; August 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287. accessed September 29, 2021.

      ]. In October 2021, the FDA approved pembrolizumab combined with platinum-based chemotherapy ± bevacizumab as first-line treatment for patients with PD-L1-positive persistent or r/mCC (CPS ≥ 1) based on the first interim analysis of the phase III KEYNOTE-826 study [

      Merck. FDA approves Merck’s KEYTRUDA® (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1). 2021. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-with-or-without-bevacizumab-as-treatment-for-patients-with-persistent-recurrent-or-metastatic-cervical-cancer-whose-tum/. accessed October 18, 2021.

      ].
      Patients were randomized to receive pembrolizumab 200 mg (N = 308) or placebo (N = 309) every 3 weeks for up to 35 cycles + chemotherapy, with bevacizumab used at the investigator’s discretion [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ]. Coprimary endpoints of PFS and OS were tested sequentially in the PD-L1 CPS ≥ 1 population, the intention-to-treat (ITT) population, and the PD-L1 CPS ≥ 10 population. PFS was significantly longer in the pembrolizumab versus placebo arms in patients with PD-L1 CPS ≥ 1 (median 10.4 vs 8.2 months; HR, 0.62; P < 0.001), the ITT population (10.4 vs 8.2 months, respectively; HR, 0.65; P < 0.001), and the PD-L1 CPS ≥ 10 group (10.4 vs 8.1 months; HR, 0.58; P < 0.001). Likewise, OS at 24 months was significantly longer in the pembrolizumab versus placebo groups among the three populations.
      The safety profile in KEYNOTE-826 was consistent with known profiles of the individual therapies [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ]. Discontinuations due to AEs were slightly higher with pembrolizumab (any agent: pembrolizumab 37.5% vs placebo 26.5%; all agents: 5.9% vs 4.9%). Adverse events that occurred in at least 10% of patients in the pembrolizumab arm included hypothyroidism (pembrolizumab 18.2% vs placebo 9.1%) and decreased white cell count (12.1% vs 7.1%). Overall, combination treatment did not intensify known toxicities associated with each agent. Patient-reported quality of life was improved or stable for more patients who received pembrolizumab versus placebo (78.3% vs 71.7%).

      Prolgolimab

      Prolgolimab (BCD-100) is an anti-PD-1 antibody with an Fc-silencing LALA mutation that is approved in Russia for the treatment of unresectable or metastatic melanoma [

      BIOCAD. Novel anti-PD-1 drug was approved for melanoma treatment. 2020. https://www.eurekalert.org/news-releases/904789. accessed August 13, 2021.

      ]. The efficacy and safety of prolgolimab versus placebo in combination with platinum-based chemotherapy (cisplatin or carboplatin + paclitaxel) ± bevacizumab in patients with untreated r/mCC is being investigated in the ongoing phase III FERMATA trial. The trial is being conducted in China, Georgia, Russia, and Turkey, and aims to enroll approximately 316 patients with SCC histology. The primary endpoint is OS, which is estimated for completion in December 2024.

      Atezolizumab

      The ongoing, pivotal phase III BEATcc/ENGOT-Cx10/GEICO-68-C/JGOG-1084/GOG-3030 study is evaluating atezolizumab versus placebo in combination with a platinum-based chemotherapy regimen (cisplatin or carboplatin + paclitaxel + bevacizumab) for patients with untreated r/mCC [
      • Grau J.F.
      • Farinas-Madrid L.
      • Oaknin A.
      A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030).
      ]. Approximately 404 patients from Europe, Japan, and the United States were planned for enrollment; recruitment was completed in September 2021. The primary endpoint is OS, which is estimated for completion in March 2023.

      Locally advanced cervical cancer

      Three immunotherapies in combination with CRT or radiotherapy are in phase III studies with primary endpoint data expected to be published between 2022 and 2024 (Table 4) [

      AstraZeneca Press Release. Update on CALLA phase III trial of concurrent use of imfinzi and chemoradiotherapy in locally advanced cervical cancer, March 24, 2022. 2022. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/update-on-calla-phase-iii-trial-for-imfinzi.html. accessed March 24, 2022.

      ].
      Table 4Selected therapies under investigation for treatment of locally advanced cervical cancer.
      TherapyMechanism of actionCervical cancer-related health authority designations/decisionsPivotal trial name/IDsStudy designPatient populationTreatment armsPrimary endpoint(s)Primary endpoint completion dateAvailable pivotal trial

      efficacy data
      Z-100Immunomodulator (bacterial extract)NoneZ100-01



      NCT02247232
      Phase III,

      double-blind

      randomized
      Adults with SCC cervical cancer, FIGO 2008 stage IIIB, not previously treatedExperimental arm:*

      Z-100 + radiotherapy



      Control arm:

      Placebo + radiotherapy
      OSExpected October 2021



      Enrollment completed July 2018
      None
      DurvalumabAnti-PD-L1 antibodyNoneCALLA



      NCT03830866
      Phase III,

      double-blind,

      randomized 1:1
      Adults with SCC, AC, or ASC cervical cancer, FIGO 2009 Stage IB2-IIB node positive or IIIA-IVA any node status, not previously treatedExperimental arm:

      Durvalumab 1500 mg IV Q4W for 24 cycles + CRT (EBRT + cisplatin 40 mg/m2 IV or carboplatin AUC2 IV, followed by image-guided brachytherapy) once weekly for 5 weeks



      Control arm:

      Placebo Q4W for 24 cycles + CRT once weekly for 5 weeks

      PFS by investigator assessment per RECIST v1.1Expected October 2022



      Enrollment completed January 2021
      Primary endpoint not met

      AstraZeneca Press Release. Update on CALLA phase III trial of concurrent use of imfinzi and chemoradiotherapy in locally advanced cervical cancer, March 24, 2022. 2022. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/update-on-calla-phase-iii-trial-for-imfinzi.html. accessed March 24, 2022.

      PembrolizumabAnti-PD-1 antibodyNoneKEYNOTE-A18/ENGOT-cx11/ GOG-3047



      NCT04221945
      Phase III,

      double-blind,

      randomized 1:1
      Patients with high-risk SCC, AC, or ASC cervical cancer, FIGO 2014 stage IB2-IIB node positive or stage III-IVA any node status, not previously treatedExperimental arm:

      5 cycles of pembro 200 mg Q3W + CRT (EBRT + cisplatin 40 mg/m2 IV QW, followed by brachytherapy), followed by 15 cycles of pembro 400 mg Q6W



      Control arm:

      Placebo + CRT, followed by placebo Q6W
      PFS by investigator assessment per RECIST v1.1



      OS
      Expected February 2024None
      *Dosing information was not available on the respective clinicaltrials.gov information webpage.
      Trial design and anticipated primary endpoint completion dates were obtained from the respective clinicaltrials.gov webpages. Therapies are listed in order of primary endpoint completion date.
      AC, adenocarcinoma; ASC, adenosquamous carcinoma; AUC, area under the curve; CRT, chemoradiotherapy; EBRT, external beam radiotherapy; FIGO, International Federation of Gynecology and Obstetrics; IV, intravenous; OS, overall survival; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SCC, squamous cell carcinoma.

      Pembrolizumab

      The phase III KEYNOTE-A18/ENGOT-Cx11 study is evaluating pembrolizumab versus placebo given during and after CRT for treatment-naïve LACC [
      • Lorusso D.
      • Xiang Y.
      • Colombo N.
      • Coleman R.
      • Randall L.
      • Duska L.
      • et al.
      254TiP - ENGOT-cx11/KEYNOTE-A18: a phase 3, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.
      ]. Patients must have stage IB2-IIB lymph node positive disease or stage III-IVA disease ± lymph node involvement per FIGO 2014 staging criteria. Approximately 980 patients from 30 countries across North America, South America, Europe, Asia, and Australia will be enrolled. The co-primary endpoints are PFS per investigator assessment and OS, with final data expected in February 2024.
      Early safety data from a small phase II study of pembrolizumab given either during or after CRT for LACC support the safety and feasibility of this combination [
      • Duska L.R.
      • Scalici J.M.
      • Temkin S.M.
      • Schwarz J.K.
      • Crane E.K.
      • Moxley K.M.
      • et al.
      Results of an early safety analysis of a study of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer.
      ]. Of 52 evaluable patients, 88% experienced ≥ grade 2 treatment-related AEs; 11 patients had at least one grade 4 AE, 23 had at least one grade 3 AE, and no grade 5 AEs were reported. Median follow-up was 4.8 months. Common AEs of clinical concern considered related to pembrolizumab included diarrhea, nausea, and vomiting. All patients who received pembrolizumab during CRT completed cisplatin therapy.

      Durvalumab

      Durvalumab is a human anti-PD-L1 IgG1ĸ monoclonal antibody approved for use in NSCLC and extensive-stage small cell lung cancer [

      Imfinzi (durvalumab). US Prescribing information. AstraZeneca; July 2021. Accessed September 29, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8baba4ea-2855-42fa-9bd9-5a7548d4cec3.

      ]. In locally advanced NSCLC, durvalumab given as consolidation therapy after CRT improved outcomes compared with placebo (median PFS: 16.8 months vs 5.6 months; ongoing response for 72.8% vs 46.8% of patients at 18 months) [
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      ]. In the phase III CALLA study, the efficacy and safety of durvalumab versus placebo given during and after CRT was investigated in immunotherapy-naïve patients who had no prior treatment for LACC [
      • Mayadev J.
      • Nunes A.T.
      • Li M.
      • Marcovitz M.
      • Lanasa M.C.
      • Monk B.J.
      CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.
      ]. Patients had high-risk LACC, defined as stages IB2-IIB disease with lymph node involvement or stages IIIA-IVA ± lymph node involvement according to FIGO 2009 staging criteria. Enrollment completed in January 2021 with 770 patients from 15 countries across North America, South America, Europe, Asia, and Africa. In March 2022, it was announced that the trial did not achieve statistical significance for the primary endpoint of PFS [

      AstraZeneca Press Release. Update on CALLA phase III trial of concurrent use of imfinzi and chemoradiotherapy in locally advanced cervical cancer, March 24, 2022. 2022. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/update-on-calla-phase-iii-trial-for-imfinzi.html. accessed March 24, 2022.

      ].

      Z-100

      Z-100 is an immunomodulatory extract from Mycobacterium tuberculosis strain Aoyama B used in Japan to treat leukopenia resulting from radiotherapy [
      • Oka H.
      • Sasaki H.
      • Shiraishi Y.
      • Emori Y.
      • Yoshinaga K.
      • Takei M.
      Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, augments anti-tumor activities of X-ray irradiation against B16 melanoma in association with the improvement of type 1T cell responses.
      ]. In a preclinical mouse model, Z-100 in combination with radiation augmented the antitumor effects of X-ray irradiation by inhibiting pulmonary metastasis and prolonging survival [
      • Oka H.
      • Sasaki H.
      • Shiraishi Y.
      • Emori Y.
      • Yoshinaga K.
      • Takei M.
      Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, augments anti-tumor activities of X-ray irradiation against B16 melanoma in association with the improvement of type 1T cell responses.
      ]. Z-100 also improved helper T-cell response from a type 2-dominant to a type 1-dominant state via upregulation of interferon-γ and IL-12, suggesting the potential to suppress tumor metastasis in preclinical studies [
      • Oka H.
      • Emori Y.
      • Sasaki H.
      • Shiraishi Y.
      • Yoshinaga K.
      • Kurimoto T.
      Anti-tumor mechanism of Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, on pulmonary metastases of B16F10 melanoma: restoration of helper T cell responses via suppression of glucocorticoid-genesis.
      ,
      • Oka H.
      • Shiraishi Y.
      • Sasaki H.
      • Yoshinaga K.
      • Emori Y.
      • Takei M.
      Antimetastatic effect of an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, Z-100, through the production of interleukin-12.
      ].
      In an earlier placebo-controlled, phase III trial of Z-100 in combination with radiotherapy or CRT (collectively referred to as RT) for patients with stage IIB-IVA cervical cancer, Z-100 did not provide a statistically significant improvement of 5-year OS compared with placebo (75.7% vs 65.8%; HR, 0.65, P = 0.07), and did not differ in recurrence-free survival [
      • Sugiyama T.
      • Fujiwara K.
      • Ohashi Y.
      • Yokota H.
      • Hatae M.
      • Ohno T.
      • et al.
      Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: a JGOG study.
      ]. However, there was an OS benefit for patients with stage III disease treated with Z-100 (HR, 0.51; P = 0.03). A phase III, placebo-controlled trial of Z-100 plus radiotherapy for patients with treatment-naïve stage IIIB (FIGO 2008) LACC was initiated in December 2014. The study is being conducted in seven countries within Asia. The trial has completed enrollment and the expected date for primary endpoint completion (OS) was October 2021. Published results are anticipated.

      Are current immunotherapy biomarkers important for cervical cancer?

      PD-L1 expression is commonly found in cervical cancer, although it may be influenced by histology and etiology of disease [
      • Heeren A.M.
      • Punt S.
      • Bleeker M.CG.
      • Gaarenstroom K.N.
      • van der Velden J.
      • Kenter G.G.
      • et al.
      Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.
      ,
      • Rischin D.
      • Gil-Martin M.
      • González-Martin A.
      • Braña I.
      • Hou J.Y.
      • Cho D.
      • et al.
      PD-1 blockade in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer.
      ]. For example, PD-L1-high SCC was more likely to be HPV-18 than HPV-16 driven. PD-L1 expression may also be prognostic of survival: patients with SCC and diffuse PD-L1 expression or PD-L1-negative disease had worse DFS versus marginal PD-L1 expression (P = 0.022 and P = 0.029), and adenocarcinoma (AC) with versus without PD-L1-positive tumor-associated macrophages was associated with worse disease-specific survival (P = 0.014) [
      • Heeren A.M.
      • Punt S.
      • Bleeker M.CG.
      • Gaarenstroom K.N.
      • van der Velden J.
      • Kenter G.G.
      • et al.
      Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.
      ].
      PD-L1 expression appears to be a biomarker for response to some ICIs, though responses are seen in PD-L1-negative tumors. Approval of pembrolizumab + chemotherapy ± bevacizumab for first-line treatment of PD-L1-positive r/mCC reflects the survival benefits driven by this patient population in KEYNOTE-826 [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ]. In contrast to the phase II KEYNOTE-158 trial of pembrolizumab monotherapy in the second-line or later setting where all responses were observed in patients with PD-L1-expressing tumors [
      • 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.
      ], some of the 69 patients with PD-L1-negative tumors in KEYNOTE-826 responded to pembrolizumab. However, there was no clear benefit in PFS (HR, 0.94) or OS (HR, 1.00). Similarly, bal + zal elicited a higher ORR in patients with PD-L1-positive second-line r/mCC versus the overall population (32.8% vs 25.6%), and 3 of 33 patients with PD-L1-negative tumors responded to treatment (9.1%) [
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      ]. In the 254 patients from EMPOWER-Cervical 1 with valid PD-L1 samples (42% of randomized patients), survival benefits for cemiplimab versus chemotherapy were seen only in the PD-L1-positive group (OS HR, 0.7; PFS HR, 0.76) [
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ]. In the PD-L1-negative group, 5 of 44 patients responded to cemiplimab and 4 of 48 patients responded to chemotherapy.
      Microsatellite instability (MSI)-high status and tumor mutational burden (TMB) are associated with response to immunotherapy in different cancer types; however, these biomarkers have not been extensively studied in cervical cancer. About 4–8% of patients with cervical cancer have MSI-high tumors [
      • Dudley J.C.
      • Lin M.T.
      • Le D.T.
      • Eshleman J.R.
      Microsatellite instability as a biomarker for PD-1 blockade.
      ,
      • Luchini C.
      • Bibeau F.
      • Ligtenberg M.J.L.
      • Singh N.
      • Nottegar A.
      • Bosse T.
      • et al.
      ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.
      ], and the TMB rate is approximately 2.5–5.4 mutations/megabase [
      • Cancer Genome Atlas Research Network
      Integrated genomic and molecular characterization of cervical cancer.
      ,
      • Chalmers Z.R.
      • Connelly C.F.
      • Fabrizio D.
      • Gay L.
      • Ali S.M.
      • Ennis R.
      • et al.
      Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
      ]. In the KEYNOTE-158 TMB sub-analysis, 16 of 75 patients with advanced cervical cancer had high tissue TMB (≥10 mutations/megabase); 5 of the 16 patients responded to pembrolizumab monotherapy whereas 7 of the 59 non-TMB-high patients responded [
      • Marabelle A.
      • Fakih M.
      • Lopez J.
      • Shah M.
      • Shapira-Frommer R.
      • Nakagawa K.
      • et al.
      Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
      ]. The population was small and requires validation in larger studies and with other ICIs. Further exploration of the known genomic features of cervical cancer, as reported in analysis on samples from The Cancer Genome Atlas [
      • Cancer Genome Atlas Research Network
      Integrated genomic and molecular characterization of cervical cancer.
      ], and their impact on outcomes from completed immunotherapy studies may also provide further clues to relevant predictive biomarkers.

      How will histology affect immunotherapy treatment for cervical cancer?

      Because HPV infection and malignant transformation of the cervix occur in the transformation zone, which is predominately composed of squamous epithelium, SCC histology comprises about 70% of cervical cancers. Adenocarcinoma, including adenosquamous (ASC) types, is the next most common histologic type, representing ∼ 20% of cervical cancers. Nonsquamous tumors are more likely to be PD-L1 negative [
      • Heeren A.M.
      • Punt S.
      • Bleeker M.CG.
      • Gaarenstroom K.N.
      • van der Velden J.
      • Kenter G.G.
      • et al.
      Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix.
      ]. Some studies analyzing all stages of cervical cancer find AC histology is a statistically significant negative prognostic factor for survival compared with SCC [
      • Lee J.Y.
      • Kim Y.T.
      • Kim S.
      • Lee B.
      • Lim M.C.
      • Kim J.W.
      • et al.
      Prognosis of cervical cancer in the era of concurrent chemoradiation from national database in Korea: a comparison between squamous cell carcinoma and adenocarcinoma.
      ,
      • Pan X.
      • Yang W.
      • Wen Z.
      • Li F.
      • Tong L.
      • Tang W.
      Does adenocarcinoma have a worse prognosis than squamous cell carcinoma in patients with cervical cancer? A real-world study with a propensity score matching analysis.
      ]; however, studies of patients with LACC or r/mCC did not find a significant difference in survival between AC/ASC and SCC [
      • Tian T.
      • Gong X.
      • Gao X.
      • Li Y.
      • Ju W.
      • Ai Y.
      Comparison of survival outcomes of locally advanced cervical cancer by histopathological types in the surveillance, epidemiology, and end results (SEER) database: a propensity score matching study.
      ,
      • Seamon L.G.
      • Java J.J.
      • Monk B.J.
      • Penson R.T.
      • Brown J.
      • Mannel R.S.
      • et al.
      Impact of tumour histology on survival in advanced cervical carcinoma: an NRG Oncology/Gynaecologic Oncology Group Study.
      ]. The HR for OS was 1.02 (P = 0.69) in a propensity-matched analysis of patients diagnosed with LACC from the SEER database 2010–2015 [
      • Tian T.
      • Gong X.
      • Gao X.
      • Li Y.
      • Ju W.
      • Ai Y.
      Comparison of survival outcomes of locally advanced cervical cancer by histopathological types in the surveillance, epidemiology, and end results (SEER) database: a propensity score matching study.
      ], and the HR for death was 1.13 (P = 0.23) in patients with r/mCC treated with chemotherapy doublets from pooled Gynecologic Oncology Group phase III studies [
      • Seamon L.G.
      • Java J.J.
      • Monk B.J.
      • Penson R.T.
      • Brown J.
      • Mannel R.S.
      • et al.
      Impact of tumour histology on survival in advanced cervical carcinoma: an NRG Oncology/Gynaecologic Oncology Group Study.
      ].
      Many of the immunotherapy trials discussed in this review allow for inclusion of patients with SCC, AC, and ASC histologic types. In EMPOWER-Cervical 1, median OS was 11.1 months with cemiplimab monotherapy versus 8.8 months with chemotherapy (HR, 0.73; P = 0.006) in patients with previously treated r/mSCC, and 13.3 versus 7.0 months in those with AC (HR, 0.56; P-value not given) [
      • Tewari K.S.
      • Monk B.J.
      • Vergote I.
      • Miller A.
      • de Melo A.C.
      • Kim H.-S.
      • et al.
      Survival with cemiplimab in recurrent cervical cancer.
      ]. Bal + zal elicited an ORR of 32.6% in patients with r/mSCC versus 8.8% in AC [
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      ]. The ORR with TV was similar in patients with non-squamous (25%) and squamous (23%) r/mCC [
      • Coleman R.L.
      • Lorusso D.
      • Gennigens C.
      • Gonzalez-Martin A.
      • Randall L.
      • Cibula D.
      • et al.
      Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.
      ]. At present, the data suggest immunotherapies may provide benefit for SCC and AC/ASC histologic types in the r/mCC setting.
      Neuroendocrine histology is an aggressive form of invasive cervical cancer occurring in approximately 1.4% of cases [
      • Tempfer C.B.
      • Tischoff I.
      • Dogan A.
      • Hilal Z.
      • Schultheis B.
      • Kern P.
      • et al.
      Neuroendocrine carcinoma of the cervix: a systematic review of the literature.
      ]. Little guidance on optimal therapy exists and patients commonly receive radiotherapy-based treatment or radical surgery combined with neoadjuvant/adjuvant chemotherapy, with recurrence averaging 16 months after treatment and with a mean OS duration of 40 months [
      • Tempfer C.B.
      • Tischoff I.
      • Dogan A.
      • Hilal Z.
      • Schultheis B.
      • Kern P.
      • et al.
      Neuroendocrine carcinoma of the cervix: a systematic review of the literature.
      ,
      • Salvo G.
      • Gonzalez Martin A.
      • Gonzales N.R.
      • Frumovitz M.
      Updates and management algorithm for neuroendocrine tumors of the uterine cervix.
      ]. Small exploratory studies and case reports in patients with previously treated neuroendocrine tumors exhibit positive results with nivolumab combinations or monotherapy [
      • Sharabi A.
      • Kim S.S.
      • Kato S.
      • Sanders P.D.
      • Patel S.P.
      • Sanghvi P.
      • et al.
      Exceptional response to nivolumab and stereotactic body radiation therapy (SBRT) in neuroendocrine cervical carcinoma with high tumor mutational burden: management considerations from the Center for Personalized Cancer Therapy at UC San Diego Moores Cancer Center.
      ,
      • Paterniti T.A.
      • Dorr K.
      • Ullah A.
      • White J.
      • Williams H.
      • Ghamande S.
      Complete response to combination nivolumab and ipilimumab in recurrent neuroendocrine carcinoma of the cervix.
      ,
      • Paraghamian S.E.
      • Longoria T.C.
      • Eskander R.N.
      Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report.
      ] and with adoptive immune cell therapy [
      • Goto S.
      • Terao Y.
      • Kamigaki T.
      • Takimoto R.
      • Naitoh K.
      • Makita K.
      • et al.
      Adoptive immune-cell therapy for the treatment of neuroendocrine carcinoma of the uterine cervix.
      ], but not with pembrolizumab monotherapy [
      • Frumovitz M.
      • Westin S.N.
      • Salvo G.
      • Zarifa A.
      • Xu M.
      • Yap T.A.
      • et al.
      Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract.
      ]. Further studies of immunotherapy in these rare tumors are needed.

      Future directions

      While the introduction of immunotherapies for cervical cancer may bring hope to many patients, the fact remains that those with greatest need may not have access. Nearly 84% of global cervical cancer cases and 88% of all deaths due to cervical cancer occur in countries with a low human development index [
      • Arbyn M.
      • Weiderpass E.
      • Bruni L.
      • de Sanjose S.
      • Saraiya M.
      • Ferlay J.
      • et al.
      Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis.
      ]. Countries with high disease burden may lack sufficient access to basic treatments such as radiotherapy and/or chemotherapy. However, even countries with sufficient resources can have underserved populations with a higher incidence of cervical cancer and poorer outcomes. In addition to the introduction of immunotherapies, earlier diagnosis and treatment could help improve survival and cure rates. Concerns of affordability and compliance with immunotherapy, especially adoptive cell therapies, may impede immunotherapy use. Many patients may not be able to afford, be compliant with, or tolerate multiple years of maintenance therapy, which may reduce the effectiveness of these treatments. Furthermore, while some immunotherapies may be considered cost effective, governmental or insurance reimbursement for a high-cost treatment in a common disease may not be sustainable.
      Understanding the toxicity of immunotherapy in a variety of ethnic groups and underserved populations will be important to help bring therapies to these regions. Newer trials are including patients from a variety of countries to address this [
      • Colombo N.
      • Dubot C.
      • Lorusso D.
      • Caceres M.V.
      • Hasegawa K.
      • Shapira-Frommer R.
      • et al.
      Pembrolizumab for persistent, recurrent, or metastatic cervical cancer.
      ,
      • O'Malley D.M.
      • Neffa M.
      • Monk B.J.
      • Melkadze T.
      • Huang M.
      • Kryzhanivska A.
      • et al.
      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.
      ,

      BIOCAD. Novel anti-PD-1 drug was approved for melanoma treatment. 2020. https://www.eurekalert.org/news-releases/904789. accessed August 13, 2021.

      ,
      • Grau J.F.
      • Farinas-Madrid L.
      • Oaknin A.
      A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030).
      ,
      • Mayadev J.
      • Nunes A.T.
      • Li M.
      • Marcovitz M.
      • Lanasa M.C.
      • Monk B.J.
      CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.
      ], and stratification by region can aid in these analyses [
      • Mayadev J.
      • Nunes A.T.
      • Li M.
      • Marcovitz M.
      • Lanasa M.C.
      • Monk B.J.
      CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study.
      ].
      As the field evolves, clinical trials should also be inclusive of patients with HIV, who are at higher risk of HPV infection and are 4–5 times more likely to develop invasive cervical cancer [

      UN AIDS. Cervical cancer and HIV—two diseases, one response. 2018. Available at: https://www.unaids.org/en/resources/presscentre/featurestories/2018/october/cervical-cancer-and-hiv. [accessed October 19, 2021].

      ]. Most immunotherapy trials across tumor types exclude patients living with HIV [

      Vora KB, Awad MM. Exclusion rates of patients living with HIV from cancer immunotherapy clinical trials. J Clin Oncol 2020;38:e19035-e. 10.1200/JCO.2020.38.15_suppl.e19035.

      ], though small retrospective and prospective studies show an overall acceptable safety profile with ICIs in people with HIV and cancer [
      • Cook M.R.
      • Kim C.
      Safety and efficacy of immune checkpoint inhibitor therapy in patients with HIV infection and advanced-stage cancer: a systematic review.
      ,
      • Uldrick T.S.
      • Goncalves P.H.
      • Abdul-Hay M.
      • Claeys A.J.
      • Emu B.
      • Ernstoff M.S.
      • et al.
      Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer-a phase 1 study.
      ]. It remains to be seen if immunotherapy for cervical cancer is effective in this population.
      Although not covered in this review, therapeutic HPV vaccines are also considered immunotherapies and great strides in clinical development have been achieved for treating cervical intraepithelial neoplasia and invasive cervical cancer [
      • Wang R.
      • Pan W.
      • Jin L.
      • Huang W.
      • Li Y.
      • Wu D.
      • et al.
      Human papillomavirus vaccine against cervical cancer: Opportunity and challenge.
      ]. One promising therapy, VGX-3100, is a DNA plasmid-based medicine which provided statistically significant regression of HPV-16/18-associated high-grade squamous intraepithelial lesions combined with virus clearance versus placebo; virus was undetected through the 52-week safety follow-up [

      Inovio. INOVIO highlights key updates on phase 3 program for VGX-3100, its DNA-based immunotherapy for the treatment of cervical HSIL caused by HPV-16 and/or HPV-18. 2021. https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx. accessed December 16, 2021.

      ,

      Inovio. INOVIO announces positive results from REVEAL 1, a phase 3 pivotal trial evaluating VGX-3100, its DNA-based HPV immunotherapy for the treatment of high-grade precancerous cervical dysplasia caused by HPV-16 and/or HPV-18. 2021. https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Announces-Positive-Results-from-REVEAL-1-a-Phase-3-Pivotal-Trial-Evaluating-VGX-3100-its-DNA-based-HPV-Immunotherapy-for-the-Treatment-of-High-grade-Precancerous-Cervical-Dysplasia-Caused-by-HPV-16-andor-HPV-18/default.aspx. accessed December 16, 2021.

      ]. Additional phase III trials are ongoing [

      Inovio. INOVIO highlights key updates on phase 3 program for VGX-3100, its DNA-based immunotherapy for the treatment of cervical HSIL caused by HPV-16 and/or HPV-18. 2021. https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx. accessed December 16, 2021.

      ].
      Immunotherapy has the opportunity to establish new standard of cares in the treatment of cervical cancers. Biomarkers to assess response to immunotherapy will also likely be important to identify ideal candidates. However, issues with access, affordability, appropriate treatment delivery, and compliance are anticipated, especially in regions with a high burden of disease.

      Role of the funding source

      The authors had full control over the content and development of this article. Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Nicole Seneca, PhD, of Parexel (Hackensack, NJ) and was funded by AstraZeneca.

      CRediT authorship contribution statement

      Bradley J. Monk: Conceptualization, Writing – original draft, Writing – review & editing. Takayuki Enomoto: Conceptualization, Writing – review & editing. W. Martin Kast: Conceptualization, Writing – review & editing. Mary McCormack: Conceptualization, Writing – review & editing. David S.P. Tan: Conceptualization, Writing – review & editing. Xiaohua Wu: Conceptualization, Writing – review & editing. Antonio González-Martín: Conceptualization, Writing – review & editing.

      Declaration of Competing Interest

      BJM reports honoraria from Abbvie, Advaxis, Agenus, Amgen, AstraZeneca, Biodesix, Clovis, Conjupro, Genmab, Gradalis, Immunogen, Immunomedics, Incyte, Janssen/Johnson&Johnson, Mateon, Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma, Roche/Genentech, Samumed, Takeda, TESARO, Inc., and VBL. TE reports research grants and honoraria from Chugai; and honoraria from Takeda. WMK reports grants from Brooklyn ImmunoTherapeutics, AOV Therapeutics, Immunovaccine Inc., Nutcracker Biotechnologies, NIH R01 CA74397, and the Cancer Research Institute Clinic & Laboratory Integration Program; royalties/licenses from Nutcracker Biotechnologies; consulting fees from AOV Therapeutics, Nutcracker Biotechnologies, and Repertoire; and stock/stock options with Nutcracker Biotechnologies. MM reports non-financial support from Roche; and honoraria from AstraZeneca, Roche, Eisai, and GSK. DT reports grants and other from Singapore Ministry of Health's National Medical Research Council [NMRC; NMRC Clinician Scientist Award (NMRC/CSA-INV/0016/2017) with grant and salary support]; grants from Singapore Ministry of Health's National Medical Research Council (Centre Grant scheme to National University Cancer Institute, Singapore), Karyopharm Therapeutics; grants and personal fees from AstraZeneca and Bayer; personal fees and nonfinancial support from Eisai, MSD, and Roche; personal fees from Merck Serono; and charitable research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund. XW has nothing to disclose. AG-M reports research grants from GSK/Tesaro and Roche; and personal fees from AstraZeneca, Clovis, Eisai, Genmab, Pharmamar, Immunogen, MSD, Amgen, Oncoinvent, Merk/Pfizer, Pharmamar, Sotio, GSK/Tesaro, Siagen, and Roche.

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