Assessment of dMMR/MSI-H

Immunohistochemistry (IHC) nuclear staining for MMR proteins using a four-antibody panel is the most commonly used method to detect dMMR, however two-antibody IHC may also be used.16 Although the original US Food and Drug Administration (FDA) approval for pembrolizumab for the treatment of dMMR/MSI-H advanced solid tumors did not specify a companion diagnostic, the VENTANA MMR RxDx Panel assay was named as an IHC companion diagnostic for assessing dMMR to identify eligibility for both dostarlimab and pembrolizumab treatment in early 2022.15

MSI is most commonly assayed using next-generation sequencing (NGS).17 In the trials that led to the MSI-H tissue-agnostic approval for pembrolizumab, PCR-based MSI testing was used with no specific assay named as a companion diagnostic at the time of approval. In February of 2022, however, the FDA approved the FoundationOne CDx NGS assay as a companion diagnostic for determining MSI-H status. Overall, both PCR- and NGS-based assays for MSI-H are highly sensitive and concordant in some tumor types.18

It is important to note that MSI tests (PCR- and NGS-based) do not provide direct information on MMR proteins. Furthermore, these assays were developed and validated for use in colorectal cancer, and therefore have non-optimal performance in other tumor types, specifically endometrial cancer. For example, endometrial cancers have a significantly higher frequency of minimal microsatellite shifts, specifically tied to MSH6 mutations,19 which may be missed by standard MSI testing.20 Therefore, IHC for dMMR is preferred over MSI testing for non-colorectal cancers by the College of American Pathologists.4 21

The selection of IHC or NGS assay for MSI and MMR assessment may have implications for treatment decisions. Pembrolizumab is FDA-approved for the treatment of both MSI-H and dMMR solid tumors, whereas the tissue-agnostic indication for dostarlimab includes only tumors that are dMMR. While MSI and MMR status are largely concordant, a small fraction of tumors may lose MMR protein expression while remaining microsatellite stable (MSS), and vice versa.22

Assessment of PD-L1 expression

A number of FDA-approved IHC PD-L1 companion diagnostics are available, using varying platforms, antibodies, positivity thresholds, and assessing only TCs, ICs, or both. All FDA-approved ICI indications in cervical cancer are for patients with tumors with a PD-L1 combined positive score (CPS)≥1, as measured by an FDA-approved test.13 CPS is measured as ratio of PD-L1-positive cells (TCs, lymphocytes, and macrophages) to the total number of TCs, multiplied by 100. In the registrational trials of pembrolizumab for the treatment of cervical cancer, PD-L1 expression was measured using an IHC assay based on the 22C3 antibody, and the PD-L1 IHC 22C3 pharmDx assay is the approved companion diagnostic for pembrolizumab use in cervical cancer.

Although limited data are available on PD-L1 assay and/or antibody concordance for gynecologic cancer specimens, studies from non-small cell lung cancer (NSCLC) and real world analyses including a variety of tumor types indicate that the 22C3, 28–8,23 24 and SP26325 antibodies are largely interchangeable. Concordance may be inferior for staining of ICs compared with TCs, and additional studies are needed to confirm and validate PD-L1 assay concordance in cervical cancer, specifically. In addition, some studies in non-gynecologic tumors have shown good concordance with PD-L1 expression in tumor biopsy samples and fine-needle aspirates26 or in decalcified bone,27 but these are not yet validated.

Assessment of TMB

TMB is measured by the number of non-synonymous mutations per coding area of a tumor genome, which can be done by whole exome sequencing or a targeted panel of selected genes.33 TMB was assessed in KEYNOTE-158 using the FoundationOne CDx assay, a 324-gene NGS panel that is FDA-approved as a companion diagnostic for the TMB-H indication for pembrolizumab. Retrospective analysis demonstrated good concordance between TMB-H assessed by whole exome sequencing and FoundationOne CDx.34 Currently, TMB assessment is performed on tumor specimens, however, data are continuing to emerge on the use of blood-based assays to assess for TMB, including methods utilizing circulating-tumor DNA (ctDNA), as discussed in the Biopsy and specimen considerations section.

Primary versus metastatic tumor biopsies

In patients with metastatic disease at initial diagnosis or recurrence, clinicians may have the choice to assess biopsies from primary or metastatic lesions. Generally, most tumors tend to demonstrate somatic subclonal diversity from primary to metastatic sites,35 yet the overall magnitude of genomic alterations and presence of driver mutations has relatively good concordance.36

Data are lacking on whether MSI and dMMR status varies between primary and metastatic biopsies in gynecologic cancer. Germline dMMR mutations associated with Lynch syndrome should be present regardless of site. Data from colorectal cancer indicate that dMMR/MSI-H concordance in primary and metastatic tumors is high in some metastatic sites but has low concordance in others, and thus is largely organ-specific.37

PD-L1 expression in cervical cancer may occasionally vary between primary and metastatic sites, although data are limited. One study of matched primary and metastatic lymph node biopsies from patients with squamous cell (n=96) and adenocarcinoma (n=31) cervical cancer found that PD-L1 expression on TCs in the primary tumor versus lymph node metastases varied 18%–31% depending on the histology, and metastases had increased levels of PD-L1 expressing ICs.38 Data are lacking on whether this is true for non-lymph node metastases in cervical cancer. Another important consideration that may affect PD-L1 expression in metastatic lesions is the immunologic contexture of the metastatic site (eg, lung metastases may be immunologically ‘hot,’ whereas liver metastases may be immunologically ‘cold’).

Considerations for IHC on archived tissue biopsies

Data from lung cancer have demonstrated that PD-L1 expression on archived tumors samples >3 years old may be diminished when assessed by IHC.39 It is not clear if this is also true for dMMR proteins in archived tumor samples. Overall, fresh biopsies should be prioritized when possible and internal controls should be used to validate a negative result.

Liquid biopsy and ctDNA assessment

Data on the use of liquid-based assays to assess biomarkers in ctDNA are continuing to mature. NGS on ctDNA to assess TMB, MSI, and/or dMMR status has been shown to generally be concordant with tissue biopsies in a variety of solid tumors,40 and specifically in endometrial cancer.41 Measurements of ctDNA may also provide dynamic information of tumor response to treatment before apparent radiographic change,42 43 but these approaches have not been validated to inform treatment decisions for any solid tumors at the time of guideline writing.

Liquid biomarker assessments have several theoretical advantages over traditional tissue biopsies, including the non-invasive nature and feasibility for longitudinal collection. An additional strategy that is being investigated in gynecologic cancer is obtaining fluid from ascites for analyses,44 when available, which may contain information on the immune microenvironment of tumors.45 46 This strategy may be especially promising in ovarian cancer, where ascites is more often available for sampling.

Cervical cancer histology

The most common histology of cervical cancer is squamous cell carcinoma, followed by adenocarcinoma and adenosquamous carcinoma, with other rare histological subtypes such as neuroendocrine, endometrioid, serous, and clear cell carcinomas also observed (some of which are discussed in the Other rare gynecologic cancer variants section). The indications for ICIs are inclusive of all histologies. Tumor size, extension, lymph node metastasis, and other factors assessed in staging generally have a greater impact on prognosis than histology.65

Cervical cancer-specific immune biomarkers

At the time of guideline publication, PD-L1 expression is the only immune-related biomarker that predicts benefit with ICIs for patients with cervical cancer. The overall prevalence of PD-L1 expression above the CPS≥1 threshold for positivity in cervical cancers is high. Overall, 34.4%–96% of cervical cancers express PD-L1, with some of the variability potentially arising due to differences in antibodies, assays, and cut-off thresholds used across studies.5 66–69 Additionally, PD-L1 expression is more prevalent in squamous cell tumors compared with adenocarcinomas. More information on measuring PD-L1 expression can be found in the Immunotherapy biomarkers for gynecologic cancer section.

The presence or density of TILs has been associated with response to ICIs in other types of solid tumors70 and specific subsets of infiltrating T cells have been associated with favorable prognosis trends in cervical tumors.71–73 High expression of PD-1 on cervical cancer TILs was associated with worse outcomes overall in patients who did not receive immunotherapy,74 consistent with a role for immune suppression in poor prognosis. Data are currently lacking on whether the presence or density of specific TILs have prognostic value regarding response to ICIs.

The utility of TMB-H and MSI-H/dMMR as predictive biomarkers for patients with cervical cancer—a malignancy with a high prevalence of tumor-specific antigens due to presentation of HPV epitopes—is still unclear. Overall, TMB in cervical cancer is moderate; the median number of somatic mutations is between 1 mut/Mb and 10 mut/Mb,75 76 and the prevalence of TMB-H in all cervical cancers is between 10%–20%.30 77 Similarly, the overall prevalence of MSI-H in cervical cancers is fairly low, ranging from 2%–12%.78–80

Expert Panel recommendations

• For patients with advanced/recurrent cervical cancer, PD-L1 testing is recommended (LE:2). MMR IHC and NGS for MSI and TMB can be considered (LE:3).

First-line immunotherapy for PD-L1-positive cervical cancer

In October 2021, the FDA granted regular approval to pembrolizumab in combination with platinum-based chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic PD-L1-positive (CPS≥1) cervical cancer. Approval was based on the phase III, placebo-controlled, double-blind study KEYNOTE-826, which randomized patients to receive pembrolizumab (200 mg every 3 weeks) or placebo plus platinum-based chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin) with or without bevacizumab. In total, 617 patients were enrolled, including 548 patients with tumors with PD-L1 CPS≥1. The primary endpoints were PFS and OS. In the first planned interim analysis (median follow-up 22 months [range 15.1 to 29.4]), both endpoints were met demonstrating superiority with the addition of pembrolizumab to standard chemotherapy and anti-angiogenic therapy.69 PFS was improved with the pembrolizumab combination compared with the placebo combination in the PD-L1 CPS≥1 population (table 2), the PD-L1 CPS≥10 population (10.4 months [95% CI 8.9 to 15.1] vs 8.1 months [95% CI 6.2 to 8.8]; hazard ratio [HR] 0.58 [95% CI 0.44 to 0.77]; p<0.001), and the intention to treat (ITT) population (10.4 months [95% CI 9.1 to 12.1] vs 8.2 months [95% CI 6.4 to 8.4]; HR 0.65 [95% CI 0.53 to 0.79]; p<0.001). Median OS was also improved with the pembrolizumab combination in all populations (table 2). Landmark OS estimates at 2 years were 53.0% (95% CI 46.0% to 59.4%) vs 41.7% (95% CI 34.9% to 48.2%) in the CPS≥1 population, 54.4% (95% CI 45.5% to 62.4%) vs 44.6% (95% CI 36.3% to 52.5%) in the CPS≥10 population, and 50.4% (95% CI 43.8% to 56.6%) vs 40.4% (95% CI 34.0% to 46.6%) in the ITT population. Secondary outcome measures for KEYNOTE-826 included ORR and DOR. In the PD-L1 CPS≥1 group the ORR for the pembrolizumab combination was 68.1% compared with 50.2% in the placebo combination. DOR was also significantly longer in this group for those patients treated in the pembrolizumab combination arm, at 18.0 months vs 10.4 months in the placebo arm.

The treatment-related adverse events (TRAEs) in KEYNOTE-826 were consistent with known safety profiles. Grade 3─5 adverse events (AEs) occurred in 81.8% of patients in the pembrolizumab group and in 75.1% of patients in the placebo group, with the most common serious AEs in both groups being anemia, neutropenia, decreased neutrophil count, and hypertension. IrAEs were described in 33.9% (11.4% grade 3─5) of the patients in the pembrolizumab group and in 15.2% (2.9% grade 3─5) of those in the placebo group.69 The most common irAEs experienced by patients receiving pembrolizumab in KEYNOTE-826 were hypothyroidism (18.2% any grade, 1.3% grade 3─5), hyperthyroidism (7.5% any grade, no grade 3─5 events), colitis (5.2% any grade, 1.6% grade 3─5), and severe skin reactions (4.6% any grade, 3.9% grade 3─5).

Immunotherapy for disease that progresses on or after chemotherapy

Accelerated approval for pembrolizumab monotherapy for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS≥1) was granted in June 2018, based on results from the multicohort, non-randomized, open-label, phase II KEYNOTE-158 basket trial (table 2).5 The accelerated approval was converted to regular approval in October 2021. At median follow-up of 10.2 months (range 0.6–22.7) the ORR was 14.6% (95% CI 7.8% to 24.2%) in the 82 patients in the cohort with PD-L1-positive tumors. None of the 15 patients with PD-L1-negative tumors had responses by RECIST v.1.1. The best responses were three patients that achieved SD and the study was not powered to formally assess efficacy in the PD-L1-negative cohort. Median PFS in the PD-L1-positive cohort was 2.1 months (95% CI 2.1 to 2.3). Median OS was 9.4 months (95% CI 7.7 to 13.1) in the total population and 11 months (95% CI 9.1 to 14.1) in the PD-L1–positive population, and the estimated OS rates in the PD-L1-positive group at 6 months and 12 months were 80.2% and 47.3%, respectively.

Any-grade AEs were experienced in 65.3% of the total population, and 12.2% were grade 3─4. Investigator-assessed irAEs of any grade occurred in 25.5% of all treated patients, and 5.1% were grade 3─4. The most common irAEs were hypothyroidism (11.2%) and hyperthyroidism (9.2%).5

The accelerated approval for this indication was contingent on results of the confirmatory trial, KEYNOTE-826, which met its primary endpoints (see the First-line immunotherapy for cervical cancer section),69 and in October 2021, the accelerated approval for this indication was converted to regular approval. The recommended immunotherapy treatments for patients with cervical cancer can be found in figure 2.

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Figure 2

Advanced cervical cancer diagnostic workup and treatment algorithm. For all patients with cervical cancer, clinical trial enrolment should be encouraged, as feasible. CPS, combined positive score; PD-L1, programmed death-ligand 1; SOC, standard of care

The anti-PD-1 ICI cemiplimab was granted priority review in the chemotherapy-experienced cervical cancer setting by the FDA in September 2021 after the phase III EMPOWER-Cervical 1 trial (NCT03257267) met its primary endpoint of improved median OS (compared with salvage chemotherapy)81 in patients with PD-L1-positive tumors (expression on ≥1% of TCs by the VENTANA PD-L1 (SP263) assay). However, the Supplemental Biologics License Application was withdrawn by the manufacturer after the company and FDA were not able to align on postmarketing studies. Importantly, while EMPOWER-Cervical 1 corroborates better responses and survival in patients with PD-L1 TC score ≥1% (ORR 18% [95% CI 11% to 28%]) treated with cemiplimab versus chemotherapy, a small number of responses to cemiplimab were also seen in patients with PD-L1 TC<1% (ORR 11% [95% CI 4% to 25%]), suggesting that more patients may respond to anti-PD-1 ICIs than are eligible for the current FDA indication for pembrolizumab. Importantly, while comparative data are lacking, anti-PD-1 ICIs are generally expected to have similar clinical efficacy.

TMB-H or MSI-H/dMMR cervical cancer

Patients with cervical cancer may also be eligible for immunotherapy under the tissue-agnostic indications for ICIs, depending on the TMB and/or MSI/MMR status of the tumor.13 15 For more details on tissue-agnostic approvals, see the Immunotherapy biomarkers for gynecologic cancer section. In KEYNOTE-158, response rates were numerically higher for the TMB-H cervical tumors (31% [95% CI 11% to 59%] in the TMB-H group vs roughly 12% of patients in the TMB-low group), however it is important to note that this arm of the trial was not designed to assess efficacy in specific disease settings.13 30 Although KEYNOTE-158 prespecified an additional postmarketing analysis on pan-tumor response rates by MMR status, the data on the six patients with cervical cancer included in the study were not presented.82 Additionally, neither of the efficacy analyses supporting the MSI-H/dMMR-based approvals for pembrolizumab or dostarlimab included patients with cervical cancer.

Expert Panel recommendations

• For patients with recurrent or metastatic cervical cancer that is PD-L1-positive (CPS≥1) and has progressed on or after chemotherapy, pembrolizumab should be considered (LE:3).

• For patients with metastatic cervical cancer that is PD-L1-positive (CPS≥1), pembrolizumab with chemotherapy with or without bevacizumab should be considered (LE:2).

• For patients with anti-PD-(L)1-resistant cervical cancer, currently there are no data to inform the sequencing of therapies and/or rechallenge with an ICI.

ICI-based combinations for the treatment of cervical cancer

The combination of balstilimab (anti-PD-1) plus zalifrelimab (anti-cytotoxic T lymphocyte antigen-4 [CTLA-4]) met its ORR endpoint in a phase II single-arm trial (NCT03495882) with an ORR of 25.6% (95% CI 18.8% to 33.9%) in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy.83 The phase I/II basket trial Checkmate358 (NCT02488759) has also reported positive results in patients with cervical cancer using ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1), regardless of PD-L1 expression.84

HPV infection has been associated with upregulation of transforming growth factor (TGF)-β signaling85 motivating the investigation of inhibition of TGF-β signaling in combination with anti-PD-(L)1. Bintrafusp alfa (also known as M7824), the bifunctional fusion protein which contains the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a mAb blocking PD-L1, resulted in an an ORR of 28.2% and DOR of 11.7 months (range 1.4 to 41.2) in 39 patients with cervical cancer in pooled data from phase I and phase II trials (NCT02517398 and NCT03427411).86 Bintrafusp alfa is also being combined with cytokines and HPV-targeting vaccines in other ongoing trials (NCT04287868; NCT04708470).

Radiation modulates the immune system via a number of mechanisms, including inducing type I IFN expression and antigen release to activate an adaptive immune response.87 Several trials are investigating the combination of chemoradiation therapy (CRT) in combination with ICIs. The randomized phase III CALLA trial (NCT03830866), which compared CRT plus durvalumab to CRT alone for the treatment of high-risk locally advanced cervical cancer, did not reach its primary PFS endpoint.88

Investigational immunotherapy strategies for the treatment of cervical cancer

Tumors evade immune eradication via multiple mechanisms beyond checkpoints.3 Augmenting the tumor-antigen-specific T cell repertoire via therapeutic vaccination is a strategy that has been well studied in cervical cancer.2 Newer approaches are attempting to combine HPV-targeting vaccines with other treatments such as CRT and ICIs to overcome immune suppression in the tumor microenvironment. Axalimogene filolisbac (ADXS11-001)is a live-attenuated E7-producing Listeria monocytogenes vaccine that has reported results from phase II trials89 and has progressed to phase III. Other vaccines being evaluated include ISA101, a synthetic long-peptide HPV-16 vaccine, which is being combined with nivolumab in a phase II trial (NCT02426892)90 and the GX-188E DNA vaccine, which is being combined with pembrolizumab in the phase II trial KEYNOTE-567 (NCT03444376).91 The BVAC-C vaccine, a B cell-based and monocyte-based vaccine targeting E6 and E7, is being investigated in a phase II study (NCT02866006) as monotherapy or in combination with topotecan.92

HPV-specific antigens can also be targeted using adoptive cell therapies (ACTs). Strategies to boost cell therapy HPV-specific cytotoxicity, including dendritic cell vaccines or viral gene delivery of E6 and/or E7, have proven to be effective in preclinical studies, and may improve clinical outcomes of these cell therapies in future studies.93 Study C-145–04 (NCT03108495) is an ongoing, open-label, multicenter, phase II trial evaluating LN-145 TIL therapy in patients with advanced cervical cancer who have undergone prior chemotherapy. At a short follow-up of 3.5 months, in 27 patients the ORR was 44% and the disease control rate (DCR) was 89%,94 supporting breakthrough therapy designation from the FDA in 2019. Additional cell therapy agents, such as T cell receptor (TCR)-engineered cell therapy, natural killer (NK) cell therapies, and chimeric antigen receptor (CAR) T cell therapy have also been employed in some small studies in patients with cervical cancer, but limited data are available.

Expert Panel recommendations

• For all patients with cervical cancer, clinical trial enrollment should be offered, as feasible.

• Non-FDA-approved immunotherapy combination strategies should only be considered in the context of a clinical trial.

Endometrial cancer molecular subgroups

Endometrial cancer is a heterogeneous disease. The most widely utilized molecular classification for endometrial cancer came from an analysis of 373 endometrial tumors by TCGA Research Network,50 which delineates four molecular subgroups: (1) Ultra-mutated (often driven by mutations in POLE), (2) Hyper-mutated (driven by MSI), (3) High somatic copy-number alterations (SCNA) (often TP53-mutated and commonly serous histology), and (4) Low SCNA (commonly endometrioid histology). TCGA subgrouping is clinically informative, and methods have been developed to improve feasibility as a standard assessment of biopsied samples, including the commonly used Proactive Molecular Risk classification tool for endometrial cancers (ProMisE).105 106 Furthermore, TCGA subgrouping may reveal tumors that are already eligible for ICI treatment due to dMMR/MSI-H and/or TMB-H status.

PD-L1 expression in endometrial cancer

The value of PD-L1 as a predictive biomarker for benefit with ICIs in endometrial cancer is limited. PD-L1 expression in endometrial cancer is heterogeneous, regardless of molecular subgroup, histology, or stage.107–110 Non-endometrioid and undifferentiated tumors tend to have higher PD-L1 expression.107 108 110 111 ORRs in early phase studies evaluating ICI monotherapy for previously treated endometrial carcinoma have been similar across PD-L1-positive and PD-L1-negative tumors.6 112 113 Some studies have reported higher PD-L1 expression on infiltrating lymphocytes of POLE-mutated and MSI-H tumors compared with MSS tumors, however little difference across subtypes was noted in PD-L1 expression on the TCs themselves.110 114 115 Other reports have observed a high degree of PD-L1 TC staining in MSS tumors with infrequent PD-L1 TC staining in POLE-mutated tumors.116 The prognostic significance of immune versus tumor PD-L1 staining in endometrial cancer is not known.

Mutation burden and dMMR/MSI in endometrial cancer

Endometrial cancers in the ultra-mutated or hyper-mutated TCGA groups are often dMMR/MSI-H, and therefore, eligible for ICI treatment under tissue agnostic and/or endometrial cancer-specific indications (see the Recommended immunotherapy treatments for endometrial cancer and the Immunotherapy biomarkers for gynecologic cancer sections for more detail on disease-specific indications and diagnostic testing for these biomarkers, respectively).13 Despite the high prevalence of dMMR in endometrial cancer, testing for dMMR/MSI-H is underutilized. One European study found that in 2018, less than 40% of patients with advanced recurrent endometrial cancer had any MSI/MMR screening.117

Ultra- or hyper-mutated endometrial cancers are typically TMB-H as well due to loss of proofreading in the replicative polymerase or lack of MMR, respectively. POLE-mutated endometrial cancers have the best prognosis compared with other molecular subgroups regardless of treatment used, largely attributed to high neoantigen burden. SNCA-high and SNCA-low subgroup tumors typically have a low mutation load.50 Corresponding with the mutation frequencies, POLE-mutated endometrial tumors have the highest predicted neoantigen load (8,342 median predicted neoantigens per sample; range 628–20,440; p<0.001) compared with MSI (541; range 146–8,063) and MSS tumors (70.5; range 7–1,877).114 POLE-mutated tumors also have higher degrees of CD8⁺ T cell infiltration as well as higher numbers of CD8⁺ and CD3⁺ TILs compared with other categories.114 115 118

Exploratory analyses of responses to anti-PD-1-based regimens by TMB status have been reported from landmark trials assessing ICIs in previously treated endometrial cancer, GARNET and KEYNOTE-775. In GARNET, patients with TMB-H tumors had higher ORRs with dostarlimab treatment than patients with TMB-low tumors in both mismatch repair proficient (pMMR) (45.5% [95% CI 16.7% to 76.6%; n=5 of 11] vs 12.1% [95% CI 7.2% to 18.6%; n=17 of 141]) and dMMR subgroups (43.8% [95% CI 33.3% to 54.7%; n=39 of 89] vs 21.4% [95% CI 4.7% to 50.8%; n=3 of 14]).119 Similarly, in KEYNOTE-775, superior ORRs to pembrolizumab plus lenvatinib were observed in tumors with TMB above the cut-off threshold of >175 mutations/exome regardless of MSI status (77% for TMB-H group [n=10 of 13] vs 33% for low TMB group [n=22 of 66]) as well as in the small number of patients with tumors that were MSS and TMB-H (100% in the TMB-H group [n=4 of 4] vs 34% in the low TMB group [n=22 of 64]).120 Despite these early and exploratory results, MMR status is the preferred biomarker over TMB to inform treatment selection in patients with previously treated endometrial cancer, where MMR status informs whether anti-PD-1 monotherapy and pembrolizumab plus lenvatinib combination therapy may be appropriate for patients with dMMR and pMMR tumors, respectively.

Expert Panel recommendations

• Tumor PD-L1 expression should not be used to guide immunotherapy treatment decisions in endometrial cancer (LE:2).

• For all patients with advanced or recurrent endometrial cancer, MMR IHC on tumor tissue should preferentially be performed as a first-line immunotherapy biomarker for dMMR (LE:1). MSI and NGS testing can be considered as second-line immunotherapy biomarker tests (LE:3).

Previously untreated stage III or IV or first recurrent endometrial cancer

While not FDA-approved at the time of guideline publication, two phase III randomized placebo-controlled trials have reported positive results with the use of anti-PD-1 ICIs in combination with carboplatin and paclitaxel in patients with previously untreated stage III or IV or first recurrent endometrial cancer. In both studies, PFS was improved with the addition of an ICI to the standard of care chemotherapy regimen, regardless of MMR status.

The RUBY trial (NCT03981796) randomized 494 patients with primary advanced stage III or IV or first recurrent (systemic therapy-naive or previously treated with neoadjuvant or adjuvant systemic therapy and had recurred or progressed ≥6 months after completion of treatment) endometrial cancer to receive dostarlimab (500 mg) with carboplatin and paclitaxel or placebo with carboplatin and paclitaxel every 3 weeks for six cycles, followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years.121 Primary endpoints were PFS in both the dMMR/MSI-H and overall populations, and OS in the overall population. In patients with dMMR/MSI-H endometrial cancer (n=118; median follow-up 24.8 months [range 19.2–36.9]), the 2-year PFS rate was 61.4% (95% CI 46.3% to 73.4%) in the dostarlimab group and 15.7% (95% CI 7.2% to 27.0%) in the placebo group (HR for disease progression or death 0.28; 95% CI 0.16 to 0.50; p<0.001). In the overall population (median follow-up 25.4 months [range 19.2–37.8]), landmark PFS at 2 years was 36.1% (95% CI 29.3% to 42.9%) in the dostarlimab group and 18.1% (95% CI 13.0% to 23.9%; HR for disease progression or death 0.64; 95% CI 0.51 to 0.80; p<0.001) in the placebo group. The 2-year OS rates were 71.3% (95% CI 64.5% to 77.1%) with dostarlimab and 56.0% (95% CI 48.9% to 62.5%) with placebo (HR for death 0.64; 95% CI 0.46 to 0.87; p=0.0021). In subgroup analyses, the 2-year PFS rates for the pMMR/MSS population were 28.4% (95% CI 21.2% to 36.0%) with dostarlimab and 18.8% (95% CI 12.8% to 25.7%) with placebo (HR for disease progression or death 0.76; 95% CI 0.59 to 0.98), and 2-year OS rates were 67.7% (95% CI 59.8% to 74.4%) and 55.1% (95% CI 46.8% to 62.5%), respectively. In the overall population, grade ≥3 AEs occurred in 70.5% of patients in the dostarlimab group and 59.8% of patients in the placebo group, with the most common AEs (any grade) being nausea (53.9% and 45.9%), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). The most common irAEs to occur in the dostarlimab group were hypothyroidism (11.2%) and rash (6.6%).

The NRG-GY018 trial (NCT03914612) randomized 816 patients with stage III, IVA, or IVB or first recurrent (systemic therapy-naïve or previously treated with adjuvant chemotherapy and ≥12 months chemotherapy-free interval) endometrial cancer to receive either pembrolizumab (200 mg) or placebo with carboplatin and paclitaxel every 3 weeks for six cycles, followed by pembrolizumab (400 mg) or placebo every 6 weeks for up to 14 cycles.122 The primary endpoint was PFS. For the 225 patients with dMMR endometrial cancer, the 1-year PFS rates were 74% for patients in the pembrolizumab group and 38% for patients in the placebo group (median follow-up 12 months; HR 0.30; 95% CI 0.19 to 0.48; p<0.001). Median PFS was not reached (95% CI 30.6 to not reached) with pembrolizumab and was 7.6 months (95% CI 6.4 to 9.9) with placebo. In patients with pMMR endometrial cancer (n=588; median follow-up 7.9 months), the median PFS was 13.1 months (95% CI 10.5 to 18.8) with pembrolizumab and 8.7 months (95% CI 8.4 to 10.7) with placebo (HR 0.54; 95% CI 0.41 to 0.71; p<0.001). Grade ≥3 AEs occurred in 63.3% of patients who received pembrolizumab and in 47.2% of patients in the placebo group in the dMMR cohort, and 55.1% and 45.3%, respectively, in the pMMR cohort. Across all patient groups, some of the more common AEs at any grade included fatigue, peripheral sensory neuropathy, anemia, and nausea.

pMMR endometrial cancer

Pembrolizumab in combination with lenvatinib was granted accelerated approval for the treatment of patients with advanced endometrial carcinoma that is pMMR or not MSI-H and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation in September 2019. Accelerated approval was based on interim results of KEYNOTE-146, a phase Ib/II single-arm basket study in solid tumors. Of the 108 patients with previously treated endometrial cancer, 94 patients had tumors that were pMMR/MSS and 11 had tumors that were dMMR/MSI-H. At 24 weeks, the combination of pembrolizumab (200 mg intravenous every 3 weeks) plus lenvatinib (20 mg daily) showed anti-tumor activity regardless of MSI status. The ORR for patients with tumors not dMMR/MSI-H was 36.2% (95% CI 26.5% to 46.7%), the ORR for patients with dMMR/MSI-H tumors was 63.6% (95% CI 30.8% to 89.1%), and the ORR across subgroups was 38.0% (95% CI 28.8% to 47.8%).6

Accelerated approval was conditional pending results from KEYNOTE-775, a phase III, open-label trial in which patients were randomized to receive pembrolizumab plus lenvatinib or investigator’s choice of doxorubicin or paclitaxel, which met its primary PFS and OS endpoints leading to conversion to regular approval in July 2021. In total, 827 patients (pMMR, n=697; dMMR, n=130) with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting were enrolled.13 123 In updated analyses (median follow-up [all comers] lenvatinib plus pembrolizumab group 18.7 months; chemotherapy group 12.2 months), in addition to continued PFS and OS benefit (HR 0.70 [95% CI 0.58 to 0.83]), more frequent and more durable responses were observed with pembrolizumab plus lenvatinib versus chemotherapy in the pMMR/MSS population (ORR 32.4% [95% CI 27.5% to 37.6%] vs 15.1% [95% CI 11.5% to 19.3%]; median DOR 9.3 months [range 1.6+ to 39.5+] vs 5.7 months [range 0 to 37.1+]). Similar efficacy outcomes were observed in the all-comers population as well.

Overall, AEs associated with pembrolizumab plus lenvatinib were consistent with known safety profiles for each agent. Any-grade TRAE rates were similar in both arms. Grade ≥3 TRAEs occurred in 90% of patients with pembrolizumab plus lenvatinib and in 74% of patients treated with chemotherapy.123 Anti-angiogenic agents such as lenvatinib can create an increased risk for hemorrhage and hypertension,124 both of which were observed in the lenvatinib plus pembrolizumab arm of KEYNOTE-775. Grade ≥3 hypertension occurred in 37.9% of patients receiving pembrolizumab plus lenvatinib, compared with 2.3% of patients who received chemotherapy.125 The most common AE attributed to pembrolizumab treatment was hypothyroidism, which occurred in 57.6% (any grade) of patients who received pembrolizumab plus lenvatinib.

dMMR endometrial cancer

Endometrial tumors have among the highest rates of dMMR/MSI in solid tumors.12 50 Dostarlimab is approved for adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen. The accelerated approval, which was granted in April 2021, was based on GARNET, an open-label, phase I basket trial (table 3). Cohort A1 of GARNET included 71 patients with dMMR endometrial cancer, and the ORR and DOR endpoints were met at an interim analysis with a median follow-up of 11.2 months (range 0.03+ to 22.11+).7 The VENTANA MMR RxDx Panel, which was used to retroactively confirm MMR status in GARNET,15 was approved as the companion diagnostic for this indication. In February 2023, the accelerated approval was converted to regular approval. The reported ORR at the time of regular approval for patients with dMMR endometrial tumors (n=141) was 45.4% (95% CI 37.0% to 54.0%).15 The DOR was not reached (range 1.2+ to 52.8+ months) and the percentage of patients with response duration ≥12 months and 24 months was 85.9% and 54.7%, respectively.

At an additional interim analysis for GARNET, median PFS was 6.0 months (95% CI 4.1 to 18.0) for patients with dMMR/MSI-H tumors (median follow-up 27.6 months; n=143) and 2.7 months (95% CI 2.6 to 2.8) for patients with pMMR/MSS tumors (median follow-up 33 months; n=156), with estimated 36 month PFS rates of 40.1% and 6.8%, respectively.126 Median OS was not reached for patients with dMMR/MSI-H tumors (95% CI 25.7 months to not reached; n=153) and 16.9 months (95% CI 13.0 to 21.8; n=161) for patients with pMMR/MSS tumors, with an estimated probability of survival at 36 months of 58.4% and 22.2%, respectively.

Patients with endometrial cancer that is dMMR or MSI-H who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation are also eligible for pembrolizumab monotherapy. Approval was granted in March 2022, based on Cohorts D and K of KEYNOTE-158 (table 3). At long-term follow-up (median 54.5 months; n=94), ORR was 50% (95% CI 39.5% to 60.5%), and the median DOR was 63.2 months (range 2.9 to 63.2).127 Median PFS was 13.1 months (95% CI 4.3 to 25.7), with a 4-year estimated PFS rate of 37%. Median OS was 65.4 months (95% CI 29.5 to not reached), and the estimated OS rate at 4 years was 59%. The VENTANA MMR RxDx panel was approved as a companion diagnostic for assessing dMMR, and the FoundationOne CDx assay is FDA-approved as a companion diagnostic for assessing MSI-H. The recommended immunotherapy treatments for patients with endometrial cancer can be found in figure 3.

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Figure 3

Advanced endometrial cancer diagnostic workup and treatment algorithm. For all patients with endometrial cancer, clinical trial enrolment should be encouraged, as feasible. For patients with HER2+ serous endometrial cancer, carboplatin plus paclitaxel and trastuzumab is also a treatment option. *Excluding prior chemotherapy given in the neoadjuvant or adjuvant setting; †Following prior systemic therapy in any setting including the neoadjuvant or adjuvant setting. dMMR, mismatch repair deficient; HER2, human epidermal growth factor receptor 2; MMR, mismatch repair; MSI-H, high microsatellite instability; MSS, microsatellite stable; pMMR, mismatch repair proficient.

GARNET reported manageable toxicity for dostarlimab monotherapy, and no major safety differences were seen between patients with dMMR or pMMR tumors.119 Any grade TRAEs occurred in 67.6% of patients, and grade ≥3 TRAEs occurred in 16.6% of patients. The most common any-grade TRAEs were fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%), and the most common grade ≥3 TRAE was anemia at 2.8%. Any-grade irAEs occurred in 23.1% of patients, the most common being hypothyroidism and diarrhea. Grade ≥3 irAEs occurred in 7.7% of patients.7 Similarly, no new safety signals were reported with pembrolizumab monotherapy in KEYNOTE-158 (n=90). Any-grade TRAEs (investigator-identified) were reported in 76% of patients, and 12% were grade 3–4. The most common TRAEs were pruritus (24%), fatigue (21%), and diarrhea (16%). Infusion reactions or irAEs occurred in 28% of patients, and 7% were grade 3–4. The most common irAEs were hypothyroidism (14%) and hyperthyroidism (8%). Six patients (7%) discontinued treatment due to a TRAE, and there were no fatal TRAEs.

TMB-H endometrial cancer

The efficacy data leading to the accelerated approval of pembrolizumab for all solid tumors that are TMB-H are described in the Immunotherapy biomarkers for gynecologic cancer section. In the patients with TMB-H endometrial cancer (n=15) in KEYNOTE-158, the ORR with pembrolizumab was 47% (95% CI 21% to 73%) and the response duration ranged from 8.4+ months to 33.9+ months.13 30 Responses were infrequent, however, in patients with endometrial cancer that was TMB-low, with only 4 of 67 patients responding.

Expert Panel recommendations

• For first-line treatment of recurrent or metastatic endometrial cancer, carboplatin plus paclitaxel with or without trastuzumab (if HER2+ serous endometrial cancer) was the standard of care at the time of guideline publication (LE:2). Anti-PD-1 ICIs in combination with carboplatin plus paclitaxel demonstrated statistically significant and clinically meaningful improvements in PFS over chemotherapy alone for the treatment of previously untreated stage III or IV or first recurrent (after prior neoadjuvant or adjuvant chemotherapy) endometrial cancer. The observed benefit was regardless of MMR status (LE:2), however, this combination was not FDA-approved at the time of guideline publication.

• For second-line treatment of patients with pMMR/MSS advanced or recurrent endometrial cancer, pembrolizumab plus lenvatinib is recommended, as indicated. For second-line treatment of patients with TMB-H/pMMR/MSS endometrial cancer (LE:2), pembrolizumab plus lenvatinib is the standard of care option (LE:2) however, anti-PD-1 monotherapy may also be an option (LE:3).

• For patients with dMMR/MSI-H advanced or recurrent endometrial cancer who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation, pembrolizumab monotherapy is recommended (LE:3). For patients with dMMR/MSI-H advanced or recurrent endometrial cancer who have disease progression following prior platinum-containing regimen in any setting and who are not candidates for curative surgery or radiation, dostarlimab monotherapy is recommended (LE:3).

Expert Panel recommendations

• For all patients with endometrial cancer, clinical trial enrollment should be encouraged, as feasible.

• Non-FDA-approved immunotherapy combination strategies should only be considered in the context of a clinical trial.

ICI-targeted therapy combinations for the treatment of ovarian cancer

Mutations in the DNA damage repair genes BRCA1 and BRCA2 are common in patients with ovarian cancer, with a prevalence of about 10%–15% overall and more frequently in tumors with serous (16%–18%) and high-grade serous (22.6%) histology.144 145 Tumors with BRCA mutations are sensitive to PARP inhibitors, which are currently approved in the front-line and recurrent maintenance setting for ovarian cancer. Tumors with BRCA mutations also have higher IC PD-L1 expression, predicted neoantigen expression, and TILs in high-grade serous ovarian tumors.146 PARP inhibition may also be immunomodulating through upregulation of IFN signaling,147 regulation of TGF-β signaling, and modulation of Tregs.148 Preclinical evidence supports enhancement of stimulator of IFN genes (STING) dependent antitumor immune response via PARP inhibition and augmented therapeutic efficacy of checkpoint blockade even in the absence of BRCA mutations,149 providing rationale for combination approach with ICIs. The phase I/II TOPACIO-KEYNOTE 162 trial (NCT02657889) assessed pembrolizumab with niraparib in patients with TNBC and recurrent ovarian cancer unselected by BRCA mutation status. An ORR of 18% (90% CI 11% to 29%) and a DCR of 65% (90% CI 54% to 75%) were reported in the ovarian cancer cohort (n=60). ORRs were consistent across tumor BRCA or homologous recombination deficiency (HRD) biomarker status.150 An ORR of 71.9% (95% CI 53.25% to 86.25%) with a 28-week DCR of 65.6% (90% CI 49.6% to 79.4%) was reported in the phase I/II MEDIOLA trial (NCT02734004) in patients with BRCA-mutated, platinum-sensitive, relapsed ovarian cancer (n=32) treated with durvalumab plus olaparib.151

Triplet combinations are also being evaluated, including ICIs with PARP inhibitors and anti-VEGF(R) agents. The GINECO BOLD trial (NCT04015739) of durvalumab plus bevacizumab plus olaparib reported a 3-month DCR of 70% in patients with platinum-resistant relapsed ovarian cancer, and a 6-month DCR of 44% in the platinum-sensitive relapsed cohort.152 Pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide is also being evaluated in a phase II randomized trial (NCT02853318), which reported an ORR of 47.5% and a median PFS of 10 months at an interim analysis.153

Investigational immunotherapy strategies for the treatment of ovarian cancer

The presence of TILs in ovarian tumors indicates an antitumor response that is suppressed. However, the lack of benefit in the early ICI trials brings into question whether the abundance, differentiation status, or antigen specificity of TILs in ovarian cancer is inadequate to reject the tumor. Thus, strategies to augment the existing TILs, such as vaccines or ACT, are being evaluated. A wide variety of therapeutic vaccines have been tested in ovarian cancer, including dendritic cell vaccines, peptide-based, viral vector-based, and cancer testes antigen (CTA) targeting vaccines, and others.154 However, efficacy has been limited,155 as demonstrated in a recent meta-analysis of vaccine approaches in ovarian cancer. The pooled ORR estimate across 12 vaccine studies was 4% (95% CI 1% to 7%) and the reported ORRs from those studies ranged from 0%–33%, the estimated PFS was 13 months (95% CI 8.5 to 16.3) and the estimated median OS was 39 months (95% CI 31 to 49). However, more recent strategies to improve vaccine immunogenicity tailored to the specific type of vaccine, along with rational combinations or sequencing of vaccines with other therapies may increase efficacy.

ACT studies for ovarian cancer were first initiated in the 1990s. Since then, CAR T cells and TCR-engineered T cells, lymphodepletion, and combination regimens have been implemented to increase efficacy. Some of the tumor-specific targets for CAR T cell therapies used in ovarian cancer include MUC16, mesothelin, HER2, and folate receptor-α.156 157 Similar to other solid tumors, however, CAR T cell therapies have seen limited success in ovarian cancer.

Ongoing phase II trials are assessing measles virus-based therapy (NCT02068794; NCT02364713), adenovirus-based therapy (NCT03225989), and vaccinia virus-based therapy (VIRO-15; NCT02759588) for the treatment of ovarian cancer. Additional immunotherapy strategies under investigation include combining cell therapies with vaccines or oncolytic viruses, intraperitoneal delivery of chemoimmunotherapy, bispecific antibodies that bring ICs into close proximity to TCs, and others. Clinical trials evaluating immunotherapy approaches in ovarian cancer are abundant, and enrollment should be offered to patients, when appropriate.

Expert Panel recommendations

• For all patients with ovarian cancer, clinical trial enrollment should be offered, as feasible.

• NGS testing should be offered to all patients with newly diagnosed ovarian cancer (LE:2).

• For patients with recurrent TMB-H and/or MSI-H/dMMR ovarian tumors with no satisfactory alternative treatment options, treatment with ICIs should be considered (LE:3).

• Tumor PD-L1 expression should not be used to inform treatment decisions for ICI use in ovarian cancer (LE:2).

The vaginal and vulvar cancer immune microenvironment

The presence of CD8⁺ and CD4⁺ TILs in vulvar tumors has been associated with a better prognosis overall regardless of the therapy administered.163 PD-L1 expression on TCs is moderate (reported between 23%–33%),164 165 whereas it is much higher in infiltrating ICs (>90%).165 Data are conflicting thus far on the prognostic utility of PD-L1 expression for vulvar tumors as well as on the association between checkpoint expression and HPV viral status.164 165 Metastases involving tumor-draining lymph nodes have been demonstrated to have an inflamed microenvironment with high expression of PD-1 and CTLA-4.166 Data are lacking on the immune microenvironment of vaginal cancer specifically, however, HPV-positive vaginal cancer likely mimics the immunophenotype of other HPV-related cancers.167

Immunotherapy outcomes in vaginal and vulvar cancers

Data on the efficacy of ICIs for the treatment of vulvar and vaginal cancer are sparse and limited to single-agent anti-PD-1 studies. The phase I/II CheckMate 358 trial (NCT02488759), which assessed nivolumab monotherapy in several virus-associated cancers, reported an ORR of 20.0% (95% CI 0.5% to 71.6%) and a DCR of 80.0% (95% CI 28.4% to 99.5%) in five patients with vaginal or vulvar cancer, four of whom had HPV-positive tumors.168 OS rates at 12 months and 18 months were 40.0% (95% CI 5.2% to 75.3%) and 20.0% (95% CI 0.8% to 58.2%), and the 6 months PFS rate was 40.0% (95% CI 5.2% to 75.3%). All of the four tumors evaluable for PD-L1 expression were PD-L1 TC≥1%. Patients with vulvar cancer of unspecified HPV status (n=101) were also included as a cohort in the phase II KEYNOTE-158 trial, which evaluated pembrolizumab monotherapy for the treatment of multiple advanced solid tumors that progressed on standard of care therapy. The ORR in this cohort was 10.9% (95% CI 5.6% to 18.7%) with a median DOR of 20.4 months (range 2.1+ to 28.0). Median PFS for the vulvar cancer cohort in KEYNOTE-158 was 2.1 months (95% CI 2.0 to 2.1) and median OS was 6.2 months (95% CI 4.9 to 9.4).169 A majority of patients (83.2%) had PD-L1-positive tumors (CPS≥1), however responses were seen in both PD-L1-positive and PD-L1-negative populations. The safety profile for ICI monotherapy for vaginal and vulvar cancers in these small cohorts was generally consistent with other tumor types. Published data are lacking on the use of ICI-based combinations in vaginal and vulvar cancers.

HPV-targeting therapeutic vaccines have also been investigated for the treatment of vaginal and vulvar cancers. In patients with high-grade, HPV 16-positive vulvar intraepithelial neoplasia (n=19), vaccination against E6 and E7 peptides resulted in a 12-month clinical response rate of 79% (95% CI 54% to 94%), with nine complete responses (CRs; 47%), and the clinical response rate was maintained at 24 months.170 Weak CD8⁺ T cell reactivity was associated with clinical non-response, providing rationale for a follow-up study that randomized 43 patients with high-grade vulvar and vaginal intraepithelial neoplasia to receive the ISA101 HPV 16-targeting vaccine with (n=22) or without the topical TLR7 agonist imiquimod (n=21).171 Responses to the vaccine were not improved with the addition of imiquimod, and the 12-month clinical response rate was 52% (95% CI 32.5% to 70.6%).172 Imiquimod, which is used as a topical 5% cream and is approved for genital and perianal wart and superficial basal cell carcinoma,173 has however, been found to be effective in treating vaginal neoplasia, vulvar neoplasia, and CIN.174

Gynecologic sarcomas

Overall, gynecologic sarcomas are rare, with uterine sarcoma being the most common.175 The trials leading to FDA approvals for ICIs in the treatment of gynecologic cancers have predominantly included patients with carcinoma histologies. Data are emerging on the use of ICIs in metastatic sarcomas, with mixed response rates across tumor types.176 Unlike in uterine carcinomas where dMMR/MSI-H has been reported in up to 30% of tumors,119 177 dMMR prevalence in uterine sarcomas or leiomyosarcomas is low, up to 6%.178 CD8⁺ T cell infiltration and PD-L1 expression on TCs and ICs in uterine leiomyosarcomas is also highly prevalent.179 However, in a phase II trial investigating nivolumab monotherapy in a cohort of 12 patients with advanced uterine leiomyosarcoma (NCT02428192), no responses were reported.180 The Alliance A091401 (NCT02500797) trial assessing nivolumab with or without ipilimumab in patients with varying sarcoma subtypes reported one response in a patient with uterine leiomyosarcoma treated with the ICI combination.181 Taken together, the data and use of ICIs in patients with gynecologic sarcomas is underwhelming and limited to very small patient numbers, and therefore the use of ICIs should only be considered based on immune biomarkers (ie, TMB and/or MMR/MSI).

Rare epithelial endometrial tumors

Epithelial endometrial tumors are most commonly endometrioid histology. More rare epithelial histologies such as clear cell, serous, carcinosarcoma, dedifferentiated, undifferentiated, and others, while less prevalent, are typically high grade.104 Data are limited on efficacy of ICIs in treating these rare subtypes. However, in KEYNOTE-775 which included patients with clear cell, serous, and mixed histologies, subgroup analyses of PFS and OS favored the pembrolizumab plus lenvatinib combination over chemotherapy across all histological subtypes.125

Gynecologic NETs

Gynecologic NETs include heterogeneous histologies and they can range from slow growing, well-differentiated tumors with low mutation burden to highly proliferative, poorly differentiated, highly mutated tumors.182 Extrapolating from basket trials that enrolled patients with various rare tumor types, NETs have low ORRs to ICI monotherapy of <10%.182 Dual ICI therapy (nivolumab plus ipilimumab) is being investigated in the DART trial (NCT02834013). Results have been reported in a cohort of patients with non-pancreatic NETs, including three patients with cervical NETs, in which one patient had a confirmed PR.183

Gynecologic melanomas

Melanomas of the genitourinary tract are a rare subset of gynecologic malignancies. While these tumors have historically been classified as mucosal, recent molecular data indicate they may be distinct from both mucosal and cutaneous melanomas.184 185 Patients with vaginal and vulvar melanoma have an overall poor prognosis185 and data on the immune microenvironment of gynecologic melanomas are scarce. Overall, the prevalence of PD-L1 expression is unclear, as reports have used inconsistent staining and scoring methodologies for measurement. However, high levels of CD8⁺ T cell infiltration have been reported in vulvar melanomas, indicative of potential responsiveness to immunotherapy and a favorable prognosticator.186 In case reports, the response rates to ICIs in gynecologic melanoma have been less remarkable than those seen in cutaneous melanoma. In one review including a total of 57 patients from various case reports and series with metastatic disease, there were 6 CRs and 13 PRs with anti-PD-1 monotherapy or in combination with anti-CTLA-4.187 Concurrent ICI and radiotherapy has been shown to improve PFS, but not OS, in cutaneous melanoma in one meta-analysis,188 and this strategy may also be appropriate for some patients with gynecologic melanoma. Neoadjuvant anti-CTLA-4 in combination with radiotherapy has also been reported in one small study (n=4), where among the three patients who underwent resection, one achieved pathologic complete response (pCR), and all three patients had local radiographic CR after surgery.189 Recurrence was reported in two patients at 9 months and 10 months post-diagnosis, and the remaining two were disease-free at 20 months and 38 months. In addition, the use of combined dual checkpoint inhibition and high-dose and low-dose radiation after progression on dual ICIs alone was successful in one case report.190

Vaginal and vulvar cancers

• For previously treated patients with recurrent or metastatic vulvar or vaginal squamous cell carcinoma, second-line treatment with pembrolizumab (for patients with PD-L1-positive/TMB-H/MSI-H/dMMR tumors) or nivolumab (for patients with HPV-related tumors) should be considered (LE:3).

• For patients with unresectable/metastatic vulvar or vaginal melanoma, treatment can follow the standard of care treatment paradigms for cutaneous melanoma.

• For patients with locally advanced vulvar or vaginal melanoma with high risk of recurrence, adjuvant treatment with an anti-PD-1 ICI with or without an anti-CTLA-4 ICI may be considered.

Other rare gynecologic cancer variants

• For patients with uterine sarcoma who have exhausted other treatment options, biomarker-driven (ie, dMMR, TMB-H, or MSI-H) treatment with an anti-PD-1 ICI may be considered.

• For patients with previously treated rare epithelial endometrial tumors, second-line treatment with combination pembrolizumab plus lenvatinib should be considered.

Gestational trophoblastic neoplasia

• For patients with recurrent GTN with prior chemotherapy treatment, treatment with an anti-PD-(L)1 ICI may be considered (LE:3).

Special patient populations

• Patients with advanced gynecologic cancer living with controlled HIV infection should not be routinely excluded from receiving ICI therapy either on or off trials. The safety and efficacy of ICIs in patients with HIV who are compliant on highly active antiretroviral therapy (HAART) are similar to those for the general population (LE:1).

• For patients with advanced gynecologic cancer and uncontrolled HIV infection, ICI therapy may still be considered and infectious disease consultation is recommended.

• Patients with advanced gynecologic cancer and chronic HBV/HCV infections can still be considered for ICI therapy (LE:1). Liver function should be checked at baseline and before every immunotherapy cycle for these patients and consultation with a hepatitis service should be considered.

• For patients with a history of active autoimmune disease requiring systemic immunosuppression (≥10 mg prednisone or equivalent, or biologics), the potential benefits of immunotherapy must be weighed against the ability to tolerate severe AEs (LE:4).

• For patients who have significant organ dysfunction due to progressive cancer or to intrinsic non-immune-related disease (eg, cirrhosis, chronic kidney disease, idiopathic pulmonary fibrosis or pneumonitis) the potential benefit of immunotherapy must be weighed against the potential for severe AEs as these individuals may have limited ability to tolerate irAEs.

• Patients with hypothyroidism, adrenal insufficiency, or insulin-dependent diabetes mellitus can generally be safely treated with immunotherapy in the setting of hormone replacement therapy and monitoring per the standard of care (LE:4).

• For patients on immunotherapy with pre-existing or immune-related adrenal insufficiency, physiologic replacement doses of steroids should be continued (LE:4).

• ICIs are generally contraindicated in SOT patients due to the high risk of allograft rejection (LE:1), but each case should be evaluated independently in consultation with the transplant service.

Response monitoring, management of radiologic progression, and toxicity

• For patients with gynecologic cancer, CA125 has limited utility in disease monitoring in patients undergoing ICI therapy (LE:4). Decisions to continue or change ICI therapy should be based on the overall clinical status of the patient and radiographic imaging.

• For patients with gynecologic cancer who attain clinical benefit with ICI therapy (ie, CR, PR or SD), routine imaging every 2–3 months for the first 2 years is recommended. Beyond 2 years, reduction in the frequency of imaging may be considered at the discretion of the physician.

• For patients with gynecologic cancer receiving ICI therapy, development of pleural effusions and/or ascites may sometimes represent pseudoprogression (LE:4), and this possibility should be considered in the context of the overall clinical picture in decisions to continue ICIs or switch therapy.

• For patients with gynecologic cancer receiving ICI therapy, a mixed response with enlargement of lymph nodes with stable or decreasing other sites of disease may sometimes represent pseudoprogression (LE:4), and this possibility should be considered in the context of the overall clinical picture in decisions to continue ICIs or switch therapy.

• For patients with gynecologic cancer and apparent radiologic progression on ICI therapy, continued treatment may be considered when the patient’s overall clinical status and performance status are maintained and the clinician believes that clinical benefit of the therapy outweighs any treatment-related toxicities (LE:1).

• For patients with gynecologic cancer who initially had clinical benefit with ICI therapy and their disease recurred after ICI discontinuation, rechallenge may be considered (LE:1).

• For patients with gynecologic cancer receiving ICI therapy, baseline symptoms for systems commonly affected by irAEs (eg, bowel, endocrine, skin) should be reviewed and documented to facilitate early recognition and management of toxicity.

• For patients who have experienced severe irAEs due to immunotherapy, the potential benefit of resuming immunotherapy relative to the risk of subsequent severe AEs must be considered.

• Patients with a history of significant irAEs due to immunotherapy who are considered candidates for resuming immunotherapy should be stable on a corticosteroid dose of no more than 10 mg prednisone or equivalent daily.

• For patients with skin-related irAEs, optimizing local cutaneous therapy may be considered as an alternative to systemic steroids (LE:4). For patients who do not respond to topical steroids, systemic steroids with rapid taper should be considered.

Gynecologic cancer-specific QOL considerations

Many patients receiving ICIs may have undergone prior surgical treatments which, depending on the extent, can be quite morbid for patients with gynecologic cancer. Patients may be coping with direct and indirect effects on sexual function, fertility, urinary and bowel function, physical changes and malformation, psychological and behavioral changes, menopausal symptoms, and other challenges.277 Management of physical and psychosocial symptoms and referral to specialists, when appropriate, should continue while on ICIs. Some common irAEs may amplify the physical symptoms. For example, endocrine-related irAEs may further complicate hormonal dysfunction, and hormonal replacement therapy may be needed. In addition, patients experiencing a decrease in estrogen and androgens due to prior surgery (specifically, oophorectomy) are at an increased risk for urinary tract infections,277 which are also a common AE associated with ICIs.278 Finally, although most patients with advanced gynecologic cancer will have undergone previous surgeries to remove the affected organs, for patients who are still able to bear children, use of contraception and referral to an oncofertility specialist is encouraged.

Assessment of QOL and outcomes from landmark trials

QOL, health-related QOL (HRQOL), and/or patient-reported outcomes (PROs) are often formally assessed in clinical trials as secondary and exploratory endpoints. ICIs have generally demonstrated favorable tolerability in terms of HRQOL279 and prolongation of the time to symptomatic deterioration compared with chemotherapy.280 ,281 However, many of the formal assessment tools used in clinical trials were developed for cytotoxic or targeted therapy, and thus may not capture common irAEs.279 282 Although the formal assessment tools and questionnaires used in clinical trials are not practical for general clinical use, clinicians should frequently assess patients for treatment-related symptoms, in addition to physical and psychological functioning and well-being.

In gynecologic cancer, dostarlimab monotherapy in patients with MSI-H endometrial cancer in the GARNET trial283 was associated with improvements in pain, insomnia, and social and emotional functioning compared with baseline (assessed by the European Organization for Research and Treatment of Cancer (EORTC): Quality of Life Questionnaire-Core 30 [QLQ-C30] for global health status [GHS]/QOL). Additionally, appetite, nausea, vomiting, constipation, diarrhea, physical and role functioning, QOL, and GHS were maintained over the trial duration. In KEYNOTE-826, patients with cervical cancer treated with pembrolizumab had numerically improved QOL (assessed by QLQ-C30) compared with the placebo group, although the difference was not statistically significant.284 Pembrolizumab plus lenvatinib was associated with no significant difference in HRQOL between the pembrolizumab plus lenvatinib and physician’s choice chemotherapy groups in KEYNOTE-775.285

Disparities in gynecologic cancer care

Disparities in access to care account for some of the global inequality in disease-specific survival for patients with gynecologic cancer. Global inequities in access to screening and preventative measures such as HPV vaccines result in sustained high mortality rates for several gynecologic cancers in countries with low healthcare resources, in contrast to the decreased incidence and mortality seen in higher-resource countries. In addition, due to the high cost, the WHO does not deem immunotherapy agents as essential medicines,286 and therefore access to ICIs for patients with gynecologic cancer in low-resource countries is further limited.

Racial, ethnic, and geographic disparities for patients with gynecologic cancer also persist in high-resource countries including the US. Socioeconomic status as well as geographic location contribute to inequitable access to care among all patients with gynecologic cancer.287 These effect modifiers, however, cannot be interpreted without an awareness of systemic racism in the healthcare system and persistent marginalization of women of color, particularly Black women, in the US. Black women have significantly lower 5-year survival rates for ovarian, endometrial, and cervical cancer compared with white women.287 Many studies have demonstrated that Black patients with gynecologic cancer are less likely to receive care in line with evidence-based guidelines.288–290 Patients who are Black, on Medicaid, or have lower income are less likely to receive immunotherapy,291 although data are lacking for gynecologic cancers specifically. Further amplifying these disparities, potential genetic, environmental, or physiological factors that may underpin some of the variance in disease outcomes or response to treatment are poorly understood because of inadequate representation of Black women in clinical trials.292 293

Transgender patients are another population that experiences inequities in cancer care.294 Data are lacking on the overall incidence and screening for gynecologic cancer in transgender men, which will depend on surgical and hormonal status.295 However, transgender men have reported avoiding routine yearly gynecologic care (31.1%) due to fear of culturally incompetent care,296 which may lead to gynecologic cancer diagnoses at a later stage. Education on culturally sensitive and guideline-directed medical care of transgender patients is lacking outside of specialized treatment centers—surveys have found that 80% of gynecologists did not receive training on care for transgender patients in residency,297 and only 29% felt comfortable caring for transmasculine patients.298 Clinicians should proactively seek out training and resources on providing culturally and clinically competent care of patients with non-traditional genders, such as those offered by Health Professionals Advancing LGBTQ Equality (previously known as the Gay and Lesbian Medical Association [GLMA]) or the University of California San Francisco Center of Excellence for Transgender Health.

Continued efforts to extend equal access to cancer care for historically marginalized populations are of upmost importance. In addition, clinical research and clinical trials should prioritize enrolling diverse patient populations.

Patient education

• For patients with gynecologic cancer receiving immunotherapy, prior to initiation and throughout treatment patient/family/caregiver education should highlight:

  • The unique mechanism of action of immunotherapy.

  • The unique side effects of immunotherapy, focusing on the early recognition of irAEs and the potential for these irAEs to become permanent or even appear after treatment has been completed.

  • That some of the more common toxicities have vague symptoms and therefore any change from baseline health should be reported.

  • That extreme fatigue, respiratory symptoms, rash, and increases in bowel movements can be early signs of irAEs and should prompt speedy notification of the treatment team.

  • That irAEs have unique management strategies that can include treatment with steroids and interruption of immunotherapy doses.

  • That combination regimens have the potential to cause additional serious AEs beyond those associated with ICIs (ie, hypertension with lenvatinib).

  • That measurable response to treatment can be delayed with immunotherapy compared with traditional cytotoxic treatments, and the evaluation criteria and timing for evaluation may be different.

  • The importance of alerting all treating providers, emergency department personnel, and first responders that the patient is on an immunotherapy with a diverse and unique range of side effects. This can be facilitated by encouraging the patient to carry information specific to their treatment and care team, such as the immunotherapy ONS wallet card, or having the information easily accessible on their phone.

QOL support

• For all patients with gynecologic cancer, holistic approaches to support QOL should be considered. This can include pharmacological management, mindfulness training programs, support groups, individualized therapy, and referral to specialists. A diverse offering increases the likelihood of meeting each patient’s unique needs.

• All patients with gynecologic cancer and, when possible, care providers should be managed by a multidisciplinary healthcare team to facilitate optimal QOL. This may include physicians, nurse practitioners/physician assistants, patient advocates, nurse navigators, oncology social workers, physical therapists, palliative care providers, financial counselors, and complementary and integrative medicine providers such as acupuncturists or massage therapists.