Immunotherapy for the Treatment of Gynecologic Cancer
Assessment and Screening
- For all patients with advanced or recurrent gynecologic cancer, MMR IHC 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).
- With the exception of cervical cancer (LE:2) (and possibly other HPV-related gynecologic cancers), PD-L1 IHC expression should not be used for clinical decision-making for patients with advanced or recurrent gynecologic cancers.
- For all patients with advanced or recurrent gynecologic cancers, NGS should be considered to assess for TMB-H eligibility for pembrolizumab treatment under the tissue-agnostic indication (LE:3).
- For all patients with gynecologic cancer, biomarker evaluation of recurrent lesions may be considered at the time of recurrence.
- 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).
- 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.
- 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.
- 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).
- 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).
- 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.
- 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).
- For all patients with rare gynecologic malignancies, clinical trial enrollment should be offered, as feasible.
- For all patients with rare gynecologic malignancies, testing for TMB-H and MSI-H by NGS (preferred) and MMR by IHC (as an alternative) is recommended, for potential treatment under tissue-agnostic indications for ICIs (LE:3). For patients with rare gynecologic malignancies, testing for PD-L1 by IHC may be considered (LE:4).
- 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.
- 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.
- 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.
Patient Education and QOL Support
- For all patients with gynecologic cancer, clinical trial enrolment should be offered, as feasible. Clinical trials should be offered to all patients, including under-represented patient populations.
- For all patients with gynecologic cancer, a thorough review of symptoms should be performed and documented at initiation of treatment to help identify early irAEs.
- 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.
- 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.
Immunotherapy for the Treatment of Gynecologic Cancer
June 9, 2023
Country of Publication
Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.
Female, Adult, Older adult
Health Care Settings
Ambulatory, Outpatient, Operating and recovery room
Nurse, nurse practitioner, physician, physician assistant
Assessment and screening, Treatment, Management
D007167 - Immunotherapy, D002583 - Uterine Cervical Neoplasms, D010051 - Ovarian Neoplasms, D000077216 - Carcinoma, Ovarian Epithelial
immunotherapy, cervical cancer, Cancer immunotherapy, gynecologic cancers, gynecologic cancer
Disis ML, Adams SF, Bajpai J, et alSociety for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancerJournal for ImmunoTherapy of Cancer 2023;11:e006624. doi: 10.1136/jitc-2022-006624