IMMU-NO versus yes: Applicability of immune checkpoint inhibitors in gynecologic cancers.

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for patients with gynecologic malignancies. ICIs have led to improved survival outcomes in uterine and cervical cancer, although with only modest success in ovarian cancer. In endometrial cancer, The Cancer Genome Atlas provided the framework for the molecular classification of endometrial cancer, enabling identification of the predominant predictive biomarker: mismatch repair (MMR) status. US Food and Drug Administration approvals for ICI monotherapy and in combination with targeted therapy based on MMR status quickly followed. Further research demonstrated a role for ICIs in combination with chemotherapy regardless of MMR status in the initial treatment of advanced or metastatic disease. In cervical cancer, ICIs are approved for use in combination with chemotherapy-sensitized radiation and in combination with systemic chemotherapy in patients who have recurrent or metastatic disease. In ovarian cancer, the tumor microenvironment, low tumor mutational burden, and the absence of a reliable predictive biomarker have limited the efficacy of ICIs, with most combination approaches failing to demonstrate meaningful benefit. A notable exception is KEYNOTE-B96, a randomized trial of pembrolizumab versus placebo with weekly paclitaxel, with or without bevacizumab, in patients with platinum-resistant ovarian cancer. Continued investigation into predictive biomarkers, resistance mechanisms, and alternative therapeutic targets is critically needed to extend the benefits of immunotherapy to patients with ovarian cancer. In this review, the authors describe the current immunotherapy landscape across gynecologic cancers, highlighting when ICI use is, and is not, supported by the evidence.