Cervical cancer remains a major global health challenge, with an estimated 600,000 new cases and 340,000 deaths annually, making it the fourth most common cancer and the fourth most common cause of cancer death in women worldwide. The disease burden is profoundly unequal, with approximately 90 percent of cervical cancer deaths occurring in low and middle income countries where limited access to screening programs and HPV vaccination perpetuates high incidence and late stage presentation. In developed countries with established screening programs, the incidence and mortality of cervical cancer have declined substantially, but metastatic and recurrent disease continues to represent a clinical challenge for which new effective treatments are urgently needed.
Human papillomavirus infection is the causative agent of virtually all cervical cancers, with HPV16 and HPV18 together responsible for approximately 70 percent of cases. The viral oncoproteins E6 and E7 disrupt normal cell cycle regulation by targeting p53 and retinoblastoma protein respectively, enabling malignant transformation of cervical epithelial cells. The viral origin of cervical cancer creates a unique immunological context in which viral antigens provide non self targets for immune recognition, theoretically making these tumors amenable to immune based therapeutic strategies. This immunological rationale underpins the investigation and development of checkpoint inhibitors for cervical cancer treatment, alongside the established PD L1 expression commonly found in cervical tumor specimens.
Immunological Features of Cervical Cancer
Cervical cancer specimens frequently demonstrate PD L1 expression on tumor cells and on tumor infiltrating immune cells, with combined positive scores showing variability across cases. The tumor infiltrating lymphocyte density in cervical cancer correlates with prognosis and may predict responsiveness to immune checkpoint inhibition, as a more immunologically active baseline tumor microenvironment suggests existing anti tumor immunity that can be amplified by PD 1 pathway blockade. The chronic nature of HPV infection and the mechanisms by which HPV infected cells evade immune clearance during malignant transformation, including downregulation of antigen presentation machinery and upregulation of PD L1, create the immunological conditions that checkpoint inhibitors are designed to reverse.
High PD L1 combined positive scores, identified in a substantial proportion of advanced cervical cancer specimens, have been associated with greater benefit from pembrolizumab in clinical trials, reinforcing the role of biomarker assessment as a guide to immunotherapy use in this disease. The correlation between HPV infection and PD L1 expression in cervical cancer suggests that the viral immune evasion mechanisms and the tumor’s PD L1 upregulation may be mechanistically linked, with HPV oncoproteins potentially driving PD L1 expression as a component of their immune evasion strategy. This biological connection may partly explain the particular sensitivity of cervical cancer to PD 1 pathway blockade.
Pembrolizumab in Recurrent or Metastatic Cervical Cancer
The KEYNOTE 826 trial established pembrolizumab as a component of first line treatment for persistent, recurrent, or metastatic cervical cancer. The trial enrolled 617 patients who had not received chemotherapy for recurrent or metastatic disease and randomized them to pembrolizumab or placebo combined with paclitaxel and cisplatin or carboplatin with or without bevacizumab. Pembrolizumab significantly improved both progression free survival and overall survival in the overall patient population and in patients with PD L1 combined positive scores of one or greater, with particularly pronounced benefits in the PD L1 high subgroup. Pembrolizumab in combination with chemotherapy and bevacizumab produced a median overall survival exceeding 24 months in patients with PD L1 combined positive scores of one or greater, a substantial improvement over the 16 to 17 months historically observed with chemotherapy and bevacizumab alone.
Keytruda received regulatory approval for use in combination with chemotherapy with or without bevacizumab for PD L1 positive persistent, recurrent, or metastatic cervical cancer based on the KEYNOTE 826 results. This approval represented a meaningful advance for patients with advanced cervical cancer, a population with limited effective treatment options and poor prognosis with conventional chemotherapy. The benefit of adding pembrolizumab was observed across histological subtypes including squamous cell carcinoma and adenocarcinoma, broadening the applicability of this treatment advance to the full spectrum of cervical cancer patients.
Second Line Pembrolizumab Monotherapy
The KEYNOTE 158 basket trial included a cohort of patients with recurrent or advanced cervical cancer who had received one or more prior lines of chemotherapy, providing evidence for pembrolizumab monotherapy in the second line setting. Among patients with PD L1 combined positive scores of one or greater, pembrolizumab produced objective response rates of approximately 14 percent, with complete responses in approximately 3 percent and a median duration of response exceeding twenty months for those who responded. While response rates in this heavily pretreated population were modest, the durability of responses and the clinical benefit achieved in patients with few remaining treatment options supported regulatory approval for second line pembrolizumab monotherapy in PD L1 positive cervical cancer.
The identification of MSI high cervical cancers as a subgroup with potential for exceptional pembrolizumab responsiveness provides additional clinical rationale for molecular profiling of cervical cancer specimens. While MSI high cervical cancer is uncommon, representing only 1 to 2 percent of cases, the remarkable response rates of MSI high tumors to pembrolizumab across tumor types suggest that MSI testing should be incorporated into the molecular evaluation of cervical cancer patients, particularly those with limited treatment options where any potential predictive biomarker of exceptional response warrants clinical consideration.
Integration with Definitive Chemoradiation
Locally advanced cervical cancer treated with definitive concurrent chemoradiation and brachytherapy has excellent locoregional control rates but remains associated with distant recurrence in approximately 30 percent of patients. The incorporation of pembrolizumab into the definitive treatment of locally advanced cervical cancer represents an active area of clinical investigation based on the hypothesis that concurrent immunotherapy with chemoradiation may improve both locoregional control and reduce distant metastasis rates through immune mediated elimination of micrometastatic disease. The KEYNOTE A18 trial has evaluated pembrolizumab added to cisplatin based chemoradiation for locally advanced cervical cancer, with initial results suggesting progression free survival improvement that may translate into an important advance in the curative intent treatment of this disease.
The combination of radiation, which induces immunogenic cell death and increases tumor antigenicity, with concurrent cisplatin based chemotherapy, which may enhance T cell priming, and pembrolizumab, which removes inhibitory constraints on effector T cells, provides a mechanistically rational multimodal approach to locally advanced cervical cancer treatment. If positive results from ongoing trials are confirmed, the addition of pembrolizumab to standard chemoradiation may become a new standard of care for locally advanced cervical cancer that extends the role of immunotherapy from metastatic disease into the curative treatment setting, potentially preventing the distant recurrences that currently limit cure rates in this disease.
Conclusion
Cervical cancer, with its viral etiology creating inherent immunogenicity and frequent PD L1 expression, represents a disease well suited to immune checkpoint inhibition. Pembrolizumab has established meaningful clinical benefits in both the first line and second line treatment of recurrent or metastatic disease, with Keytruda now representing a component of standard first line treatment for PD L1 positive advanced cervical cancer. Ongoing investigation in the locally advanced curative setting and the continued refinement of biomarker driven patient selection will further define the role of pembrolizumab across the full spectrum of cervical cancer, potentially extending its benefits to include improvement in cure rates for patients with locally advanced disease managed with definitive chemoradiation.
