Cervical cancer – State of the science: From angiogenesis blockade to checkpoint inhibition

Abstract

Vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival when bevacizumab was added to chemotherapy: 17.0 vs 13.3 months; HR 0.71; 98% CI, 0.54-0.95; p = .004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival and response. These benefits were not accompanied by deterioration in quality of life. GOG 240 identified vaginal fistula as a new adverse event associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 vs 13.3 months; HR 0.77; 95% CI, 0.62-9.95; p = .007. Post-progression survival was not significantly different between the arms in GOG 240. Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second line therapies in this patient population. Targeting the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus-positive head and neck carcinoma and cutaneous squamous cell carcinoma can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. Phase II studies using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, recently activated. Important considerations in attempts to inhibit the inhibitors include pseudoprogression and post-progression survival, abscopal effects, and immune-related adverse events, including endocrinopathies.

Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers

“…Immunotherapy is also being compared to chemotherapy in this setting. GOG3016/ENGOT-Cervix 9 is a phase III trial of cemiplimab (Anti-PD1) vs. investigator’s choice chemotherapy in recurrent/metastatic cervical cancer resistant to platinum-based therapy after two or more lines of treatment (NCT03257267) [ 66 ].…”

Human Plasma Levels of Vascular Endothelial Growth Factor, Matrix Metalloproteinase 9, and Tissue Inhibitor of Matrix Metalloproteinase 1 and Their Applicability as Tumor Markers in Diagnoses of Cervical Cancer Based on ROC Analysis

“…Despite widespread availability of HPV vaccines, CC is one of the major causes of cancer-related death in women worldwide. 23 , 24 It has been proven that the enhanced activity of the VEGF, MMPs, and their tissue inhibitors is strongly linked to a number of tumors. 25 – 29 Vascular endothelial growth factor is considered to be an important factor in blood vessel formation (angiogenesis), which is closely connected with tumor progression and metastasis.…”

Immunotherapy Treatment Against Cervical Cancer

“…Nivolumab is a PD-1 immune checkpoint inhibitor designed to enhance the immune system response and restore the antitumor immune response. It is an IgG4type human monoclonal antibody that enhances Tcell responses, including the antitumor response, by binding to the PD-1 receptor and blocking its interaction with PD-L1 and PD-L2 31 .…”