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.

Keywords: Advanced cervical cancer; Anti-angiogenesis therapy; Bevacizumab; Checkpoint inhibitors; Metastatic cervical cancer; Recurrent cervical cancer.

Figure 1.. Proposed mechanism of action of bevacizumab.

Panel A: The VEGF ligand binds VEGF receptor to initiate the molecular cascade which results in tumor angiogenesis. Panel B: Bevacizumab blocks angiogenesis through ligand-binding and sequestration. Adapted pending permission from Eskander RN, Tewari KS. Development of bevacizumab in advanced cervical cancer: pharmacodynamics modeling, survival impact and toxicology. Future Oncol. 2015;11(6); 909–22.

Figure 2:. Gynecologic Oncology Group protocol 240.

Panel A. Trial schema. Panel B. At the second interim analysis, the addition of bevacizumab to chemotherapy was associated with increased overall survival: 17.0 vs 13.3 months [hazard ratio of death, 0.71; 98% CI, 0.54–0.95; p=0.004]. (Tewari KS, et al. New Engl J Med 2014;370:734–43. © 2014 Massachusetts Medical Society. Used with permission). Panel C. At the protocol-specified final analysis the chemotherapy plus bevacizumab arms continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16.8 vs 13.3 months [hazard ratio of death 0.77; 95% CI, 0.62–0.95; p=0.007]. (Tewari KS, et al Lancet 2017;390:1654–63. © 2017 Elsevier Ltd. Used with permission).

Figure 3.. CTL-4 and the PD-L/PD-L1 pathways regulate activation of the immune system at different time points and different effector cells.

Panel A. CTL-4 functions to scale the T-cell response based on antigen binding affinity. CTL-4 resides in intracellular vesicles, and when need to dampen response it is translocated to the cellular surface. Panel B. In contrast, the PD-L/PD-L1 is utilized in peripheral tissues to damp immune responses in the setting of inflammation, limiting damage to healthy tissue. (Reproduced with from permission from Pardoll DM. Nature Reviews Cancer. 2012;12:252–64).

Figure 4.. Schema of the Gynecologic Oncology Group Protocol 3016 (EMPOWER-Cervical 1).

This phase III randomized clinical trial is designed to study the activity and toxicology of the anti-PD-1 molecule, cemiplimab vs physician’s choice chemotherapy as a second-line therapy for patients with platinum-resistant recurrent and/or metastatic cervical cancer. Courtesy of Matthew Fury, MD, PhD, used with permission.