Julia Fehniger, MD
Franco Muggia, MD
For nearly 20 years, chemoradiation using single-agent platinum therapy has been the standard of care for advanced or recurrent cervical cancer.1 More recently, the Gynecologic Oncology Group (GOG) 240 trial tested the addition of bevacizumab (Avastin) to platinum-based chemotherapy, which conferred an overall survival advantage of 4 months for patients receiving this experimental treatment vs standard chemotherapy.2 Immunotherapy represents a possible new option to consider for these patients, and the future challenge will be how to incorporate these agents into clinical trials and, eventually, practice.
Virtually all cervical cancers are human papillomavirus (HPV)-related, which allows tumor cells to evade the host’s immune system.3 It is not surprising, therefore, that the immune response plays a role in both their origin and pattern of spread. For years, investigators focused on identifying the immunosuppressive factors that contributed to the development of HPV-related conditions by facilitating viral integration and subsequent progression from dysplasia to in situ carcinoma, local invasion, and eventual metastasis.4
KEYNOTE-028
The addition of immune checkpoint inhibition to cancer therapeutics has shifted the focus to harnessing dormant immune responses to viruses to aid in targeting drug delivery to cancer cells. The expression of HPV-16 E7 viral proteins, for example, has been associated with programmed cell death ligand 1 (PD-L1) expression in cervical cancer cells in preclinical studies.5 This connection provided a rationale for including advanced cervical cancers in the phase Ib KEYNOTE-028 trial, which investigated the safety and efficacy of the checkpoint inhibitor pembrolizumab (Keytruda) in PD-L1–positive advanced solid tumors. Frenel and colleagues reported the results from the cervical cancer cohort of KEYNOTE-028 in the Journal of Clinical Oncology, summarized in this issue of The ASCO Post.6
This study included 24 patients with advanced cervical cancer for whom standard therapy failed and/or was not considered appropriate; 92% had received prior radiation, and 63% had received two or more lines of chemotherapy. All patients had PD-L1–positive expression, defined as membranous staining ≥ 1%, with 18 patients testing positive in the tumor only, and 6 positive in both the tumor and stroma.
Treatment consisted of pembrolizumab every 2 weeks continued for up to 24 months, until evidence of disease progression, unacceptable toxicity, or investigator decision. All but one patient’s tumor demonstrated squamous cell histology, and all patients had metastatic disease.
The findings of Frenel and colleagues support biologic arguments for the use of checkpoint inhibitors in advanced or metastatic cervical cancer. Ongoing studies may better define the patient population who derive benefits from these novel approaches.— Julia Fehniger, MD and Franco Muggia, MD
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Treatment-related toxicities were common, with 75% of patients experiencing any treatment-related adverse event. Four patients reported treatment-related serious adverse events: one each with rash, pyrexia, colitis, and Guillain-Barré syndrome; patients experiencing the latter two grade 3 toxicities discontinued treatment because of these side effects. There were no grade 4 adverse events or treatment-related deaths.
The study’s primary outcome, overall response rate, was 17% based on investigator review. Four patients experienced a partial response; in two of these cases, the response persisted for more than 6 months. There were no cases of complete response, and two-thirds of patients had progressive disease.
Median overall survival was 11 months, and at 6 months, 67% of patients were alive. Since prior studies of chemotherapy for these patients had yielded response rates ranging from 0% to 19%, with most regimens yielding response rates of less than 10%, the overall response rate in the KEYNOTE-028 cervical cancer cohort made a compelling argument to proceed with a formal open-label phase II trial of pembrolizumab in this patient population, going forth as KEYNOTE-158.
Patient Selection
Is there a subset of patients who would derive the most benefit from treatment with checkpoint inhibitors? Of the 45 patients screened for participation, 86% of tumors demonstrated PD-L1 expression, with 24 eventually being selected for treatment. Although preclinical studies have shown an association between HPV proteins and PD-L1 expression, it was initially uncertain whether this high percentage would be noted in a pretreated population with recurrent or metastatic disease. Also, beyond the need for PD-L1 expression associated with the tumor to obtain responses of cervical cancer to pembrolizumab, one may need to consider whether other tumor characteristics, such as squamous histology or the presence of microsatellite instability, are associated with treatment response.
Cervical cancer is not the only virus-associated malignancy where checkpoint inhibitors have been investigated. Checkpoint inhibitors, for example, have been approved for HPV-related squamous cell carcinoma of the oral cavity and for Merkel cell tumors.7,8 The interplay between HPV and these malignancies may only partially explain the success of immunotherapy agents against cervical cancer, however. Squamous cell cancers from various anatomic sites, including skin, esophageal, and lung cancers, have shown responsiveness to checkpoint inhibitors. Finally, do disruptions in the epithelial lining, hyperplasia, and other factors promoting necrosis and keratinization contribute to enhanced immune-mediated destruction following treatment with immune checkpoint inhibitors?
In Conclusion
The findings of Frenel and colleagues support biologic arguments for the use of checkpoint inhibitors in advanced or metastatic cervical cancer. Ongoing studies may better define the patient population who derive benefits from these novel approaches. A more complete understanding of the pathologic, clinical, and immunologic characteristics that contribute to response to these agents will accelerate the integration of this promising therapeutic modality in this ever-challenging malignancy affecting many women worldwide. ■
DISCLOSURE: Drs. Fehniger and Muggia reported no conflicts of interest.
Dr. Fehniger is a Fellow in the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, New York University School of Medicine. Dr. Muggia is Professor of Medicine in the Department of Hematology/Medical Oncology, Perlmutter Cancer Center, New York University School of Medicine.
REFERENCES
1. Rose PG, Bundy BN, Watkins EB, et al: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340:1144-1153, 1999.
2. Tewari KS, Sill MW, Long HJ III, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743, 2014.
3. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12-19, 1999.
4. Waggoner SE, Woodworth CD, Stoler MH, et al: Human cervical cells immortalized in vitro with oncogenic human papillomavirus DNA differentiate dysplastically in vivo. Gynecol Oncol 38:407-412, 1990.
5. Liu C, Lu J, Tian H, et al: Increased expression of PD-L1 by the human papillomavirus 16 E7 oncoprotein inhibits anticancer immunity. Mol Med Rep 15:1063-1070, 2017.
6. Frenel J-S, Le Tourneau C, O’Neil B, et al: Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: Results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. November 2, 2017 (early release online).
7. National Cancer Institute: FDA approves pembrolizumab for head and neck cancer. Available at www.cancer.gov/news-events/cancer-currents-blog/2016/fda-pembrolizumab-hnscc. Accessed December 10, 2017.
8. National Cancer Institute: Avelumab becomes first approved treatment for patients with Merkel cell carcinoma. Available at www.cancer.gov/news-events/cancer-currents-blog/2017/avelumab-fda-merkel-cell. Accessed December 10, 2017.
