Despite medical progress, relapsed and recurrent metastatic cervical cancer remains a leading cause of morbidity and mortality in women, with a 5-year survival rate of <5%. Although combination chemotherapy is an established treatment in the first-line setting, most patients continue to see disease progress. For second-line and third-line settings, options for cures are rare. While several drugs are awaiting approval for use in both first-line and second-line settings (Merck and Regeneron), with clear incremental benefit to patients, they are unlikely to represent an advance toward curative outcomes.

Cervical cancer presents a myriad of challenges for patients. Without standardized access to preventative vaccinations and timely PAP and HPV screening, the majority of patients receive a diagnosis after their disease has progressed too far to achieve curative outcomes. Data suggests that only 44% of women will be diagnosed with early, localized disease, when the 5-year relative survival rate is 91.9%. Comparatively, 52% of women will be diagnosed with regional or distant disease, with a 5-year relative survival rate of 17.6%.[1]

Historically, fatal cervical cancer in the US has been a disease afflicting mainly those living in low-income households and immigrant communities, as these patients often lack access to quality care. This economic factor is particularly apparent in the survival rates seen in Black cervical cancer patients, only 51.5% of whom are alive ten years post-diagnosis.[2]

Women who must choose between paying a doctor’s copay or buying groceries for the week, or between being docked a day’s pay and risking unemployment or keeping a doctor’s appointment, are unlikely to have regular preventative screenings, leading to late diagnosis and inconsistent, or entirely absent, treatment options. Women who are diagnosed early, but face difficulties commuting between home and hospital following surgery, radiation therapy, or chemotherapy infusions, or who cannot financially afford to take the time-off required to attend treatment sessions, are at high-risk of losing their survival advantage early diagnosis provides.[3]

In addition, the cost of cervical cancer treatment can be debilitating, as the rising popularity of medical fundraising on crowdsourcing platforms like GoFundMe attests. Even if a patient does manage to raise the required funds, courses of treatment are often painful, traumatic, and bring damaging long-term complications. Radiation and chemotherapy leave pelvic scarring and adverse side effects, like neuropathy, anemia, and hearing loss. Bevacizumab gives women an additional 3.7 months of overall survival, alongside increased rates of hypertension, thromboembolic events, and fistula.[4]

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Immunotherapy is not a Cure for All
While immunotherapies have finally become a treatment option for cervical cancer patients, following the approval of 2L pembrolizumab, efficacy is confined to patients with PD-L1+ tumors. And as pembrolizumab can only be discounted or rebated in cervical cancer without implications for other indications, the cost of treatment continues to be prohibitive for most patients. Without a choice of other immunotherapy or combination immunotherapy options, which may be more effective and affordable, these women will continue to go untreated, or suffer the effects of cheaper, toxic chemotherapies, leading to premature deaths. [5]

In one of the largest clinical trials of checkpoint inhibitors to date, in patients with recurrent or metastatic cervical cancer, balstilimab (an anti PD-1 antibody; previously known AGEN2034) induced durable tumor responses in patients who have both PD-L1-positive and PD-L1-negative tumors, and regardless of histology. These data also suggest patients treated with balstilimab suffer far fewer toxicities than patients treated with currently approved therapies. Meaningful responses have also been demonstrated in patients previously unresponsive to platinum chemotherapy. Balstilimab monotherapy has achieved overall response rates of 15% in all patients, with a median duration of 15.4 months. In the PD-L1+ group response rates have been 20%, and in PD-L1- group response rates have been 8%. [6]

In a second large trial in patients with recurrent or metastatic cervical cancer, balstilimab in combination with zalifrelimab (an anti CTLA-4 antibody; previously known as AGEN1884) has achieved overall response rates of 25.6% in all patients, with a median duration of response not yet reached after a 19.4 month median follow-up; overall response rates were 32.8% in patients with PD-L1+ tumors, and 9.1% in PD-L1- tumors. These results suggest a significant benefit over all existing, and soon to be approved, therapies. [7]

Foundation for the Future
I am determined to reshape the treatment landscape and standard of care for patients suffering from gynecological cancers, with products and combinations already in clinical development for use in cervical cancer. In addition, next-generation antibodies have shown significant activity in a wide range of cancers, including ovarian, endometrial, and cervical, and will be entering clinical trials designed for gynecological cancers soon.

Women’s health is an often-neglected medical field. Fewer women receive early diagnoses than their male counterparts, have their pain taken less seriously, and face fewer and more grueling, outdated treatment options. Women living in low-income housing, and women of color, are even more likely to have their symptoms ignored or repressed by healthcare workers, if they are even able to seek medical advice.

Change is urgently needed in women’s health. Not just in cervical cancer, but many other gynecological cancers and other areas of significant unmet need. We need to break down the barriers keeping women from accessing life-saving therapies and the hope of a better tomorrow.

Clinical trials
Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer – NCT03104699
Balstilimab Versus Investigator Choice Chemotherapy in Patients With Recurrent Cervical Cancer (BRAVA) – NCT04943627
RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer – NCT03894215

Highlights of Prescribing Information
Pembrolizumab (Keytruda®; Merck & Co)[Prescribing Information]
Bevacizumab (Avastin®; Genentech/Roche)[Prescribing Information]

[1] Cancer Stat Facts: Cervical Cancer. National Cancer Institute, Surveillance, Epidemiology and End Results Program. Online. Last accessed September 25, 2021
[2] Hallowell BD, Endeshaw M, McKenna MT, Senkomago V, Razzaghi H, Saraiya M. Cervical Cancer Death Rates Among U.S.- and Foreign-Born Women: U.S., 2005-2014. Am J Prev Med. 2019 Jun;56(6):869-874. doi: 10.1016/j.amepre.2019.01.007. Epub 2019 Apr 17. PMID: 31005467; PMCID: PMC6527456.
[3] Candisky, C. “Well-being of Ohio women varies greatly among counties.” The Columbus Dispatch. 2019; October 7.
[4] Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. doi: 10.1056/NEJMoa1309748. Erratum in: N Engl J Med. 2017 Aug 17;377(7):702. PMID: 24552320; PMCID: PMC4010094.
[5] Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3. PMID: 30943124.
[6] O’Malley DM, Oaknin A, Monk BJ, Selle F, Rojas C, Gladieff L, Berton D, Leary A, Moore KN, Estevez-Diz MDP, Hardy-Bessard AC, Alexandre J, Opperman CP, de Azevedo CRAS, Randall LM, Feliu WO, Ancukiewicz M, Ray-Coquard I. Phase II study of the safety and efficacy of the anti-PD-1 antibody balstilimab in patients with recurrent and/or metastatic cervical cancer. Gynecol Oncol. 2021 Aug 24:S0090-8258(21)01316-0. doi: 10.1016/j.ygyno.2021.08.018. Epub ahead of print. PMID: 34452745. [Article]
[7] O’Malley, DM et al. ESMO Congress 2021. Online / Presentation. Last accessed September 25, 2021.

Featured Image: A friendly doctor holding a patient’s hand sitting at her desk for encouragement, empathy and support following a medical examination. Photo courtesy: ©2016 – 2021 Fotolia/Adobe. Used with permission.

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