Despite advances in cancer treatment, cervical cancer, particularly locally advanced disease, remains a challenging entity with a poor prognosis. For patients with persistent, recurrent, or metastatic cervical cancer, pembrolizumab has demonstrated efficacy¹ and is a category 1 recommendation on NCCN guidelines (along with platinum-based chemotherapy).

Earlier this year, KEYNOTE-A18 demonstrated a significant overall survival benefit at long-term follow-up with concurrent and adjuvant pembrolizumab for newly diagnosed, locally advanced cervical cancer patients.² There remains a lack of phase III prospective data demonstrating a benefit for early stage disease and, as such, NCCN guidelines explicitly state that “pembrolizumab may be added with chemoradiation (CRT) ONLY for patients with FIGO 2014 stage III-IVA cervical cancer.” So we know it may help patients with advanced disease, but the question becomes how much and at what cost?

Moreover, do we really know how immunotherapy works? The question isn’t that ridiculous considering that each individual immune system is unique; to arbitrarily throw antibodies in a system abrogates those intricacies and bypasses mechanisms that any one body may harbor. We’ve all seen the side effects of immunotherapy, some of which are surprising and debilitating to patients. At the molecular level, we don’t actually know how each patient is responding to an immunomodulatory agent. Maybe it is revving up their immune system to fight the cancer. Or maybe it is confusing their immune system to attack normal tissue randomly. And for young women in particular, is it unmasking (Dare I say causing?) an autoimmune disorder? Throw in the proposed immunomodulation — both upregulation and suppression — facilitated by different doses of radiation,^3-6 and we really start to muddy the waters of what exactly we are doing to a body.

We know pembrolizumab may help patients with advanced cervical cancer, but the question becomes how much and at what cost?

It is also fascinating to consider the biology of the malignancy itself. Theoretically, cervical cancer should confer similar biologic mechanisms as virally driven head and neck cancer, and yet, we have not seen immunotherapy come to fruition for definitive treatment of HPV-mediated oropharyngeal cancer (although, there have been promising data in the metastatic setting). It certainly puts us in our place as we confront the fact that there is still  much we don’t know; it’s like we are staring at the ocean floor and only comprehend a fraction of it. Plus, we are aiming at a moving target.

At the end of the day, we do have to maintain a healthy dose of skepticism about whether immunotherapy is indicated. Additional prudence is needed given the significant financial costs. Certainly, we have seen impressive benefits with immunotherapy in some disease sites – durvalumab has changed the game in the world of lung cancer and the benefit of pembrolizumab in locally advanced cervical cancer is promising. But it behooves us to recognize that such an advantage may not be conferred upon all sites. Cancer is, if nothing else, a wily, mutative beast.

References

1. Chung HC, Ros W, Delord JP, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(17). doi:10.1200/JCO.18.01265
2. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024;403(10434):1341-1350. doi:10.1016/S0140-6736(24)00317-9
3. Rodríguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 2018;39(8). doi:10.1016/j.it.2018.06.001
4. Kho VM, Mekers VE, Span PN, Bussink J, Adema GJ. Radiotherapy and cGAS/STING signaling: Impact on MDSCs in the tumor microenvironment. Cell Immunol. 2021;362. doi:10.1016/j.cellimm.2021.104298
5. Nabrinsky E, Macklis J, Bitran J. A review of the abscopal effect in the era of immunotherapy. Cureus. Published online 2022. doi:10.7759/cureus.29620
6. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: A beneficial liaison? Nat Rev Clin Oncol. 2017;14(6). doi:10.1038/nrclinonc.2016.211