Evaluation of results from KEYNOTE-826 and its impact within the East Asian population with real-world applications

On the surface, one would think that cervical cancer is an enigmatic disease process that current scientific knowledge is unable to adequately address. Clearly, nothing is further from the truth in that despite significant knowledge regarding its proximate cause, namely persistent high-risk human papilloma virus (HPV) infection, as well as effective screening options and a highly effective primary prophylactic approach with high-risk HPV vaccination, cervical cancer persists and impacts countries across the globe (1,2). While the impact in more industrialized countries like the United States (US) is less pronounced, with a 2025 predictive incidence of around 13,000 cases with approximately 4,300 deaths (3), worldwide impact is more dramatic with cervical cancer cases greater than 650,000 with nearly 350,000 deaths, both ranking fourth in terms of female cancer incidence and mortality (4). Again, considering the US, despite steady increases in HPV vaccination with rates topping 60% in 2021, vaccination rates have remained static (1). More sobering perhaps, is that despite this knowledge and available preventative strategies, recent population-based US survey data suggest cervical cancer screening remains 14% below 2019 estimates (5).

Despite the challenge mentioned above, the last decade has been a transformative time in the management of multiple gynecologic cancers as a litany of agents and novel treatment approaches have been approved for use across the treatment landscape. Enthusiastically, and as was recently described by Dinkins et al., gynecologic cancers were responsible for near 10% of Food and Drug Administration (FDA) solid tumor drug approvals from 2019 to 2024 (6). Paradigm changing clinical trials in cervical cancer patients resulted in multiple FDA drug approvals. Specifically, the FDA approved the use of pembrolizumab in combination with chemoradiation for locally advanced stage cervical cancer, tisotumab vedotin for recurrent cervical cancer following progression after chemotherapy and the focus of the current study, the addition of pembrolizumab to chemotherapy with or without bevacizumab for recurrent or primary metastatic programmed death-ligand 1 (PD-L1) positive cervical cancers (7). However, the applicability of these landmark trial results across diverse populations remains an important consideration, as regional and ethnic differences in HPV subtype distribution, medical system drug approvals, and treatment delivery may influence outcomes. Asian populations, which bear a disproportionate share of the global cervical cancer burden, have been underrepresented in pivotal immunotherapy trials or reported primarily through subgroup analyses. The present study therefore focuses on outcomes in an East Asian cohort.

The integration of immune checkpoint inhibition with chemotherapy into the management of persistent, metastatic, or recurrent cervical cancer has now become a mainstay for first-line treatment based on the initial results of KEYNOTE-826 (8). In the final analysis, patients with a PD-L1 combined positive score (CPS) ≥1, both had significant improvement in progression-free survival (PFS) as well as overall survival (OS) (9). While the manuscript stratified race between white and non-white, further subgroup classification can be important given national and international differences in epidemiology and tumor biology (10-12). Compared to global rates, Asian countries have disproportionately higher rates of incidence and death from cervical cancer, which has been attributed to HPV vaccination uptake and treatment variations (13). Focus within this part of the world is important given that half of the world’s population lives in Asia and Asian Americans represent the fastest growing population within the US (14). Only half of the Asian countries have implemented national vaccine campaigns which has resulted in only 3–6% of adolescent girls receiving the first dose of HPV vaccine (15). Regarding treatment variations, survey data indicated variable utilization of bevacizumab and cisplatin in the first-line treatment regimen for metastatic cervical cancer, with the most common regimen being carboplatin and paclitaxel (16).

In this exploratory analysis from KEYNOTE-826, East Asian patients were primarily from Japan (59%), followed by South Korea (25%) and Taiwan region (16%), accounting for approximately 16% of the entire study population (17). Compared to the global KEYNOTE-826 population, most of the baseline characteristics were similar between the intention-to-treat (ITT) arms; however, the East Asian subset was generally healthy at baseline based on ECOG =0 with 72% as compared to 56% in the entire global population. Moreover, and consistent with prior evaluations of treatment modality preferences, more patients received bevacizumab (75% vs. 64%) in the East Asian ITT cohort compared to the global population (16). Notwithstanding, East Asian patients had comparable responses both with PFS and OS compared to the overall ITT population. Within the CPS ≥1 subgroup, there was a greater magnitude of benefit with the addition of pembrolizumab within the East Asian cohort, shown by the hazard ratios (HR) for the median PFS being 0.36 compared to 0.62 in the overall population. For the median OS, the HR were 0.43 and 0.60, respectively. This reinforces the importance of the treatment although, this may be impacted by the combination of population differences and a small sample size (Table 1).

Furthermore, the objective response rate (ORR) also demonstrated a more profound effect with the addition of pembrolizumab both for the ITT and CPS ≥1 East Asian cohort. Reassuringly, no additional safety signals were observed, which is consistent with larger studies evaluating the utilization of pembrolizumab within Asian populations (18). While tumor biology can differ between races, these findings are clinically meaningful and reinforce the utilization of pembrolizumab-based therapy with or without bevacizumab. Beyond this exploratory analysis, different subgroup analyses focusing specifically on Japanese cohorts also demonstrated similar clinical benefit, when compared to their respective overall clinical trial population (19,20). Together, these data provide increasing reassurance of clinical benefit with the addition of immunotherapy in the management of cervical cancer within Asian geographic regions.

As with many exploratory analyses, limitations of this analysis include the smaller sample size which inevitably reduces result precision. In a subgroup analysis of GOG-3016 evaluating the Japanese cohort which composed 9.2% of the study population, the addition of Cemiplimab monotherapy failed to show an OS benefit, which conflicts from the findings from the entire study (21). Immunotherapy and bevacizumab are infusion-dependent interventions which may restrict real-world implementation in less developed regions where limited medical infrastructure has been identified as a barrier to access (22). Specifically with bevacizumab, East Asian physicians cited the lack of regional reimbursement concerns, which may limit patient administration due to a patients’ inability to afford treatment (23). While some countries in East Asia have national health insurance models, out-of-pocket expenses have increased over the years for patients, most recently estimated to comprise 36% of total medical expenses (24). A compounding financial barrier to treatment is that in many countries there are only centralized areas to provide specialized treatment, which leads to a further fragmentation of therapy options for those living in rural areas. Rural populations are often required to travel though mountainous regions or cross large bodies of water further exacerbating transportation barriers. In patients that can afford the treatment, up to 8% will require migration to urban areas for their cancer care (25). These drastic measures in receiving standard care can lead to the inability for patients to start and even continue or complete therapy. Alternative administration approaches, such as subcutaneous pembrolizumab, which may reduce both treatment time for a patient as well as time incurred by a medical professional are intriguing, although cost may remain an insurmountable barrier (26).

Furthermore, while pembrolizumab approval is limited by PD-L1 expression in Europe and the United States, this limitation is not present in Japan and can potentially be explained by the lower rate of PD-L1 testing that is performed in the region (27). While an overwhelming majority of cervical cancer patients have CPS ≥1 when PD-L1 testing is performed, caution will need to be exercised to allocate immunotherapy in populations that have demonstrated benefit. Likewise, patients would need access to facilities to care for immunotherapy-specific adverse events (AEs). Within this exploratory analysis, there were numerically more patients that experienced any immune-mediated Grade 3 AEs in the pembrolizumab arm (17.5% vs. 5.0%) which is also reflected in the overall study (33.9% vs. 15.2%), with notable increases in severe skin reactions (7.0% vs. 0.0%), hepatitis (5.3% vs. 0.0%), and thyroiditis (1.8% vs. 0.0%). The AEs require adequate staff and patient education and remain a management challenge and can be exacerbated in areas with limited access to specialized support. Development of telemedicine outreach and multidisciplinary teams for identification and management of AEs may be an option, as this has been successful in other parts of the world through prevention, monitoring, early detection, and treatment of immune related AEs (28).

Taken together, this analysis supports the global relevance and importance of the addition of pembrolizumab to chemotherapy ideally with bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. These data in conjunction with similar subgroup analyses should provide necessary confidence for clinicians in East Asia to support the overall therapeutic benefits shown in KEYNOTE-826. With the confirmation of efficacy, the future challenge now remains on the equitable access of these treatments.

Despite the recent improvements in outcomes for patients with cervical cancer, continued and ongoing research is needed across the spectrum of this largely preventable disease. At present, the National Cancer Institute (NCI) lists 25 current treatment trials for individuals impacted by cervical cancer (https://www.cancer.gov/research/participate/clinical-trials/disease/cervical-cancer/treatment?pn=1). Importantly, patient engagement in clinical trials has been shown to improve overall survival, especially during the first line of therapy, although less than 5% of cervical cancer patients enrolled on a clinical trial (29).Despite these benefits, racial and minority disparities in terms of clinical trial enrollment have widened for all gynecologic disease sites (30). We should continue to encourage clinical trial participation focusing on the inclusion of a diverse group of patients. Novel trial designs which may address barriers to access to include among others, possible financial support for patients in rural areas in terms of transportation to a central area or the creation of a closer mobile platform are needed. Perhaps more widespread use of research navigators, as we have employed at our Comprehensive Cancer Center and as described from our gynecologic cancer experience by Boitano et al. (31). Research navigators within Asia have shown benefit for continuity of care and reduction in treatment discontinuation, especially in areas with limited internet connectivity and access to mobile healthcare (32). However, despite research focused navigations, our own experience demonstrated improved enrollment for patients with endometrial and ovarian cancers, while those with cervical cancer did not have a higher likelihood of cervical cancer clinical trial enrollment, 27.7% of patients eligible for cervical cancer trials enrolled as compared to 72.2% did not enroll (31).

Cervical cancer remains a challenge largely due to a patient population that is impacted not only by the potential intensity of the treatment regimen for locally advanced, persistent or recurrent disease, but also variables such as limited access to care as well as financial toxicity. Risk factors for financial toxicity in women with gynecologic cancers include a diagnosis of cervical cancer, younger age, Black race or Hispanic ethnicity, among other variables (33). Within KEYNOTE-826, the study regimen included infusion-dependent treatment every three weeks for up to 35 cycles after undergoing standard-of-care chemotherapy every three weeks for six cycles. Moreover, transportation to chemotherapy centers can be challenging, especially when cervical cancer is more prevalent with lower income countries and more commonly affecting families impacted by poverty (34). In the international setting, funding and human resource capacity were the two most impactful barriers for cancer trial initiation in low- and middle-income countries (35). This is especially pertinent, and timely, given the recent US federal funding cuts, which have negatively impacted multiple fields of research including cancer (36). These cuts are estimated around a 40% reduction in the National Institutes of Health’s (NIH) funding along with consolidation of institutes within the agency. Moreover, these cuts not only risk stagnation in scientific advancement, but also stifle necessary international collaborative opportunities. More than 99% of all new drugs received at least partial funding through the NIH and it is estimated that the proposed future budget cuts could result in a 15% reduction in new therapies for patients (37). Beyond focusing on preventative strategies on vaccine and screening uptake, for those affected by persistent, recurrent, or metastatic cervical cancer, future solutions will require ingenuity that balance the continued pursuit of specialized pharmaceutical care with the obligation of ensuring equality of care.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gynecology and Pelvic Medicine. The article has undergone external peer review.

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-75/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-2025-1-75/coif). C.A.L. received grant funding from the NIH, performed contract research for Agenus, received honorarium for invited cervical cancer related lectures with travel support from Merck and served on a scientific advisory board regarding cervical cancer supported by Seattle Genetics/Pfizer. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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