Do ethnic differences influence the response to immunotherapy in advanced cervical cancer?

Cervical cancer (CC) remains a major global public health issue despite being a preventable disease. According to the GLOBOCAN database, an estimated 662,301 women were diagnosed with CC and approximately 348,800 died from the disease worldwide in 2022 (1). Incidence and mortality rates vary widely across regions and countries, with a higher burden in low- and middle-income countries (LMICs), such as in sub-Saharan Africa, South and Southeast Asia, and Latin America, compared with high-income countries (HIC) (2). These disparities reflect persistent challenges, including inadequate healthcare infrastructure, limited access to screening and vaccination, and inequities in timely and effective treatment (3,4).

Historically, first-line treatment for persistent, recurrent, or metastatic disease was based on the GOG 240 trial, a phase III randomized study evaluating standard chemotherapy regimens (paclitaxel plus cisplatin or paclitaxel plus topotecan) with or without bevacizumab. The trial demonstrated that paclitaxel combined with cisplatin achieved comparable efficacy with lower toxicity than paclitaxel plus topotecan, establishing it as the standard chemotherapy backbone. Furthermore, the addition of bevacizumab significantly improved progression-free survival (PFS) from 6.0 to 8.2 months [hazard ratio (HR) 0.68; 95% confidence interval (CI), 0.56–0.84; P=0.0002] and overall survival (OS) from 13.3 to 16.8 months (HR 0.77; 95% CI, 0.62–0.95; P=0.007) (5).

From the mid-2010s onwards, we witnessed the development of new therapeutic options such as immunotherapy, with immune checkpoint inhibitors demonstrating clinically meaningful benefit across multiple tumor types, and antibody-drug conjugates (ADCs). Specifically for first-line metastatic CC, there are two phase III studies evaluating the incorporation of immunotherapy into standard treatment with platinum doublet therapy combined with bevacizumab: the KEYNOTE-826 trial evaluating the combination with pembrolizumab and the BEATcc trial using atezolizumab, both of which demonstrated an OS benefit; however, in the BEATcc trial, the use of bevacizumab was mandatory (6,7).

The phase III KEYNOTE-826 trial randomized patients to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles, in combination with platinum-based chemotherapy with or without bevacizumab. Eligible patients were ≥18 years of age with persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that had not been previously treated with systemic chemotherapy and was not suitable for curative-intent therapy. Prior radiotherapy and radiosensitizing chemotherapy were allowed, provided treatment was completed at least 2 weeks before randomization and all associated toxicities had resolved. Additional key inclusion criteria included measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and availability of a new or archival tumor tissue sample from a non-irradiated lesion for determination of programmed death-ligand 1 (PD-L1) status (6).

The addition of pembrolizumab reduced the risk of death by 40% in patients with PD-L1-positive tumors [combined positive score (CPS) ≥1], by 37% in the intention-to-treat (ITT) population, and by 42% in women with CPS ≥10. The risk of disease progression was reduced by 42%, 39%, and 48% in these respective groups (8).

In the exploratory analysis on the final results of the KEYNOTE-826 trial evaluating the East Asian population, published by Kim et al., 97 women were included, 89.7% (n=87) had tumors with a PD-L1 CPS ≥1. PFS was improved with pembrolizumab plus chemotherapy in both the ITT population (HR 0.42; 95% CI, 0.23–0.77) and in the PD-L1 CPS ≥1 population (HR 0.36; 95% CI, 0.19–0.68). Median PFS in the ITT population was 18.0 months [95% CI, 10.4–not reached (NR)] in the pembrolizumab plus chemotherapy arm versus 10.4 months (95% CI, 6.4–12.2) in the chemotherapy-alone arm; corresponding values in the PD-L1 CPS ≥1 population were 29.3 months (95% CI, 12.0–NR) versus 10.9 months (95% CI, 6.4–12.2) (9).

OS was also improved with immunotherapy in the ITT population (HR 0.53; 95% CI, 0.28–0.99) and among women with PD-L1 CPS ≥1 tumors (HR 0.43; 95% CI, 0.22–0.86). Median OS was not reached (95% CI, 26.9–NR) versus 20.4 months (95% CI, 15.7–29.2) in the ITT population and not reached (95% CI, 28.6–NR) versus 17.4 months (95% CI, 15.3–37.8) in the PD-L1 CPS ≥1 population (9). The safety profile was manageable. Nonetheless, discontinuation of any study treatment due to adverse events occurred more frequently in the pembrolizumab plus chemotherapy arm than in the chemotherapy-alone arm (51% vs. 33%) (9).

Outcomes in the East Asian population were consistent with those previously reported in the global results of the KEYNOTE-826 trial. Notably, numerical outcomes in this subgroup were slightly superior, suggesting that the benefits of pembrolizumab may be preserved or even enhanced in East Asian patients. However, since this is a subgroup analysis, such data should be interpreted with caution. The numerically improved outcomes do not constitute definitive evidence of superior immunotherapy efficacy in Asian populations and should be considered hypothesis-generating, warranting confirmation in prospective studies.

The baseline characteristics were largely comparable between the East Asian and global populations. Nevertheless, the population evaluated in the subgroup analysis included a higher proportion of patients with an ECOG performance status 0 and increased use of bevacizumab. These factors may have contributed to the better outcomes observed in this cohort, given that bevacizumab has been associated with improvements in PFS and OS in prior studies (5), and ECOG performance status is independently correlated with functional capacity and prognosis, irrespective of treatment modality (10). Besides, race and ethnicity remain important considerations in clinical research (11).

The efficacy of immune checkpoint inhibitors in the Asian population has been observed across multiple tumor types. A meta-analysis of 19 prospective randomized trials including 11,020 patients demonstrated that Asian patients experienced greater improvements in PFS and OS compared with non-Asian patients (12). Similar trends have been reported in gastric cancer (13), esophageal squamous cell carcinoma (14), advanced non–small cell lung cancer (15), and hepatocellular carcinoma (16). However, a higher incidence of treatment-related adverse events has also been observed (17).

The mechanisms by which the Asian population may derive greater benefit from immunotherapy remain unclear. Differences in genomic profiles, as well as environmental and behavioral factors, may contribute to the observed disparities in treatment outcomes (18). In addition, emerging data indicate that variations in the tumor microenvironment and the high prevalence of endemic viral infections in Asia may modulate responses to immunotherapy (17). Although these factors may help explain population-specific variations in effectiveness and toxicity, there is no robust evidence supporting their role as determinants of differential response to immune checkpoint inhibition. Therefore, they should be interpreted as biologically considerations rather than established predictive factors. CC remains associated with human papillomavirus (HPV) infection, and viral subtype has been shown to influence carcinogenesis and the tumor microenvironment (19), which may impact prognosis (20). However, its role in modulating response to PD-1 blockade has not been conclusively demonstrated.

A similar publication regarding the BEATcc study evaluating only the Japanese population also demonstrated better PFS (15.8 vs. 11.1 months) and OS (34.1 vs. 31.6 months) when compared to the overall study population (PFS: 13.7 vs. 10.4 months; OS: 32.1 vs. 22.8 months). Furthermore, the control group in the publication with exclusively Asian patients performed better than the same control group from the overall study population (7,21). These data should be interpreted with caution, as cross-study and subgroup comparisons are inherently limited. Although they may suggest potential differences in patient characteristics, treatment patterns, or other contextual factors, they do not provide definitive evidence that Asian patients have an intrinsically better prognosis.

These findings underscore the clinical benefit of combining pembrolizumab with chemotherapy in patients with persistent, recurrent, or metastatic CC, representing a substantial therapeutic advance with meaningful implications for this population. Novel therapeutic strategies are currently under investigation, and ADCs have emerged as potentially effective treatments in gynecologic malignancies. Clinical trials evaluating the combination of pembrolizumab with sacituzumab tirumotecan as first-line maintenance treatment for CC (NCT07216703), as well as the combination of izalontamab brengitecan, a bispecific ADC simultaneously targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), with pembrolizumab and bevacizumab in patients with recurrent or metastatic CC (NCT07054567), may represent future treatment strategies. However, access to these therapies remains a significant challenge, as approximately 90% of all new cases of CC occur in LMICs (2), making cost a major barrier to patient access. Strategies to ensure equitable access to medications should be discussed by the scientific community in order to reduce worldwide treatment disparities (22).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0214/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0214/coif). G.V.G. reports personal fees for speaker activities from GSK. A.C.d.M. reports institutional research funding from Amgen, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, GSK, MSD, Novartis, Regeneron, Roche, and Daiichi; personal fees for lectures or presentations from AstraZeneca, Bristol Myers Squibb, GSK, MSD, Novartis, Adium, Daiichi, Pfizer, and AbbVie; travel support from MSD, Daiichi, AbbVie, and AstraZeneca; and advisory board participation for AstraZeneca, Bristol Myers Squibb, GSK, MSD, Novartis, Roche, and Daiichi. The other authors have 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.

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References

1. Li Z, Liu P, Yin A, et al. Global landscape of cervical cancer incidence and mortality in 2022 and predictions to 2030: The urgent need to address inequalities in cervical cancer. Int J Cancer 2025;157:288-97. [Crossref] [PubMed]
2. Gopalkrishnan K, Karim R. Addressing Global Disparities in Cervical Cancer Burden: A Narrative Review of Emerging Strategies. Curr HIV/AIDS Rep 2025;22:18. [Crossref] [PubMed]
3. Bradley CJ, Given CW, Roberts C. Health care disparities and cervical cancer. Am J Public Health 2004;94:2098-103. [Crossref] [PubMed]
4. Neibart S, Zhou N, Chino J, et al. Health equity, disparities, and barriers to cervical cancer care in the U.S.: A consensus statement by SGO, ACOG, ASCCP, ASTRO, and ABS addressing the WHO cervical Cancer elimination campaign goals related to treatment. Gynecol Oncol 2025;200:186-92. [Crossref] [PubMed]
5. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017;390:1654-63. [Crossref] [PubMed]
6. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med 2021;385:1856-67. [Crossref] [PubMed]
7. Oaknin A, Gladieff L, Martínez-García J, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 2024;403:31-43. [Crossref] [PubMed]
8. Monk BJ, Colombo N, Tewari KS, et al. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol 2023;41:5505-11. [Crossref] [PubMed]
9. Kim YM, Nishio S, Kim SI, et al. Pembrolizumab plus chemotherapy with or without bevacizumab in East Asian participants with persistent, recurrent, or metastatic cervical cancer: results from KEYNOTE-826 final analysis. J Gynecol Oncol 2025;36:e110. [Crossref] [PubMed]
10. West HJ, Jin JO. JAMA Oncology Patient Page. Performance Status in Patients With Cancer. JAMA Oncol 2015;1:998.
11. Özdemir BC, Dotto GP. Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin? Trends Cancer 2017;3:181-97. [Crossref] [PubMed]
12. Peng L, Qin BD, Xiao K, et al. A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy. Oncoimmunology 2020;9:1781333. [Crossref] [PubMed]
13. Zhang Z, Liu Z, Chen Z. Comparison of Treatment Efficacy and Survival Outcomes Between Asian and Western Patients With Unresectable Gastric or Gastro-Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis. Front Oncol 2022;12:831207. [Crossref] [PubMed]
14. Ren W, Zhang H, Li Y, et al. Efficacy and safety of PD-1/PD-L1 inhibitors as first-line treatment for esophageal squamous cell carcinoma: a systematic review and meta-analysis. Front Immunol 2025;16:1563300. [Crossref] [PubMed]
15. Zhang J, Liu M, Li D, et al. PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for Chinese patients with advanced non-small-cell lung cancer: an updated meta-analysis based on phase 3 randomized controlled trials. World J Surg Oncol 2025;23:273. [Crossref] [PubMed]
16. Tang P, Zhou F. Efficacy and safety of PD-1/PD-L1 inhibitors combined with tyrosine kinase inhibitors as first-line treatment for hepatocellular carcinoma: a meta-analysis and trial sequential analysis of randomized controlled trials. Front Pharmacol 2025;16:1535444. [Crossref] [PubMed]
17. Peng L, Wu YL. Immunotherapy in the Asiatic population: any differences from Caucasian population? J Thorac Dis 2018;10:S1482-93. [Crossref] [PubMed]
18. Yao Y, Li B, Xu Y, et al. East Asian patients who received immunotherapy-based therapy associated with improved survival benefit in advanced non-small cell lung cancer: An updated meta-analysis. Cancer Med 2024;13:e7080. [Crossref] [PubMed]
19. Mo B, Ye Y, Yu M, et al. Prevalence and genotype distribution of HPV combined with cervical pathological results in women from Sichuan, China: A cross-sectional study based on post-vaccination period 2019 to 2023. Cancer Med 2024;13:e70148. [Crossref] [PubMed]
20. Peng L, Hayatullah G, Zhou H, et al. Tumor microenvironment characterization in cervical cancer identifies prognostic relevant gene signatures. PLoS One 2021;16:e0249374. [Crossref] [PubMed]
21. Takekuma M, Nishio S, Yamaguchi S, et al. Atezolizumab, bevacizumab, and platinum chemotherapy in cervical cancer: results of Japanese population from BEATcc. J Gynecol Oncol 2025;36:e116. [Crossref] [PubMed]
22. Neibart S, Zhou N, Chino J, et al. Health equity, disparities, and barriers to cervical cancer care in the U.S.: A consensus statement by SGO, ACOG, ASCCP, ASTRO, and ABS addressing the WHO cervical Cancer elimination campaign goals related to treatment. Gynecol Oncol 2025;200:186-92. [Crossref] [PubMed]