Page 184 - EJMO-9-2

Eurasian Journal of
Medicine and Oncology PD-1/L1 inhibitors in advanced CC: Multicenter retro

These findings underscore the urgency of redefining agents primarily function by targeting the VEGF and
cervical cancer treatment paradigms through biomarker- subsequently disrupting the VEGF receptor signaling
driven stratification. Present guidelines, which pathway, thereby inhibiting tumor growth and metastasis.
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predominantly rely on FIGO staging and histology, lack Numerous studies have substantiated the significant anti-
the granularity to address inter-patient variability in tumor efficacy of anti-angiogenic drugs across diverse
immune microenvironment composition. Prospective cancer types, including cervical cancer. 34-37 The aberrant
studies should prioritize dual stratification by PD-L1 vasculature within tumors often impedes immune cell
status and tumor size while incorporating next-generation infiltration. By modulating the tumor microenvironment,
biomarkers such as tumor mutational burden, HPV anti-angiogenic agents facilitate enhanced immune cell
integration sites, and spatial transcriptomics to resolve penetration and activity, thus augmenting the efficacy
intratumoral heterogeneity. For example, the ongoing of immunotherapy. 38,39 Furthermore, Bräutigam et al.
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CALLA trial (NCT03830866) evaluates durvalumab demonstrated that lenvatinib, in combination with a PD-1/
with chemoradiotherapy in locally advanced cervical PD-L1 inhibitor, effectively suppressed the proliferation
cancer, with planned correlative analyses of PD-L1 and of cervical cancer cell lines. Xu et al. reported that the
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HPV DNA dynamics. In addition, real-world evidence combination of anlotinib and sintilimab demonstrated
from cohorts with rare subtypes (e.g., adenosquamous or improved PFS and OS in recurrent advanced cervical
neuroendocrine carcinoma) is critical to refine therapeutic cancer. Consequently, the potential of combining anti-
algorithms for histology-specific vulnerabilities. angiogenic therapy with immunotherapy as a first-line
In addition, this investigation centers on the stage IVB treatment for advanced cervical cancer warrants further
cervical cancer patient population, characterized by the most investigation.
unfavorable prognosis, exhibiting a 5-year survival rate below Furthermore, research has indicated that the
40%, with approximately half of these patients succumbing combination of poly (adenosine diphosphate ribose)
within the initial year post-diagnosis. 31,32 This outcome polymerase (PARP) inhibitors with anti-PD-1 therapies
is primarily driven by the presence of distant metastatic has exhibited notable clinical efficacy in advanced
lesions. Present clinical management faces a dual challenge: solid tumors, especially in patients harboring BRCA1/2
(i) the paucity of high-quality clinical evidence due to the mutations. Chang et al. observed that niraparib
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limited patient numbers at this stage and (ii) the stringent upregulated PD-L1 expression and amplified the
eligibility criteria of existing clinical trial protocols, which antitumor effect of PD-L1 blockade in a murine model
further restrict opportunities for optimizing therapeutic of cervical cancer, thereby illustrating the modulation of
strategies. In this study, we enrolled a limited cohort of stage the local immune microenvironment of cervical cancer
IVB cervical cancer patients and assessed the impact of by niraparib, providing a rationale for the combination
immunotherapy as a first-line treatment. Regrettably, we did of a PARP inhibitor and PD-L1 blockade as a potential
not observe any therapeutic benefit within this subgroup. therapeutic strategy for cervical cancer. It is crucial
We propose two potential explanations for this null result. to acknowledge that despite the promising outcomes
First, the study’s limited sample size may have compromised of combination therapy, the evidence base remains
statistical power and introduced potential confounding limited for a comprehensive evaluation of the efficacy of
factors. Second, the heterogeneous nature of the advanced PARP inhibitors in conjunction with immunotherapy.
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tumor microenvironment (particularly the compromised These integrated treatment modalities represent a novel
multiorgan function induced by metastases) may have therapeutic approach for individuals who have advanced
impeded the response mechanism to ICIs, as evidenced cervical cancer, potentially leading to improved OS rates
by the significant upregulation of peripheral blood T-cell and enhanced quality of life within this patient cohort.
exhaustion markers (e.g., lymphocyte activation gene 3 In summary, our study demonstrated concordance with
and T cell immunoglobulin and mucin domain 3). These the KEYNOTE-A18 trial, reinforcing the clinical validity
observations suggest that immunotherapy approaches of immune checkpoint inhibition in advanced cervical
for extensively metastatic cervical cancer may necessitate cancer management. Notably, these collective findings
a departure from the conventional paradigm, and future have directly informed recent regulatory and clinical
research should prioritize the dynamic monitoring of practice updates. In January 2024, the Food and Drug
large patient cohorts and the elucidation of the molecular Administration approved pembrolizumab combined with
mechanisms governing the metastasis-specific immune concurrent chemoradiotherapy in FIGO 2014 Stage III-
microenvironment. IVA cervical cancer patients, a decision grounded in the
Beyond immunotherapy, anti-angiogenic therapy survival advantages observed in both our cohort and the
represents another therapeutic modality. These KEYNOTE-A18 population. This regulatory milestone
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Volume 9 Issue 2 (2025) 176 doi:10.36922/ejmo.8074