Critical review of the Keynote-18 trial: Limitations and implications
Year: 2025
Type: article
Abstract: Dear Sir/Madam, The standard therapy for locally advanced cervical cancer is concurrent chemo-radiotherapy with external beam radiotherapy with at least 5 cycles of platinum-based chemotherapeutic drugs followed by brachytherapy. The five-year overall survival in locally advanced cervical cancer ranges from 47 to 80% and declines with the advancing stage. With the advent of Programmed Death-Ligand 1 (PD-L1) inhibitors, investigators set out to increase the response by adding PD-L1 inhibitors to chemo-radiotherapy in cervical cancers. The ENGOT-CX11/GOG-304/KEYNOTE-A18 was first published in March 2024, establishing progression-free survival (PFS) benefit, and the overall survival analysis was published in September 2024.[1] AGE AND PD-L1 STATUS Older patients (65 years and above) and those with PD-L1-negative tumors showed less favorable outcomes, though the small sample sizes in these subgroups make it difficult to draw definitive conclusions. Further studies focusing on these subgroups are needed. One key consideration is identifying which patient populations are most likely to benefit from this combined immunotherapy and chemoradiotherapy approach. The trial enrolled a broad cohort, including both squamous cell carcinoma and adenocarcinoma histology across FIGO 2014 stages IB2 to IVA. The biomarker analysis—although all-comers were included regardless of PD-L1 status—suggests that those with PD-L1 positive tumors (combined positive score ≥1) may represent a group with greater immunogenic potential and possibly derive a larger therapeutic advantage. USE OF FIGO 2014 STAGING CRITERIA The trial utilized the outdated FIGO 2014 staging criteria, which may limit its generalizability. The more recent FIGO 2018 staging system might better classify disease extent and influence treatment strategies.[2] NO FORMAL PFS TESTING AT SECOND INTERIM ANALYSIS PFS was not formally tested in the second interim analysis, limiting the ability to assess long-term disease stability across subgroups. Continuous monitoring of PFS could provide further insights. ADVERSE EVENTS AND IMMUNE-RELATED TOXICITY The Pembrolizumab group had higher rates of immune-mediated adverse events, particularly thyroid-related issues. For some patients, the risk of these adverse effects may outweigh the survival benefits, adding to the overall treatment burden. COMPARISON WITH OTHER IMMUNOTHERAPIES There is a discrepancy in survival benefits when compared to similar trials, such as them Study of Durvalumab with Chemoradiotherapy for Women with Locally Advanced Cervical Cancer (CALLA) trial with durvalumab, raising concerns about the generalizability of findings to all PD-1/PD-L1 inhibitors. Further drug-specific research is recommended. The findings of KEYNOTE-A18 must also be interpreted in the context of the CALLA trial, which evaluated durvalumab (an anti–PD-L1 agent) in a similar population and failed to show a significant improvement in PFS. The discordance between these two trials raises important questions about drug class effects, trial design, and patient biology. KEYNOTE-A18 employed pembrolizumab (PD-1 blockade) and continued immunotherapy for a longer duration (up to 2 years), whereas CALLA used durvalumab (PD-L1 blockade) with a shorter duration (1 year). The mechanism of action of PD-1 versus PD-L1 inhibitors, subtle though it may seem, could account for differences in T-cell reinvigoration and systemic immune activation. Furthermore, the differing follow-up durations and timing of interim analyses may also influence early versus late separation of survival curves, potentially underestimating long-term benefit in one trial relative to another. SINGLE TREATMENT ARM FOR IMMUNOTHERAPY Only one treatment regimen (Pembrolizumab plus chemoradiotherapy) was tested, limiting comparative insights into other possible regimens or sequential treatments that might yield better results. FUNDING AND POTENTIAL CONFLICTS OF INTEREST The study was funded by Merck Sharp and Dohme, the manufacturer of Pembrolizumab, which could introduce potential conflicts of interest. This highlights the need for independent confirmation of the results. Limited Follow-Up for Long-Term Outcomes The median follow-up period was 29.9 months, which may not be long enough for high-risk cervical cancer patients. Longer-term follow-up could provide more comprehensive data on sustained benefits and late-onset adverse effects. Overall treatment time As per guidelines, the overall treatment time for cervical cancer must be completed within 49–56 days. There is a decrease in survival by 1% for every single day of treatment prolongation. However, in this trial, the completion of treatment has taken up to 2 years to complete, including the adjuvant treatment. We are still unaware of the long-term follow-up results of the patients included in the trial.[3] Cost burden The cost of the entire treatment including adjacent pembrolizumab injections might sum up to 50 lakhs. Such a huge sum might cause a financial burden and make treatment for common cancers like cervix malignancy in developing countries inaccessible. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Institution: All India Institute of Medical Sciences
Language: English
Subfield: Obstetrics and Gynecology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7117730675