PONE-D-24-34168Efficacy and safety of Pembrolizumab in cervical cancer: protocol for systematic review and meta-analysis of randomized clinical trialsPLOS ONE

Dear Dr. Cobucci,

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

Reviewer #5: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

Reviewer #5: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overview:

This protocol for a systematic review and meta-analysis on the efficacy and safety of pembrolizumab in cervical cancer is timely and addresses a critical area in cancer immunotherapy. The study follows a rigorous methodology with adherence to PRISMA-P guidelines and a clear research focus. However, there are several areas where the protocol needs further elaboration and clarification before it can be considered for publication.

Strengths:

Relevant Research Topic: The use of pembrolizumab in cervical cancer is a highly relevant and important topic given the increasing use of immunotherapy in oncology. This protocol addresses a significant knowledge gap in understanding the efficacy and safety of pembrolizumab, particularly in women with advanced-stage cervical cancer.

Methodological Rigor: The use of PRISMA-P recommendations, PROSPERO registration, and detailed plans for data extraction and synthesis demonstrates a solid methodological framework. The authors have clearly outlined their search strategy, inclusion criteria, and statistical approach, which enhances the reproducibility and reliability of the systematic review.

Detailed Risk of Bias Assessment: The authors have indicated their intention to use the Cochrane Risk of Bias 2.0 tool, which is a strength. The explicit focus on minimizing selection, performance, and reporting bias shows the team’s attention to producing high-quality evidence.

Major Areas for Revision:

Lack of Justification for Pembrolizumab Dosages and Treatment Variability:

The manuscript mentions that subgroup analyses will be conducted based on different doses of pembrolizumab and its combination with other therapies, but there is no clear explanation of how the dosage variability will be categorized or analyzed. Since pembrolizumab’s effects may depend on dosage and treatment combinations, I strongly recommend that the authors provide more detailed justification on how they plan to handle this heterogeneity in the analysis.

Insufficient Clarification on Study Timeframes:

The timeframe for inclusion of randomized clinical trials is not explicitly stated. Although the search strategy mentions that the databases will be searched up until July 2024, it is unclear whether the authors are only including trials that have been completed or also ongoing trials with preliminary results. Clarifying this point would help set expectations regarding the evidence that will be synthesized.

Ambiguity in Handling Grey Literature:

The protocol indicates that grey literature will be included, but there is limited information about how the authors plan to assess the quality of non-peer-reviewed studies. Given that grey literature can introduce higher risk of bias, it is critical that the authors provide a detailed plan for evaluating these sources using robust criteria. Without a clear strategy, the inclusion of grey literature could compromise the reliability of the findings.

Statistical Analysis Plan Lacks Detail:

While the protocol mentions using the ‘meta’ package in R for statistical analysis, it does not elaborate on the specific models or tests that will be used for certain key outcomes. For example, will the authors use fixed-effects or random-effects models for survival analysis, and how will they handle studies with missing data? More detail on how these challenges will be addressed is needed for transparency and reproducibility.

Unclear Plan for Addressing Heterogeneity:

The authors acknowledge that heterogeneity is likely, especially considering the variability in study design, pembrolizumab doses, and combined therapies. However, the protocol lacks a clear plan for handling this heterogeneity. I recommend a more detailed strategy for conducting subgroup and sensitivity analyses to identify and address sources of heterogeneity.

Limited Focus on Patient Populations:

The protocol states that women with cervical cancer at stage IB2 onwards will be included. However, more clarity is needed on how the authors will handle studies that involve mixed populations (e.g., cervical cancer patients alongside other cancer types). Will such studies be excluded, or will the cervical cancer cohort be analyzed separately? This needs to be addressed to avoid confusion and ensure that the meta-analysis is focused on cervical cancer.

Specific Suggestions

Expand on Search Strategy Development:

Although the search strategy for PubMed is briefly outlined, it would be beneficial to provide a more detailed breakdown of how search terms were chosen and how the strategy will be adapted for other databases. Providing an example of search terms for another database (e.g., Embase or Scopus) would help readers understand the thoroughness of the search process.

Provide a Clearer Outline of the Subgroup Analyses:

While subgroup analyses are mentioned, more detail is needed on how these will be conducted. For instance, how will the authors define “combined therapies,” and what specific interactions between pembrolizumab and other drugs (e.g., bevacizumab) will be evaluated? Clarifying this would improve the methodological transparency of the protocol.

Clarify the Role of the GRADE Framework:

The protocol briefly mentions that the GRADE framework will be used to assess the certainty of evidence, but it does not explain how this assessment will influence the interpretation of findings. Will low-certainty evidence be weighted less heavily in the overall conclusions? Providing more detail on how GRADE will be applied would be helpful for understanding the implications of the findings.

Consider Including More Detailed Sensitivity Analyses:

The sensitivity analyses described in the protocol are somewhat limited in scope. I suggest expanding this section to include other factors that may affect study outcomes, such as varying definitions of adverse events or different follow-up periods across trials. A more thorough sensitivity analysis would improve the robustness of the findings.

Conclusion:

This protocol has the potential to contribute valuable insights into the efficacy and safety of pembrolizumab in cervical cancer. However, several critical areas need revision, including clarification of subgroup analyses, handling of grey literature, and expansion of the statistical analysis plan. With these revisions, the protocol will be better positioned to generate high-quality, reliable evidence that can guide clinical decision-making. Therefore, I recommend major revisions to strengthen the methodology and transparency of this work.

Reviewer #2: This study proposed a protocol for systematic review and meta-analysis for Pembrolizumab in cervical cancer. It is a through study protocol with strict inclusion criteria and rigorous data collection plan, and reasonable scrutinization regarding data analysis. However, there are some issues to be addressed before publication:

1. A major concern is the inclusion criteria. The authors intend to include previously untreated cervical cancer patients, however, currently, immunotherapy is usually used in late stage or recurrent cases as a salvage strategy. Only including previously untreated cases might appear somewhat biased and does not reflect actual clinical practice. I would suggest broadening the inclusion criteria to all cervical cancer patients received pembrolizumab treatment.

Other PD-1 inhibitors, such as Nivolumab should be included as well if there are available studies.

2. In search strategy, (lines #129-136) the authors included pembrolizumab and bevacizumab, but left out other standard treatment strategies, such as chemotherapy, radiotherapy, or surgery.

3. Line #152, I don’t think the patients have to be “recently” diagnosed and suggest “recently” be strike out.

4. Line #158, I think bevacizumab should be included as well.

5. For the subgroup analysis, I suggest look at subgroups divided by expression levels of immune checkpoint molecules, such as PD-1, PD-L1, to see if certain molecular signatures are associated with ICI treatment effects. This will shed lights on what patient populations will benefit most from ICIs.

5. Line #184, “DMB” should be “DMD”.

6. Line #45, “will be included” should be deleted for a correct sentence structure.

Reviewer #3: Dear Dr.Ricardo Ney Oliveira Cobucci,

I hope this message finds you well. I have had the opportunity to review your manuscript entitled "Efficacy and safety of Pembrolizumab in cervical cancer: protocol for systematic review and meta-analysis of randomized clinical trials," and I appreciate the efforts you have invested in this significant area of research. While the topic is undeniably important and timely, there are several aspects of the study design and scope that, if addressed, could enhance the manuscript’s contribution to the field significantly.

1. Comprehensive Literature Search: Your protocol outlines a focused search strategy that, while robust, may benefit from an expanded scope to include grey literature and databases such as The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch); Clinical Trials Registry Platform (http://www.who.int/ictrp/en/); European Medicines Agency (EMA)(https://www.ema.europa.eu/ema/); US Food and Drug Administration (FDA) (www.fda.gov). To ensure even more comprehensive coverage, please consider meticulously scanning the abstracts presented at major international congresses during the three years preceding our search. This strategy aims to capture any studies that have been presented at these events but have yet to be fully published. This broader approach will help capture emerging studies and ensure a more comprehensive analysis, enhancing the relevance and applicability of your findings.

2. Search Terms and Inclusion Criteria: The manuscript currently limits its search terms primarily to specific names associated with Bevacizumab. Considering the diversity of treatment modalities in cervical cancer, including chemotherapy, radiotherapy, and surgery, broadening the search terms to encompass these areas could provide a more holistic view of the landscape and potential interactions or comparative efficacies.

3. Discussion of Combined Therapies: Your manuscript would benefit from a more detailed discussion on the role and implications of combining Pembrolizumab with Bevacizumab. Highlighting this in both the introduction and discussion sections would clarify the therapeutic context and relevance of your findings to current treatment protocols.

4. Analysis of Adverse Events: Considering serious adverse events as a secondary endpoint is a prudent choice.

However, a comprehensive analysis of all adverse events, if feasible, would provide a deeper understanding of safety profiles, which is crucial for clinical decision-making.

5. Handling of Missing Data: It is essential to outline a clear and rigorous method for handling missing data in your analysis. This includes efforts to retrieve missing information and statistically estimating unavailable data, which would strengthen the validity and reliability of your study results.

6. Clarity of Research Questions: Finally, I recommend structuring a separate section that distinctly lists the research questions your study seeks to answer, including benefits, risks, and subgroup analyses. This would greatly enhance the clarity and focus of your manuscript, making it more accessible to readers and reviewers.

While the manuscript presents a valuable protocol, addressing these points could significantly strengthen your study's impact and scientific contribution. I believe these enhancements will better position your manuscript for publication, offering a substantial advancement in our understanding of Pembrolizumab's role in treating cervical cancer.

Reviewer #4: The author expressed the need for further research on pembrolizumab as a treatment option for cervical cancer.

However, the outcome selection seems to be not ideal.

Previous meta-analysis used the outcome of complete response (CR), partial response (PR), stable disease (SD), disease progression (PD), overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS)

The latest RCT reported OS and PFS.

Authors need to re-consider the outcome that would be included.

Reviewer #5: The proposed systematic review and meta-analysis protocol is well-structured, comprehensive, and adheres to established guidelines. The topic is highly relevant given the increasing role of immunotherapy in treating cervical cancer, and the need for high-level evidence to support its use. However, there are several areas where the protocol could be strengthened or clarified to ensure the robustness and reliability of the final review.

1. The research question is clearly stated and addresses a significant gap in the current literature. However, the objectives could benefit from a more explicit statement on how the results of this review will impact clinical guidelines and practice. Consider expanding on the potential implications of the findings.

2. Under “Search Strategy”, while the search terms for PubMed are provided, it would be helpful to include a more detailed explanation of how these terms will be adapted for other databases.

3. Under introduction, “The results of these studies have been published and are ongoing – interesting.” - The predefined extraction scheme is thorough, but it may be beneficial to specify how you will handle missing data or studies are still ongoing with incomplete reporting.

4. For statistical analysis, the plan to use the random-effects model in cases of high heterogeneity is appropriate. However, you might want to also clarify how you will interpret and present results if significant heterogeneity is detected.

5. Also under statistical analysis, it may be useful to specify the criteria for defining the subgroups, particularly in relation to different doses of pembrolizumab and patient characteristics.

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Xiaoyi Zhang, MD

Reviewer #2: No

Reviewer #3: Yes: Bingyu Li

Reviewer #4: No

Reviewer #5: Yes: Yuhang Liu

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Efficacy and safety of Pembrolizumab in cervical cancer: protocol for systematic review and meta-analysis of randomized clinical trials

PONE-D-24-34168R1

Dear Dr. Ricardo Ney Oliveira Cobucci,

Ricardo Ney Oliveira CobucciWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Cho-Hao Howard Lee, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Dear Authors,

Thank you for submitting the revised version of your manuscript titled "Efficacy and Safety of Pembrolizumab in Cervical Cancer: Protocol for Systematic Review and Meta-Analysis of Randomized Clinical Trials." After thoroughly reviewing your revisions, I am pleased to say that you have addressed all of the previous concerns and suggestions with a high degree of care and attention to detail. The manuscript now meets the necessary standards for publication.

Strengths:

Comprehensive Search Strategy: The detailed and robust search strategy, which now includes additional databases and a clear outline of grey literature handling, ensures that the systematic review will capture the most relevant studies on pembrolizumab in cervical cancer. Your methodical approach is well-structured and leaves little room for gaps in the literature.

Clear Subgroup and Sensitivity Analyses: The revisions provide a much clearer explanation of how subgroup and sensitivity analyses will address potential heterogeneity in treatment combinations and dosages. The inclusion of molecular signatures, such as PD-1 and PD-L1 expression, in subgroup analyses is particularly valuable and enhances the methodological rigor of the study.

Well-Defined Outcome Measures: I appreciate the additional clarity and justification regarding the primary and secondary outcomes. The inclusion of a broader range of safety outcomes in your adverse event analysis ensures a more comprehensive evaluation of pembrolizumab's safety profile, which is critical for informing clinical decision-making.

Thorough Risk of Bias and GRADE Assessments: Your attention to the risk of bias in grey literature, as well as the detailed explanation of how the GRADE framework will be applied, strengthens the transparency and reliability of the forthcoming systematic review. This will provide clinicians and researchers with high-quality evidence to guide treatment decisions.

Strong Statistical Plan: The updated statistical analysis plan, which now includes clearer details on how missing data will be handled and how fixed-effects or random-effects models will be applied, provides a solid foundation for the meta-analysis. This will ensure that the synthesis of evidence is both rigorous and reliable.

Conclusion:

In my view, the manuscript is now well-prepared for publication. The revisions have significantly improved the clarity, depth, and methodological rigor of the protocol. The systematic review and meta-analysis proposed in this study have the potential to offer meaningful insights into the efficacy and safety of pembrolizumab in the treatment of cervical cancer, which is a highly relevant topic in oncology today. I believe this work will be a valuable addition to the literature, and I recommend it for acceptance without further revision.

Reviewer #2: The authors have revised according to my suggestions and provided resonable justification for the parts that remain unchanged. In all, this protocol is ready for publication.

Reviewer #3: I agree with the author's revisions. However, I have one small comment: the newly added text in the Revised Manuscript (without Track Changes) has a gray background. This should be removed prior to publication.

Reviewer #4: No further recommendations. Hopefully this protocol and the following study will be able to address the efficacy of Pembrolizumab in cervical cancer.

Reviewer #5: I appreciate the revision from the authors and the manuscript now looks good to me. I wish the best of luck to their research endeavors.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Xiaoyi Zhang, MD

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Reviewer #5: Yes: Yuhang Liu

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