-->PONE-D-25-65811-->

Economic Evaluation of Finotonlimab plus bevacizumab as First-line Therapy for advanced Hepatocellular Carcinoma

PLOS One

Dear Dr. Feng,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Jincheng Wang

Academic Editor

PLOS One

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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following financial disclosure:

“Ethics approval

As this study is entirely based on previous research [8] and publicly available data, it does not include any new research involving human participants or animals by any of the authors, and therefore does not require approval from an independent ethics committee.”

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Additional Editor Comments:

This study presents a cost-effectiveness analysis of finotonlimab plus bevacizumab biosimilar versus sorafenib for advanced HCC using a partitioned survival model, with a well-below-threshold ICER of ¥50,492.98/QALY. However, several issues require revision. The exclusive use of lognormal distribution for all survival curves needs biological justification, particularly given its non-monotonic hazard implication for HCC. Extrapolation to 10 years is questionable given the poor prognosis of advanced HCC, and the authors should report the proportion of patients surviving beyond 5 years under each distribution. The utility values derived from a 2016 non-Chinese study are insufficiently justified given their demonstrated sensitivity impact, and alternative sources should be explored. Most critically, sorafenib is no longer the standard comparator in China — the absence of comparison against atezolizumab plus bevacizumab or sintilimab plus bevacizumab substantially limits clinical relevance. Minor issues include inconsistent AE inclusion criteria between the Methods and Discussion sections.

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Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

Reviewer #2: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: No

Reviewer #2: Yes

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-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

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-->4. 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

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Thank you for your assigning me to review the submitted manuscript. This is not a methodologically rigorous economic evaluation, with significant limitations in data fitting, subsequent treatment costs, and disutility values. Therefore, the author should reconstruct the model and update the results.

Major comments:

1. Finotonlimab combined with a bevacizumab biosimilar yields superior efficacy at a higher cost, so why does the Log-logistic distribution yield a dominant result? This is an absolutely erroneous outcome. We seriously doubt the accuracy of the overall study.

2. “Furthermore, owing to the high heterogeneity of hepatocellular carcinoma, not all patients benefit equally from current standard therapies.” Which groups of people? Please support your statement with relevant literature and data.

3. Please provide CHEERS 2020 in the supplementary materials.

4. Removing the inclusion and exclusion criteria of clinical trials, as these are unrelated to the study methodology. A brief description of patient characteristics is sufficient.

5. To our knowledge, the subsequent treatment regimen recommended in the CSCO 2024 guidelines does not best supportive care. Please calculate the subsequent treatment costs based on the different drugs (Immunotherapy, Targeted therapy, Chemotherapy) and proportions used in clinical trials (Supplementary Table 4).

6. Why choose the partitioned survival model rather than the Markov model? What are the differences between them?

7. According to the Economic Evaluation Guidelines 2025, the discount rate is 4.5%, with a range of 0-5%.

8. Please update the GDP per capita to 2025 (￥99800).

9. Typically, seven-parameter survival models are employed for data fitting. Please add Gamma and Generalised Gamma, and present the AIC and BIC values for different parameter survival models in the supplementary materials.

10. What does “Laboratory and imaging tests” include? Please specify the specific tests and costs (Blood tests, CT scans, bone scans, etc.).

11. How are the costs of adverse events incorporated into the model?

12. Why are the utility values derived from Reference 22 rather than published real-world studies? Why were disutility values associated with adverse events not considered? A rigorous economic evaluation should incorporate disutility values.

13. What is the difference between 1000 and 10,000 times second-order Monte Carlo simulations? Why choose 1000 times?

14. Please reconstruct the model, as the current results are absolutely incorrect.

15. The current discussion does not meet the standards outlined in the economic evaluation guidelines(CHEERS 2020). The author should explain why the novel treatment regimen is or is not cost-effective. The author should briefly review existing economic evaluations related to advanced hepatocellular carcinoma, identifying the optimal/preffered treatment regimen in available economic evaluations and comparing it with the findings of this study.

Reviewer #2: This manuscript presents a well-conducted pharmacoeconomic analysis suggesting finotonlimab plus bevacizumab biosimilar is cost-effective versus sorafenib for advanced HCC in China. While the methodological framework is generally appropriate, several critical issues must be addressed to ensure robustness and transparency. Below are the major and minor concerns:

1、Drug Cost Assumptions Need Validation：The model assumes full drug costs without accounting for possible charity drug programs during the trial (2022–2025), as both Finotonlimab and bevacizumab biosimilar were unapproved in China at the time. Maybe sensitivity analysis are needed, try to explore reduced pricing scenarios if possible (e.g., discount rates negotiated post-approval).

2、Incomplete Adverse Event (AE) Cost Capture：Serious AEs (≥Grade 3) reported in the Phase III trial (e.g., 27 cases of immune-related AEs and even fatal events) are not incorporated into Table 3 or model inputs. AE-associated costs (e.g., hospitalization, treatment discontinuation) may significantly impact cost-effectiveness.

3、Patient Flow and Discontinuations：The Materials & Methods section lacks clarity on:

Sample size: Exact patient numbers randomized to each arm Treatment discontinuations: Rates due to AEs/progression, which affect drug utilization and cost.

4、Some figures (particularly Figure 2) currently suffer from poor readability due to:small font sizes for axis labels and legends

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Reviewer #1: No

Reviewer #2: No

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-->PONE-D-25-65811R1-->-->Economic Evaluation of Finotonlimab plus bevacizumab as First-line Therapy for advanced Hepatocellular Carcinoma-->-->PLOS One

Dear Dr. Feng,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

ACADEMIC EDITOR: After revisions, this paper has been improved. However, there is still a problem commented by a reviewer: It is recommended that three times the per capita GDP be employed as the willingness-to-pay threshold, i.e. 99,800 × 3 = 299,400. Please address.

Please submit your revised manuscript by Jun 05 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only the individual author can complete the verification step; PLOS staff cannot verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Jincheng Wang

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

After revisions, this paper has been improved. However, there is still a problem commented by a reviewer: It is recommended that three times the per capita GDP be employed as the willingness-to-pay threshold, i.e. 99,800 × 3 = 299,400. Please address.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

Reviewer #2: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: No

Reviewer #2: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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

**********

-->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

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: This study still contains obvious errors; please treat academic research with due seriousness. It is recommended that three times the per capita GDP be employed as the willingness-to-pay threshold, i.e. 99,800 × 3 = 299,400. What was the author’s intention in writing ‘three times per capita GDP’ as ‘two times per capita GDP’ (199,600)? (At a WTP threshold of three times China’s 2025 per capita GDP (¥199,600), the probability of the dual-agent regimen being cost-effective was 0%.)

Reviewer #2: (No Response)

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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: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Economic Evaluation of Finotonlimab plus bevacizumab as First-line Therapy for advanced Hepatocellular Carcinoma

PONE-D-25-65811R2

Dear Dr. Feng,

We’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.

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Kind regards,

Jincheng Wang

Academic Editor

PLOS One

Additional Editor Comments (optional):

Authors have addressed all comments, and I think this paper can be accepted for publication.

Reviewers' comments: