PONE-D-25-42455Efficacy and safety of Atezolizumab plus Bevacizumab and Lenvatinib as first-line systemic therapies for hepatocellular carcinoma: a real-world studyPLOS ONE

Dear Dr. Thanapirom,

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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ACADEMIC EDITOR:

Main methodological issues to be corrected:

- include more variables (baseline laboratory markers or liver stiffness measurements, concurrent or previous treatments, comorbidities...) in the model

- provide more information about the patients' follow-up  over 1 year after observation onset and about post-progression therapies (to improve reliability of prognosis data)

- detail response evaluation and interpretation criteria more deeply (to exclude interpretation biases due to the retrospective design of the study) 

Minor issues:

- change figures as requested

- English language editing

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Carmelo Caldarella, Ph.D., M.D.

Academic Editor

PLOS ONE

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Additional Editor Comments :

Dear Authors, the Reviewers have carefully analyzed your manuscript and concluded that there are some methodological issues that require re-evaluation in order to make this paper more scientifically sound and clear to the reader, as well as to improve reliability and reproducibility of the results achieved.

Particularly, more variable (like baseline laboratory markers or liver stiffness measurements, concurrent or previous treatments, comorbidities) should be included in the model, and more information about the patients who survived longer than the first 12 months from observation onset and about post-progression therapies should be included, so that differences in prognosis are more reliable and clinically useful.

Moreover, response evaluation and interpretation criteria should be reported with more details, considering that retrospective studies are more prone to interpretation biases than prospective ones.

Some figures and English text editing is also desirable.

Waiting for the revised version of your manuscript

Best regards,

Carmelo Caldarella, PhD MD

Academic Editor, PLOS ONE

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Reviewers' comments:

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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

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: This study demonstrates that ATEZO/BEV significantly improves OS compared to LEN in patients with unresectable HCC, despite similar PFS, ORR, and DCR. Both treatments have comparable safety profiles. I have some advice for you.

1.Figures have disappeared at the bottom of this manuscripts.

2.Some grammatical errors in articles should be revised.

Reviewer #2: The authors present a retrospective real-world analysis comparing atezolizumab plus bevacizumab to lenvatinib as first-line systemic therapies in patients with unresectable hepatocellular carcinoma. The clinical relevance of this work is undeniable, as head-to-head randomized controlled trials directly addressing this therapeutic comparison are lacking, and clinicians often rely on retrospective evidence and propensity score-matched analyses to guide treatment selection. The manuscript is clearly written, and the study benefits from a relatively well-characterized cohort and careful application of propensity score matching. The findings, particularly the survival advantage with atezolizumab plus bevacizumab despite similar progression-free survival and objective response rates, are potentially meaningful. Nevertheless, there are several important methodological issues and interpretative limitations that must be addressed before the work can be considered for publication.

The first major concern relates to the retrospective design and the inherent biases that arise despite the use of propensity score matching. The inclusion criteria, exclusion parameters, and data collection windows are not fully detailed. It is unclear whether all patients treated in the specified time frame were consecutively included, or whether certain subgroups might have been underrepresented. Without clear clarification, the risk of selection bias remains high. Moreover, although the authors applied one-to-one nearest-neighbor matching, the choice of a caliper of 0.2 and the covariates included in the logistic regression model may not be sufficient to account for important clinical confounders. For example, baseline laboratory markers such as platelet count, neutrophil-to-lymphocyte ratio, or liver stiffness measurements, which are increasingly recognized as important prognostic determinants in hepatocellular carcinoma, were not considered. Similarly, the presence of comorbidities, previous local therapies, or concomitant supportive care measures could have significantly impacted survival outcomes. A sensitivity analysis including additional variables, or at minimum a discussion of why these parameters were excluded, would strengthen the validity of the comparisons.

Another methodological limitation is the relatively short follow-up period, with a median under twelve months. The observed median overall survival in both arms is substantially lower than in pivotal clinical trials, which may reflect the advanced stage and higher tumor burden of the enrolled population, but may also stem from limited observation time and immature survival data. This discrepancy raises concerns about the robustness of the survival estimates. The authors should provide more granular details on censoring, the proportion of patients alive at last follow-up, and whether survival curves plateaued or continued to decline steeply beyond one year. Without this information, the survival advantage of atezolizumab plus bevacizumab over lenvatinib might be overestimated.

Treatment exposure and post-progression therapies also represent an area requiring greater detail. The discussion acknowledges that socioeconomic barriers influenced second-line treatment access, yet the manuscript does not provide clear data on how many patients in each arm received subsequent systemic therapy, locoregional salvage interventions, or best supportive care only. Given the well-documented impact of treatment sequencing on overall survival in hepatocellular carcinoma, the omission of these details limits interpretability. A breakdown of post-progression therapies, stratified by treatment arm, would allow readers to better understand whether the survival difference observed is attributable to first-line efficacy or subsequent management differences driven by cost and accessibility.

The methods for assessing response also warrant scrutiny. The manuscript reports that mRECIST criteria were applied, but it is not specified whether evaluations were conducted by blinded radiologists, whether inter-observer variability was assessed, or whether central review was performed. These details are not trivial, since retrospective real-world imaging assessments can be inconsistent, and progression-free survival may be particularly sensitive to variations in interpretation. Additionally, while objective response rate and disease control rate were reported, duration of response—an endpoint of growing importance in immunotherapy-based regimens—was not addressed. Including this analysis would have enhanced the understanding of how responses differ qualitatively between the two regimens.

The handling of alpha-fetoprotein and other tumor biomarkers deserves more thorough exploration. The multivariate analysis confirms alpha-fetoprotein ≥500 ng/mL and tumor size as independent predictors of poor overall survival, which is consistent with prior literature. However, des-gamma-carboxy prothrombin (DCP), another validated biomarker with both diagnostic and prognostic implications, was not included in the dataset. Given its widespread use in Asian populations, the omission is striking and should be at least acknowledged. Furthermore, alpha-fetoprotein dynamics during treatment, rather than baseline levels alone, could provide valuable insight into biological activity and treatment efficacy. A sensitivity analysis considering AFP response at eight to twelve weeks might have clarified whether biochemical response aligned with radiologic and survival outcomes.

The study presents safety data, but the adverse event reporting is somewhat superficial. It is not indicated whether adverse events were prospectively recorded in electronic health records or retrospectively extracted, and the grading system, while referenced, is not explicitly described in the results. Importantly, the lack of reporting on immune-related adverse events such as hepatitis, colitis, or pneumonitis, even if absent, is problematic when discussing immunotherapy-based combinations. Moreover, adverse events leading to dose reduction or permanent discontinuation should be highlighted, since tolerability and treatment persistence critically affect outcomes in real-world practice.

From a statistical standpoint, the use of propensity score matching is appropriate, but the presentation of results would benefit from additional clarity. Balance diagnostics, such as standardized mean differences for baseline covariates before and after matching, are not reported. Without this, it is difficult to assess whether the matching adequately eliminated systematic imbalances. Furthermore, the authors rely heavily on p-values for interpreting differences, yet confidence intervals are often wide and overlap substantially, particularly for progression-free survival. The discussion should place greater emphasis on the uncertainty of these estimates rather than drawing strong conclusions based on borderline statistical significance.

A broader issue is the limited generalizability of the findings. The cohort is derived from a single tertiary hospital in Thailand, with a very high prevalence of viral hepatitis as the underlying etiology. While this is representative of regional epidemiology, hepatocellular carcinoma in Western populations is increasingly driven by metabolic dysfunction-associated steatotic liver disease, which may respond differently to immunotherapy or anti-angiogenic agents. The authors should more clearly acknowledge that extrapolation of their findings to non-viral HCC should be cautious.

Finally, the study leaves unaddressed the pressing need for integrated biomarker-driven algorithms in hepatocellular carcinoma. Real-world comparative studies such as this one are valuable, but they risk remaining descriptive unless coupled with efforts to stratify patients more precisely based on molecular or immune signatures. The immunomicroenvironment of hepatocellular carcinoma is highly heterogeneous, with some tumors characterized by immune exclusion and others by immune infiltration. Atezolizumab plus bevacizumab might preferentially benefit the latter group through synergistic enhancement of anti-tumor immunity and vascular normalization. Incorporating assessments of immune infiltrates, PD-L1 expression, or circulating immune markers would have allowed the authors to begin addressing which patients derive the greatest benefit. Such analyses could ultimately feed into decision-support algorithms that combine clinical features, biomarkers such as AFP and DCP, and immunomicroenvironmental characteristics to guide individualized first-line therapy selection (please refer to PMID: 36901717 and expand).

In conclusion, this study makes a timely contribution to the literature by comparing atezolizumab plus bevacizumab with lenvatinib in unresectable hepatocellular carcinoma, and its findings align with the growing perception of immunotherapy-based combinations as superior in terms of survival benefit. However, methodological shortcomings, limited biomarker integration, and the absence of granular data on follow-up and subsequent therapies restrict the strength of the conclusions. Addressing these issues would substantially enhance the manuscript’s impact. Looking forward, the integration of tumor biology, circulating biomarkers, and immunomicroenvironment profiling into real-world datasets will be critical to developing robust algorithms that can guide screening, surveillance, and first-line treatment strategies in hepatocellular carcinoma.

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Reviewer #1: No

Reviewer #2: No

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Efficacy and safety of Atezolizumab plus Bevacizumab and Lenvatinib as first-line systemic therapies for hepatocellular carcinoma: a real-world study

PONE-D-25-42455R1

Dear Dr. Thanapirom,

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.

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,

Carmelo Caldarella, Ph.D., M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors, I am pleased to inform you that the revised manuscript has been appreciated by our Reviewers and now it is suitable for publication in this journal.

Best regards,

Carmelo Caldarella

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: All comments have been addressed

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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

**********

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: The study demonstrates that ATEZO/BEV significantly improves OS compared to LEN in patients with unresectable HCC, despite similar PFS, ORR, and DCR. Both treatments have comparable safety profiles.

Reviewer #2: The authors have clarified several of the questions I raised in my previous review. Most of the major problems have been addressed by this revision.

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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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