PONE-D-20-09864

Second-line treatment in advanced gastric cancer: data from the Spanish AGAMENON registry

PLOS ONE

Dear Dr. Gallego Plazas,

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Additional Editor Comments:

In general the paper was well-written, a lot of efforts were spent on it. In addition to addressing the reviewers' concerns, you have to emphasize the main outstanding points of your paper that will catch the readers attention to your paper. Emphasize the points what this retrospective analysis adds or confirms to current knowledge. Consequently you should re-write the conclusion part of the paper since there is no take home points or important findings there. The last para of discussion in unnecessary please delete it (beginning with the readers must..). According to the heterogeneity of the treatment groups cox-regression analysis does not seem to be appropriate unless the including variables are appropriately described for this analysis, since there were lots variables (age, gender, tumor type, performance status, etc). Which model did you use for cox-regression?

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Reviewers' comments:

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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: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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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: Author describe and comparison the CTs for 2nd line GC patients from real-world data of Spain.

1. In multivariate analysis for survival, did you include the potential prognostic factor, for example PS, ALP, No of mets and others? As you mentioned, the patients who received mono CT as second line have different condition compared to polyCT.

2. Do you have a data of the patients who received ICI as 3rd and later line? Because the response of ICI may continue for a long time, the use of ICI may influence the survival of each groups.

3. In Asian countries, first line platinum agent continue more than 6 courses if the patients have no toxicities and inconvenient. The re-introduction of platinum depends of the strategy of using of first line platinum administration. How the first line platinum are used for the patients with GC in Spain?

Reviewer #2: Sanchis et al presented a retrospective/observational study on second line treatment options for advanced gastric cancer AGC according to clinical practice in several cancer centers in Spain and Chile. AGC, after first line therapy failure, has poor prognosis but recent developments has added to the clinical practice scenario, new therapeutic approaches with a clear benefit on survival. The addition of VEGFR2 antagonist ramucirumab to taxanes, for instance, increased OS compared to mono-chemotherapy regimens.

The topic addressed by this manuscript is important and the paper is well written, however it lacks novelty and simply provide a description of several regimens used in second-line setting throughout the last 12 years. It appears clear that the use of ramicurumab is climbing in the most recent time due to the wide spreading of this agents from 2015 when RAINBOW trial was published. Moreover, the methods appear to be sound but the correlation of PFS and OS with each treatment strategy in the results section is not easily readable and should be expanded and better performed to ensure that readers understand exactly what the researchers wanted to state. Thirdly, platinum re-introduction, when feasible, could be a valid therapeutic option, however the conclusion of the manuscript appears to be way stronger due to low number (8.3%), the paucity of patients that will be able to tolerate the reintroduction of platinum-doublet in this setting and the results, totally comparable to Ram-taxane, which shows a better toxicity profile.

Lastly, the dissertation on PFS as adequate surrogate of OS is interesting. This is a current unmet need in oncology research. Specifically, in this study, authors focused on PPS (post progression survival). According to their data, it that could have some relevance in Her2 positive AGC since the anti-her2 action of trastuzumab, even though a radiologic progression, keeps the ability to control the Her-2 enriched population which could lead to a longer overall survival. However, for Her2-negative tumors, the magnitude of the benefit is lower, reaching less than 3 months in the best subgroup. In this case, QoL has much more impact and relevance for patients and should be primarily assessed in studies on poor prognosis cancer after first setting

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Reviewer #1: Yes: Ken Kato

Reviewer #2: No

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Second-line treatment in advanced gastric cancer: data from the Spanish AGAMENON registry

PONE-D-20-09864R1

Dear Dr. Gallego Plazas,

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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