New Strategies and Combinations to Improve Outcomes in Immunotherapy in Metastatic Non-Small-Cell Lung Cancer

Round 1

Reviewer 1 Report

Cancer is one of the leading problems in the world, currently research is focused on many aspects on treatment and diagnosis, but still it’s becoming challenging in understating molecular mechanism.

The author in this paper discusses the new strategies and combination of improve treatment for lung cancer.

The paper is written very clear and made some important update and treatment in lung cancer, although paper is written nicely with minimum results presented but miss over all schematic presentation to simplify the concept for broad range of readers. If possible, I would suggest to include current models in each section to follow-up reading in text (example, in case of  VEGF, targeted therapy and other immunomodulators and Adoptive cell therapy)

Author Response

Dear Reviewer,

Thank you for your kind and helpful comments. We had hoped that the included figure would help a range of readers conceptualise the content of the review but recognise that it does appear complex. We have modified the figure based on your suggestions. We have specifically added more explanations to the components of the figure in order to improve clarity.

With respect to follow-up reading, we have attached a supplementary table of recent and current trials investigating each therapeutic strategy. We had intended for this table to be included in the original version but there appear to have been some technical issues with the initial upload of the paper. We have spoken with the publisher and they will ensure that this will now be attached for your review.

Thank you again for your time in reviewing this paper. We hope that you will find the edits and additional material satisfactory for publication.

Reviewer 2 Report

--The purpose of this review article is not described well in the abstract section, which is required to improve. The authors indicated Table S1 in the text, but I don’t get access to evaluate. 
--Immunotherapy is considered a promising therapeutic strategy for NSCLC, but more knowledge and suitable compounds are required for maximum therapeutic efficacy, described well in this review.  The authors didn’t describe the search strategy， please add.

-Please change the blue color in the text, page 9, reference 61-63 

-Please make clear the purpose of this study in the abstract section.

-Table S1 can't be accessible; please take appropriate action.

-Please check the reference style carefully.

-Please check typographical errors throughout the manuscript.

 

Author Response

Dear Reviewer,

Thank you very much for your time and your comments. Please see a detailed response below to each of the points you helpfully raised.

-"The purpose of this review article is not described well in the abstract section, which is required to improve. Please make clear the purpose of this study in the abstract section."

Thank you for this suggestion. We did discuss the purpose of the review in the introduction section but agree that it should also have been included in the abstract. We have edited the abstract accordingly and thank you for helping to make the review’s purpose clearer to potential readers.

-"The authors didn’t describe the search strategy， please add."

This manuscript is an invited narrative review (i.e. secondary literature) and not a systematic review or primary research article. We agree that a systematic review would require a specific search strategy. However, this would not normally be included in an invited review.

-"Table S1 can't be accessible; please take appropriate action."

We apologise for the technical difficulties that unfortunately resulted in the table not being accessible. We have discussed this with the publisher and they will ensure it is available for your perusal.

-Please check the reference style carefully. Please check typographical errors throughout the manuscript. Please change the blue color in the text, page 9, reference 61-63

Thank you for pointing out the hyperlink in references 61-63. We did apply the publisher’s EndNote style file but that seems not to have worked cohesively throughout the manuscript. We have checked for and modified minor typographical errors but would appreciate if you could highlight for us any specific examples that we could address further.

Thank you again for your time in reviewing this paper. We hope that you will find the edits and additional material satisfactory for publication.

Reviewer 3 Report

The paper intituled “New strategies and combinations to improve outcomes in immunotherapy in metastatic non-small cell lung cancer” is focused on a very relevant and emergent topic about lung cancer immunotherapy strategies, centering the attention on the role of TIME. In that regard, the authors conducted an overview of the significant intervenients suitable for therapeutic intervention.

Suggestions: 

1. It is advised to include in the abstract the aim of the paper. Also, to clarify in the introduction the methodology assumed.
2. There is some inconsistency concerning references, namely lack of some relevant references, that should be included, as follow:

Line 73-74: please add a reference

Line 81-88: these concepts were previously described, requiring a reference

Line 97-98: In contrast, ….. please add a reference

Line 133-134: The use of pembrolizumab (PD-1 inhibitor) in mNSCLC led to 5 year survival rates of 23% 133 for treatment naïve patients and 15% for those previously treated” Needs a reference for each of the presented results.

Line 151: the activity in brain metastases is not so well demonstrated. Please add the corresponding reference or reformulate it.

327-328: add reference related breast and melanoma data.

408-409. add reference

417: punctuation

3. Line 46-47: English improvement
4. Figure 1: please identity all elements illustrated in the legend, including them in the explanation
5. Suggestion to include in the main text a table or tables summarising the most promising strategies to help the reader easily catch the relevant information.

Author Response

Dear Reviewer,

Thank you very much for your time and comprehensive comments. We have updated our manuscript to include all your suggested changes and very much appreciate your input.

Please see our detailed response below to each of the points you helpfully raised.

1. "It is advised to include in the abstract the aim of the paper. Also, to clarify in the introduction the methodology assumed."

Thank you for these suggestions. We did discuss the purpose of the review in the introduction section but agree that it should also have been included in the abstract. We have edited the abstract accordingly and thank you for helping to make the review’s purpose clearer to potential readers. In terms of methodology, this was an invited narrative review and not a systematic review but we have now specified this more clearly in the manuscript.

2. "There is some inconsistency concerning references, namely lack of some relevant references, that should be included, as follow."

Thank you for identifying these referencing inconsistencies. We greatly appreciate the time spent to recognise these. We have now included references at these points as appropriate. Where we have not made changes relates to the following points

- "Line 133-134: The use of pembrolizumab (PD-1 inhibitor) in mNSCLC led to 5 year survival rates of 23% 133 for treatment naïve patients and 15% for those previously treated” Needs a reference for each of the presented results."

The paper we referenced here reported 5-year results for both treatment naïve and pre-treated patients who received pembrolizumab in KEYNOTE-001. Thus, this sentence is referring to data from a single study hence it is included as a single reference.

- "327-328: add reference related breast and melanoma data."

The paper we referenced here reported triple negative breast cancer and melanoma as the only tumor sites to demonstrate partial response. If there is a specific study that we have missed, please let us know as we would be happy to include it.

3. "Line 46-47: English improvement"

This has been rewritten

4. "Figure 1: please identity all elements illustrated in the legend, including them in the explanation"

We have made some modifications to the figure, including a legend, and added more explanations of the various components. We hope this will help readers better understand the figure and how it relates to the content of the review.

5. Suggestion to include in the main text a table or tables summarising the most promising strategies to help the reader easily catch the relevant information.

We had attached a supplementary table of recent and current trials investigating each therapeutic strategy but there appears to have been a technical issue and unfortunately this was not released with the paper. We have spoken with the publisher and they will ensure that this will now be attached for your perusal.

Thank you again for your time in reviewing this paper. We hope that you will find the edits and additional material satisfactory for publication.

Round 2

Reviewer 2 Report

I have no further comment. Thank you for replying and editing carefully.