Complete Blood Count-Based Biomarkers as Predictors of Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients with PD-L1 < 50% Treated with First-Line Chemoimmunotherapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an nice study about the potential prognostic impact of blood count-based biomarkers as predictors of clinical outcomes in advanced NSCLC patients treated with first line chemoimmunotherapy. The subject is of great clinical interest, because chemoimmunotherapy is the treatment of choice for most patients with advanced NSCLC currently, and the availability of reliable blood-based biomarkers could help guide management better. Main limitation of the study is the relatively small patient number, main strengths are the systematic analysis of multiple biomarkers and the rigorous statistics including multivariable testing.

A couple of points could help further improve the manuscript:

1. Was there any molecular profiling performed to exclude EGFR/ALK and other treatable mutations? Could you please provide some details about the methods used and the genes analyzed?

2. In the Discussion, the authors could also consider further blood-count based biomarkers which have shown potential clinical utility for immunotherapy-treated NSCLC, like the advanced lung cancer inflammation index (ALI, e.g. https://pubmed.ncbi.nlm.nih.gov/34481329/)

3. minor: there is an inconsistency in the writing of PD-L1 (sometimes it appears as PDL1)

Author Response

Dear reviewer

Thank you for revising our manuscript and for your valuable suggestions. Our responses are listed point by point below and highlighted in yellow in the revised manuscript. 

Issue 1. Was there any molecular profiling performed to exclude EGFR/ALK and other treatable mutations? Could you please provide some details about the methods used and the genes analyzed?

Reply: All the tumours of the patients submitted to chemoimmunotherapy were analyzed for somatic mutations (genes EGFR, KRAS and BRAF through Next Generation Sequencing) and fusions (genes ALK, ROS1, MET, RET and NTRK through real time PCR); therefore, wild type status was ascertained in all the cases before starting the treatment. A phrase stating it was added in the section “Materials and Methods” of the article.    

Issue 2. In the Discussion, the authors could also consider further blood-count based biomarkers which have shown potential clinical utility for immunotherapy-treated NSCLC, like the advanced lung cancer inflammation index (ALI, e.g. https://pubmed.ncbi.nlm.nih.gov/34481329/)

Reply: We added a paragraph commenting on further blood – based prognostic indexes, including the ALI).

Issue 3. minor: there is an inconsistency in the writing of PD-L1 (sometimes it appears as PDL1)

Reply: The text was re-edited and typing errors were corrected.

Reviewer 2 Report

Comments and Suggestions for Authors

The aim of this study was to investigate a series of complete blood cell count-based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. However, this study has the following problems:

1. There are several studies in the field related to this research, but this study lacks depth and innovation in its research design.

2. The number of cases included in this study is small, and there is no external validation cohort, leading to weak persuasive power of the research results.

3. The discussion section does not sufficiently compare this study with other relevant research in the field, and the study's innovations and limitations are not adequately highlighted.

Comments on the Quality of English Language

English expression needs further elaboration.

Author Response

Dear reviewer

Thank you for revising our manuscript and for your valuable suggestions. Our responses are listed point by point below and highlighted in yellow in the revised manuscript. 

Issue 1. There are several studies in the field related to this research, but this study lacks depth and innovation in its research design.

Reply: There are several studies investigating the predictive roles of blood-based biomarkers and indexes in NSCLC patients undergoing immunotherapy, but only a few studies in those undergoing chemoimmunotherapy. In addition, our study investigated for the first time some indexes in this setting, as stated in the final part of the “Discussion”. We believe this, in addition to our results, represent an interesting innovation and might stimulate further research in this field.

Issue 2. The number of cases included in this study is small, and there is no external validation cohort, leading to weak persuasive power of the research results.

Reply: It is true, the number of the cases is small as we stated in the weak points of the study, where we now added also the lack of external validation. We are clear regarding the weaknesses of the study, but we believe that it has also interesting “pros”, which are stated in the same paragraph. 

Issue 3. The discussion section does not sufficiently compare this study with other relevant research in the field, and the study's innovations and limitations are not adequately highlighted.

Reply: we added data from other three studies regarding systemic inflammations indexes in chemoimmunotherapy. Most of the studies currently present in the medical literature focus on the use of ICIs in general, not specifically in patients treated with ICIs and chemotherapy combined. If the reviewer knows about further studies on blood-based biomarkers in NSCLC patients treated with chemoimmunotherapy, we will be happy to include them in the “Discussion” of our paper.   

Please be aware that the text of the article was thoroughly checked and English language errors and typos were corrected.

Best regards

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

This revised manuscript can be accepted.

Comments on the Quality of English Language

This revised manuscript can be accepted.

Author Response

Dear academic editor

Thank you for your suggestions. Here is a point-by-point reply to your notes; all the changes made are highlighted in yellow in the last version of the manuscript.

 

Issue 1. The title or abstract should highlight that this population is restricted to biomarker negative, PD-L1 <50%.
Reply: Chemoimmunotherapy is currently recommended only for patients with PD-L1 lower than 50%. We added it in the abstract, but we don’t think it is necessary to put it in the title.

Issue 2. The patients are classified as ADK or SQU - it is surprising that there weren't mixed histologies or undifferenciated cases. If so, they were included. In which category?  This should be clarified in the methods section. A sensitivity analysis should be done excluding cases or mixed/undiff histology to validate the results of the overall group if this is the case.
Reply: The diagnosis of mixed histologies (i.e adenosquamous carcinoma) is generally made in surgical specimens. We had only 5 cases which were previously submitted to surgery, but none of them has a mixed histology. We had several scarcely differentiated cases, but the expression of TTF-1 or P40 in IHC was clear in all the cases, and allowed to establish the favour histology in each case. We added a phrase in the “Materials and Methods” section to make it clear.  

Issue 3. The PD-L1 information is stratified as yes/no. I am assuming this means <1% vs 1-49%: can you clarify this in the paper?

Reply: Yes, you are right, it was not clear this way; we changed it in all the tables putting (1-49%/<1%).

 

Issue 4. There is a typo in table 7 Neutrophyls.

Reply: the error was corrected.