Real-World Outcomes of Chemoradiotherapy in Patients with Stage II/III Non-Small-Cell Lung Cancer in the Durvalumab Era: An Observational Study

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Can be improved

Are all the cited references relevant to the research?

Can be improved

Is the research design appropriate?

Yes

Are the methods adequately described?

Yes

Are the results clearly presented?

Can be improved

Are the conclusions supported by the results?

Yes

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1:

Comment: This is a good real-life study on lung cancer patients.

Thank you for your positive assessment and for taking the time to review our manuscript.

Comment: The abstract needs to be summarized. Look at what the journal says.

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have added a 'Simple Summary' in accordance with the journal’s formatting requirements and streamlined the abstract to improve clarity.

Comment: The introduction could explain a little about what Durvalumab is.

Response 2: Agree. We have added a brief explanation of what Durvalumab is in the Introduction to enhance understanding.

Comment: Line 113: explain what the abbreviation means.

Response 3: Thank you for this helpful comment. We have reviewed and revised all abbreviations throughout the manuscript to ensure that they are clearly defined at their first mention.

Comment: Lines 162 to 165 have different fonts. Check this because it happens again in the manuscript.

Response 4: Thank you. We have carefully checked the formatting and have corrected all inconsistencies in font throughout the manuscript.

Comment: Figure 1: better quality.

Response 5: Thank you for this suggestion. Figure 1 has been replaced with a high-resolution version (300 dpi) to ensure better quality.

Comment: The tables are too large. Include the most relevant information and put the rest in the supplement.

Response 6: Thank you for the recommendation. We have shortened Table 2 (Patient Characteristics) and moved the full version to the Supplement. In addition, Table 5 was also moved to the Supplement. Regression tables were retained in full to transparently present the statistical models.

Comment: I would put the limitations of the study at the end of the discussion and include the strengths.

Response 7: Thank you. We have moved the limitations section to the end of the Discussion and added a new section explicitly discussing the strengths of the analysis.

4. Response to Comments on the Quality of English Language

Point 1:

The English is fine and does not require any improvement.

Response to Reviewer 2 Comments

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes

Are all the cited references relevant to the research?

Yes

Is the research design appropriate?

Yes

Are the methods adequately described?

Yes

Are the results clearly presented?

Yes

Are the conclusions supported by the results?

Yes

3. Point-by-point response to Comments and Suggestions for Authors

Comments:

I wonder if the authors could comment more on the choice to include stage II patients in this evaluation even though they have significantly improved survival compared to stage III and the title of the article implies that only patients with stage III disease are included.

I found it interesting that the median OS was worse with the durvalumab group, however the progression free survival almost double that of those that did not receive the immunotherapy. I wonder if the authors could surmise how the progression and overall survival are so different. The lack of univariate difference between receiving durvalumab and not is interesting, and I wonder if the authors could discuss this in more detail, and make some statements as to why they would think that there is an uncovering of a significant effect when it is included in the multivariate analysis.

It seems that the primary impactors on survival in the univariate and multivariate assessments are the KPS and CCI, and I wonder if this is the primary drivers of survival in the study rather than the impact of durvalumab.

Response:

Response: Thank you very much for your thoughtful and constructive comments. We appreciate the opportunity to clarify the points raised.

Regarding the inclusion of stage II patients: We agree that this should be addressed more explicitly. Patients with stage II disease were included in this study only if mediastinal lymph node involvement (N2) was present and the intent was curative treatment with definitive chemoradiotherapy, following the same protocol used for stage III NSCLC. This reflects a common clinical reality in multidisciplinary tumor board decisions, where treatment intensification is considered appropriate for selected patients in stage II with nodal disease. We have now clarified this in the Discussion section.

Regarding the reported median overall survival (OS): Thank you for noting this inconsistency. There was an error in the previous calculation. The corrected median OS is now reported as follows: patients who received durvalumab had a median OS of 5.00 years, while those who did not receive durvalumab had a median OS of 1.75 years. This correction is reflected in the revised Results section and supports the findings from the multivariable analysis.

With respect to the discrepancy between univariable and multivariable results: We agree that this is an important point for discussion. As stated in the revised Discussion, patients with better functional status (KPS >80%) and lower comorbidity burden (CCI ≤2) were more likely to receive durvalumab. These factors are also strongly associated with improved survival and thus represent confounders in the univariate comparison. The multivariable model adjusted for these variables and uncovered the independent association of durvalumab with both OS and PFS. This analytical approach allows for a more valid estimation of treatment effect in a real-world cohort.

Finally, while KPS and CCI emerged as strong prognostic factors, our subgroup analysis and multivariable modeling indicate that durvalumab remained independently associated with improved outcomes. Therefore, the influence of baseline health status does not negate the added value of durvalumab treatment but rather underscores the importance of proper patient selection in routine clinical practice.

I wonder if the authors could comment more on the choice to include stage II patients in this evaluation even though they have significantly improved survival compared to stage III and the title of the article implies that only patients with stage III disease are included.

I found it interesting that the median OS was worse with the durvalumab group, however the progression free survival almost double that of those that did not receive the immunotherapy. I wonder if the authors could surmise how the progression and overall survival are so different. The lack of univariate difference between receiving durvalumab and not is interesting, and I wonder if the authors could discuss this in more detail, and make some statements as to why they would think that there is an uncovering of a significant effect when it is included in the multivariate analysis.

It seems that the primary impactors on survival in the univariate and multivariate assessments are the KPS and CCI, and I wonder if this is the primary drivers of survival in the study rather than the impact of durvalumab.

Response:

Response: Thank you very much for your thoughtful and constructive comments. We appreciate the opportunity to clarify the points raised.

Regarding the inclusion of stage II patients: We agree that this should be addressed more explicitly. Patients with stage II disease were included in this study only if mediastinal lymph node involvement (N2) was present and the intent was curative treatment with definitive chemoradiotherapy, following the same protocol used for stage III NSCLC. This reflects a common clinical reality in multidisciplinary tumor board decisions, where treatment intensification is considered appropriate for selected patients in stage II with nodal disease. We have now clarified this in the Discussion section.

Regarding the reported median overall survival (OS): Thank you for noting this inconsistency. There was an error in the previous calculation. The corrected median OS is now reported as follows: patients who received durvalumab had a median OS of 5.00 years, while those who did not receive durvalumab had a median OS of 1.75 years. This correction is reflected in the revised Results section and supports the findings from the multivariable analysis.

With respect to the discrepancy between univariable and multivariable results: We agree that this is an important point for discussion. As stated in the revised Discussion, patients with better functional status (KPS >80%) and lower comorbidity burden (CCI ≤2) were more likely to receive durvalumab. These factors are also strongly associated with improved survival and thus represent confounders in the univariate comparison. The multivariable model adjusted for these variables and uncovered the independent association of durvalumab with both OS and PFS. This analytical approach allows for a more valid estimation of treatment effect in a real-world cohort.

Finally, while KPS and CCI emerged as strong prognostic factors, our subgroup analysis and multivariable modeling indicate that durvalumab remained independently associated with improved outcomes. Therefore, the influence of baseline health status does not negate the added value of durvalumab treatment but rather underscores the importance of proper patient selection in routine clinical practice.

1. Summary

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Can be improved

Are all the cited references relevant to the research?

Can be improved

Is the research design appropriate?

Yes

Are the methods adequately described?

Yes

Are the results clearly presented?

Yes

Are the conclusions supported by the results?

Yes

3. Point-by-point response to Comments and Suggestions for Authors

Comment 1: There are many more later studies based on real-time data or phase 4 that I think should be named apart from the PACIFIC, please reconsider this point.

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have revised the Introduction section to include additional relevant real-world studies such as the RELEVANCE study, KINDLE-Korea, the Canadian PD-L1-stratified analysis by Denault et al., and the recent data from Arunachalam et al.

Comment 2: Line 100 vs. Lines 116–119: They are talking about the same topic (stage) but it is separate, please consider reorganizing the introduction so that the same topics are together.

Response 2: Agree. We have reorganized the Methods section to ensure that the description of the study population is presented in a more structured and cohesive way. Stage II–III NSCLC is now introduced consistently in one paragraph.

Comment 3: Lines 198–200: “These findings suggest a gradual implementation of durvalumab …” – this interpretation belongs in the Discussion.

Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we have moved this removed this statement from the results section.

Comment 4: Lines 366–367 – “PD-L1 expression … growing evidence…”: I think it would be appropriate to make a more critical comment given that the statistical study does not have sufficient power per sample size to assess overall survival results according to PDL1.

Response 4: Thank you for pointing this out. We agree with this comment. Therefore, we have revised the corresponding paragraph in the Discussion to include a critical note regarding the limitations of PD-L1–specific analyses. It now emphasizes that subgroup analysis according to PD-L1 status is underpowered due to sample size limitations.

Comment 5: Durvalumab is approved in some countries for patients with positive PD-L1. I think this factor should have been sub-stratified from the outset (I don't see it as the case), and, furthermore, it is described in the results, but not really clear, direct, or priority.

Response 5: Thank you for this thoughtful comment. We agree that PD-L1 status represents an important clinical variable. Therefore, we confirm that stratification by PD-L1 status and durvalumab administration was performed in our analysis. Additionally, the multivariable models were adjusted for treatment period (pre-2019 vs. post-2019) to reflect the clinical implementation of PD-L1–guided durvalumab indication in Germany.

4. Additional Clarifications 
We thank the reviewer for their critical and constructive feedback. We would like to clarify that in our statistical models, we accounted for temporal treatment patterns (treatment period) and stratified both durvalumab and PD-L1 variables. We believe this comprehensive approach strengthens the internal validity of our findings within the constraints of the cohort size.

Comment 1: There are many more later studies based on real-time data or phase 4 that I think should be named apart from the PACIFIC, please reconsider this point.

Response 1: Thank you for pointing this out. We agree with this comment. Therefore, we have revised the Introduction section to include additional relevant real-world studies such as the RELEVANCE study, KINDLE-Korea, the Canadian PD-L1-stratified analysis by Denault et al., and the recent data from Arunachalam et al.

Comment 2: Line 100 vs. Lines 116–119: They are talking about the same topic (stage) but it is separate, please consider reorganizing the introduction so that the same topics are together.

Response 2: Agree. We have reorganized the Methods section to ensure that the description of the study population is presented in a more structured and cohesive way. Stage II–III NSCLC is now introduced consistently in one paragraph.

Comment 3: Lines 198–200: “These findings suggest a gradual implementation of durvalumab …” – this interpretation belongs in the Discussion.

Response 3: Thank you for pointing this out. We agree with this comment. Therefore, we have moved this removed this statement from the results section.