Evolution of Immune Checkpoint Blockade in Metastatic NSCLC: A Narrative Review of Emerging Bispecific Antibodies and the Practical Challenges of Clinical Integration

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I suggest to widen the materials and methods

Which databases were used and which outcomes and criteria were considered in clinical studies?

Please include a section on side effects, common and new, and main wardings and contraindications

The iRECIST criteria for response evaluation should be also mentioned

I suggest to include the following reference for the discussion about interference of concurrent therapies

 Crit Rev Oncol Hematol. 2019 Oct;142:26-34. 

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

1. The simple summary is clear, but it would be improved by adding a brief line explaining what bispecific antibodies are.
2. The abstract is clear. Define what bispecific antibodies are and why they are used.
3. The introduction is very brief and should be expanded to clearly discuss the limitations of existing therapies and provide a more detailed explanation of bispecific antibodies and their therapeutic rationale.
4. The authors are advised to include the limitations of existing therapies in the Introduction following - 10.3390/genes14071370
5. In the introduction, the authors should also clearly state the research gap addressed by this review and explicitly mention its limitations.
6. The methodology section lacks sufficient detail on the literature search strategy, including databases used, time frame, and study selection criteria, which limits transparency and reproducibility of the review.
7. Table 1: It includes many clinical trials, but authors are encouraged to summarize the status of D-1/L1 Inhibitors in Advanced or Metastatic NSCLC following Table 1.
8. A more balanced discussion that also includes bispecific trials with limited or negative results, clearer comparisons of toxicity with standard chemo-immunotherapy, and a deeper focus on biomarker-based patient selection would make the manuscript more objective and strengthen its overall impact.
9. The discussion places strong emphasis on PD-1×VEGF bispecific antibodies, although overall survival data are still limited, particularly in non-Asian populations.
10. 3.4: Authors are advised to discuss the advantages of BsAbs over biologic combinations. It will be appreciated if the authors include it in a schematic way.
11. What about the practical challenges part? 3.6 discusses the challenges, but these are very common. Authors are advised to justify the term practical challenged with possible solutions.
12. The conclusion is clear and well written, but it slightly overstates the clinical readiness of bispecific antibodies. Emphasize that further validation in large clinical trials is still required.
13. Standardize capitalization (ICI vs Ici). It should be corrected throughout the manuscript.
14. Abbreviations should be defined consistently at first mention.
15. Minor grammatical correction needed in long sentences.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

This is a review of immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. It provides a systematic summary of existing PD-1 and PD-L1 inhibitors, as well as bispecific antibodies, along with related challenges.
There are no particular points to note regarding the main body.
One point: Please double-check the content of Table 1. The information listed under “Remarks” appears inconsistent across trials. While the approval status for Sugemalimab is noted, Tislelizumab is also not approved in some regions. Additionally, only EMPower Lung1 data is listed for Cemiplimab, but EMPower Lung3 data has already been published.

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I suggest to include a short paragraph about tolerability and interactions with drugs of bispecific antibodies compared with classical immunotherapy. 

I would suggest to include the following references

J Clin Med. 2025 Nov 12;14(22):8021.

Crit Rev Oncol Hematol. 2019 Oct;142:26-34.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The present version of the manuscript may be accepted for publication. 

Author Response

Thank you very much for considering that the present version of the manuscript may be accepted for publication.
I sincerely appreciate your time, constructive comments, and valuable insights throughout the review process. Your feedback has been extremely helpful in improving the clarity and quality of our work.

Thank you again for your thoughtful review.