Naloxegol, an Oral Peripherally Acting Opioid Receptor Antagonist, Administered Concurrently with First-Line Systemic Therapy for Advanced Lung Adenocarcinoma (Alliance A221504): A Feasibility and Safety Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study explores the feasibility and safety of naloxegol in patients with advanced lung adenocarcinoma and addresses an important clinical issue. While the study design is appropriate, several key elements—including clearer endpoint definitions, reporting of early trial termination, and expanded discussion of feasibility and safety—require further clarification to improve interpretability.

 

There is no mention in the simple summary that the trial was stopped early, which is important for appropriate interpretation of the results.

 

Although the summary mentions a feasibility primary endpoint, the specific components of the primary endpoint are not clearly described and could be stated more explicitly for clarity.

 

Although the prognostic relevance of opioid receptor signaling is well described, the Introduction would benefit from additional discussion of the feasibility and safety of naloxegol, especially its concurrent use with systemic anticancer treatments.

 

In Figure 1 (CONSORT diagram), some text extends beyond the boundaries of the boxes and should be adjusted for better readability.

 

The Discussion would benefit from a more detailed discussion of the factors contributing to slow accrual and the subsequent early termination of the study.

Author Response

We thank the reviewers for their insightful and constructive comments and suggestions. We believe that the resulting revisions have considerably improved and strengthened our manuscript, and hope that it will now be found acceptable for publication in Cancers.

 

Report 1

This study explores the feasibility and safety of naloxegol in patients with advanced lung adenocarcinoma and addresses an important clinical issue. While the study design is appropriate, several key elements—including clearer endpoint definitions, reporting of early trial termination, and expanded discussion of feasibility and safety—require further clarification to improve interpretability.

 

There is no mention in the simple summary that the trial was stopped early, which is important for appropriate interpretation of the results.

We have stated in the Simple Summary about the trial closing early due to slow accrual.

 

Although the summary mentions a feasibility primary endpoint, the specific components of the primary endpoint are not clearly described and could be stated more explicitly for clarity.

We have included more information on the feasibility endpoint to the “Simple Summary.”

 

Although the prognostic relevance of opioid receptor signaling is well described, the Introduction would benefit from additional discussion of the feasibility and safety of naloxegol, especially its concurrent use with systemic anticancer treatments.

In the Introduction and Discussion, we have cited previous reports showing the safety of naloxegol in patients with cancer. However, ours was the first study (to the best of our knowledge) to prospectively examine the safety and efficacy of naloxegol vs placebo in patients receiving specific anticancer treatments (as stated in the first sentence of the Discussion).

 

In Figure 1 (CONSORT diagram), some text extends beyond the boundaries of the boxes and should be adjusted for better readability.

Figure 1 has been corrected.

 

The Discussion would benefit from a more detailed discussion of the factors contributing to slow accrual and the subsequent early termination of the study.

We do not know the specific reasons responsible for slow accrual, therefore we have not speculated about this aspect. The decision to terminate the study was taken by various overseeing committees in the Alliance. This has now been mentioned in the Discussion.

Reviewer 2 Report

Comments and Suggestions for Authors

1. The title is not clear. It should state the preliminary nature of the trial.
2. In a simple summary, it should also include the limitations of the study.
3. The abstract should clearly state the limitations and avoid overemphasizing positive results, as they may be due to the small sample size rather than a true treatment effect.
4. The introduction should first clearly describe lung cancer, then explain the role of opioids, and finally present the study rationale and objectives in a clear, logical sequence.
5. While discussing lung cancer in the introduction, add some content and refer to the following article: 10.3390/molecules29092077.
6. The rationale for dose selection, the handling of missing PRO data, and the implications of a small sample size should be clarified in the methodology.
7. The early termination due to low accruals should be emphasized in the methodology.
8. While prior studies are cited in the discussion, the differences in study populations and design are not fully acknowledged, which may overstate the novelty of findings.
9. The discussion suggests the mechanistic effects of naloxegol without supporting evidence. Authors need to strengthen this section with evidence.
10. The manuscript highlights improvements in emotional well-being and bowel function despite small sample sizes and exploratory analyses, which could be misleading.
11. The conclusion makes the results seem stronger than they are. It should just say the treatment is safe, and any benefit seen is only a hint for future research.
12. A thorough language and grammar revision is recommended.

Comments on the Quality of English Language

Authors are advised to check and rectify the language, grammar, and syntax. 

Author Response

Report 2

1.The title is not clear. It should state the preliminary nature of the trial.

The title has been modified to address this concern.

 

2.In a simple summary, it should also include the limitations of the study.

We have added language in the Simple Summary that describes the limitation of this study to evaluate endpoints in view of early termination for slow accrual.

 

3.The abstract should clearly state the limitations and avoid overemphasizing positive results, as they may be due to the small sample size rather than a true treatment effect.

We have modified the abstract accordingly. However, while small sample size may result in “false negatives” due to inadequate power, it is unlikely that small sample size will not represent a true effect when statistical tests confirm significance. Nevertheless, we state that our findings require confirmation.

 

4.The introduction should first clearly describe lung cancer, then explain the role of opioids, and finally present the study rationale and objectives in a clear, logical sequence.

The Introduction has been re-written accordingly.

 

5.While discussing lung cancer in the introduction, add some content and refer to the following article: 10.3390/molecules29092077.

We thank the reviewer for bringing this exciting work to our attention. This paper describes the effect of a nano-encapsulated red algae extract on a lung adenocarcinoma cell line in vitro. Since we were unable to identify the specific relationship of the work in this paper to opioids or their antagonists (the focus of our study), we have respectfully omitted referring to it in our Introduction.

 

6.The rationale for dose selection, the handling of missing PRO data, and the implications of a small sample size should be clarified in the methodology.

The 2 doses naloxegol selected were those that are FDA-approved, and this is specified in the Methods. We have added language regarding the handling of missing PRO data and the implications of a small sample size in the Materials and Methods section.

 

7.The early termination due to low accruals should be emphasized in the methodology.

The Materials and Methods section now includes language regarding this point.

 

8.While prior studies are cited in the discussion, the differences in study populations and design are not fully acknowledged, which may overstate the novelty of findings.

Previous studies have now been described in more detail regarding study populations, design and specifically the lack of data regarding the potential effects of naloxegol on the safety and outcomes related to chemotherapy.

 

9.The discussion suggests the mechanistic effects of naloxegol without supporting evidence. Authors need to strengthen this section with evidence.

The mechanistic basis for the expected effects of naloxegol is extensively discussed (with relevant references) in the Introduction. As advised by the reviewer, we have now added additional information and citations regarding the pharmacology of naloxegol, in the Discussion.

 

10.The manuscript highlights improvements in emotional well-being and bowel function despite small sample sizes and exploratory analyses, which could be misleading.

We have added language in the Discussion and Conclusion to address this concern.

 

11.The conclusion makes the results seem stronger than they are. It should just say the treatment is safe, and any benefit seen is only a hint for future research.

The conclusion has been modified to address this concern.

 

12.A thorough language and grammar revision is recommended.

This has been done.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have adequately addressed all reviewer comments, and the revisions have satisfactorily improved the clarity and quality of the manuscript. I have no further concerns.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all the queries. The manuscript may be accepted for publication. 

Comments on the Quality of English Language

Authors are advised to check and rectify the language, grammar, and syntax.