Dear Dr. Radigan,

Please submit your revised manuscript by Feb 22 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Andres Mauricio Acevedo-Melo, M.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #1: Partly

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #1: No

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #1: This manuscript sets out the protocol for evaluating the feasibility of a novel genomic RNA test to aid precision medicine decisions in treating metastatic cancer. The authors describe the rationale well and designed a trial to assess the possibility of integrating the precision medicine test into the standard care pathway. I appreciate that this is an early stage trial and including patients with metastatic cancer is challenging. Please see my suggestions for improving the manuscript. I hope you find this helpful.

1. Please can you explain why there is no ongoing oversight for this trial. The SPIRIT checklist is NA for sponsor and committees for example. If these are not required for this trial design, please include the rationale for this on the SPIRIT checklist, or if proxies for this oversight are available (i.e IRB or PI responsibility).

2. Can you give some more justification or rationale for the sample size target of 5-20 patients. Is this in relation to how many patients this institution cares for, for example? Can you reasonably expect meaningful statistical results from 5 patients?

3. Can you include in the supplementary materials the baseline patient and clinical characteristics and endpoint measures, for example, in a simple proforma – presumably you are collecting this information somehow? And when these assessments are made, if at different times during the trial.

a. Also, in Fig1, I am not clear what Q is in Q3 months and Q6 months.

4. Can you make the following methods clearer…

a. (line 161 & Fig1) What happens to those patients with samples <50% tumor?

b. (lines 159-165) can you make it clearer who is doing the biopsy and that Columbia University Medical Center is doing the Darwin testing. I think this is clearer in Fig 3, than it is in the text.

c. Are you going to report how many patients were ineligible for patient selection overall and why (e.g. no consent, NEAT score)? This would also be useful to know for patient acceptability – e.g. out of how many patients >18 with up to 10 lesions and classify as oligometastases, were included in the trial.

5. Would the long term goal be for an RCT to evaluate the efficacy of precision medicine using the Darwin tests for metastatic cancer survival? If so, would it be useful to include the acceptability of randomisation to precision medicine, in theory, for both patients and clinicians?

Reviewer #2: Very Minor Thought

This appears to be a well-designed feasibility trial with the feasibility objectives to be correctly summarised without formal statistical analysis. As the authors will no doubt concede, statistical significance is unlikely when the suggested comparisons of progression free survival and overall survival are made. However, 95%CI intervals for the HRs estimated would be informative.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org

Feasibility trial of Darwin OncoTreat and OncoTarget precision medicine testing to improve outcomes for patients with limited metastatic disease that failed first-line systemic therapy

PONE-D-24-45282R1

Dear Dr. Radigan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Andres Mauricio Acevedo-Melo, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

All comments have been succesfully addressed

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses??>

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable??>

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete??>

The PLOS Data policy

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: Yes

**********

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

Reviewer #2: As I suggested, the authors have now included 95%CI for the HRs concerned.

I have no further comments to add.

I wish them well with their study

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: No

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