PONE-D-20-04879

EGFR testing and erlotinib use in non-small cell lung cancer patients in Kentucky

PLOS ONE

Dear Dr Kolesar,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Randall J. Kimple

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper examined the prevalence of EGFR testing and erlotinib use in Kentucky using registry and insurance claim data. The manuscript is clear and well-written with appropriate statistical design. This work may raise community awareness and lead to improved adoption of guidelines for the management of NSCLC; both are strengths.

Several concerns are included below regarding the design and applicability of this work:

1. The cohort examined in this study was from 2007-2011. Since then, management for NSCLC, especially testing and treatment for EGFR-driven disease, has undergone major transformations. With the publication of the FLAURA trial in 2018 and subsequent FDA approval of osimertinib for treatment-naïve EGFR mutated NSCLC, the standard of care for front-line therapy has changed and erlotinib is no longer the recommendated therapy for advanced EGFR-driven NSCLC. The relevance and applicability of this study are questionable given this evolving practice pattern. If the authors could update their cohort to reflect the change in practice pattern, it would significantly strengthen the work.

2. Along these lines, if the authors are able to include more recent data, i.e. post 2016, it would be informative and enhance the story to look at testing pattern and drug usage for other mutation-driven NSCLC such as ALK. Crizotinib was approved in 2016 so the authors would need to have access to registry and insurance claim data post-2016.

3. Similar studies looking at this question have been published previously with more recent data (after 2011), with similar conclusions. The authors even cited one such study in their references. Thus, it is hard to differentiate the novelty of the current work from its predecessors.

4. It would be more informative if the authors were able determine that among the patients who received EGFR testing, how many tested positive? Among those who tested positive, how many received erlotinib.

5. Confounders and biases, some the authors have addressed in the conclusion:

a. Study did not address why utilization of EGFR testing and erlotinib is so low. Was this due to physician education, patient understanding, availability of testing, lack of insurance coverage? The design of the study examined mostly patient-specific and possibly insurance factors but did not address availability of resources or physician-related factors.

b. All patients in this study had insurance coverage. So those who did not were excluded. Unclear how this reflects the broader population of Kentucky.

c. The % of EGFR testing and erlotinib prescription may be falsely low compared to other similar studies or even the national average because the design of the study captured all patients rather than patients who fit the demographics of EGFR-driven disease. Since the general NSCLC patient population in Kentucky probably has lower EGFR prevalence compared to some areas in the US, i.e. West Coast, if looking at all-comers, both testing and treatment may be lower because the prevalence of EGFR mutation is lower.

d. Table 5 Cox-regression survival analysis I do not think that EGFR testing and erlotinib being statistically significant in this model are meaningful because, as the authors pointed out, testing is a likely surrogate for receiving guideline-appropriate care, and EGFR-driven disease is relatively more indolent with better prognosis. Both of these have favorable impact on survival.

6. Minor: please state explicitly how many patients were actually included in the cohort.

Reviewer #2: This study analyzed factors associated with EGFR testing and erlotinib prescribing in Kentucky from 2007 to 2011. The analysis used the Kentucky Cancer Registry linked with health claims from Medicaid, Medicare and private insurance groups. The study concludes that EGFR testing and prescribing of erlotinib occurred at a low rate in Kentucky and factors including residing in rural areas and type of insurance were associated with decreased use and reduced survival. While the methodology appears, appropriate, my main concern is the overall relevance of this study in 2020.

This paper looks at EGFR testing and erlotinb use during a time when EGFR inhibitors were still under clinical investigation and not FDA approved as front line therapy. Practice patterns of oncologists were still adjusting as new data came out. Multiple previous papers, which the authors have cited, have already been published on this topic showing the slow rate of testing and the obstacles of implementing EGFR testing. The analysis has multiple limitations as outlined in the second from last paragraph. It is therefore hard to draw firm conclusions from the data. Not sure, how this data is relevant in 2020 or how it would be used to advanced patient care or current public health policy in Kentucky. The conclusion that rural areas and poverty are barriers to providing health care have already been well documented. An analysis of current data and/or an analysis that examines specific barriers to EGFR testing (such as state policy on testing or laboratory specific barriers or educational programs for oncologists) would have been more impactful.

Comments to be addressed:

• It is unclear what this this study contributes to the field. The analysis appears to be 10 years too late to impact public health policy on precision medicine. Can you explain why this analysis is relevant in 2020? What is the status of EGFR or broad genomic testing for NSCLC in Kentucky in 2020?

• Can the authors speak more about access to EGFR testing in Kentucky? Was testing being done in Kentucky or was it being sent out of state? How many centers in Kentucky were doing EGFR testing during this time? Was there a state effort during this time to assist in EGFR testing?

• Can the authors discuss the barriers that individual oncologists faced with EGFR testing? Was there slow dissemination of knowledge among the healthcare team? What is the distribution of oncologists in regards to rural and metro locations?

• It is unclear if you are analyzing front line use of erlotinib or second-line use or erlotinib. Please clarify in the methods.

• Why was gefitinib not included in the analysis? It was FDA approved in 2003 as second line therapy in metastatic NSCLC.

• Discussion paragraph #5: The survival difference seen in those that had EGFR testing can also be attributed to younger age and because a higher proportion were most likely EGFR mutated and actually derived benefit from erlotinib.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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PONE-D-20-04879R1

EGFR testing and erlotinib use in non-small cell lung cancer patients in Kentucky

PLOS ONE

Dear Dr. Kolesar,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 07 2020 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.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Randall J. Kimple

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Since both reviewers raised the concern of novelty and relevance of the study, please ask the authors to explain why they did not choose to expand the analysis using the Kentucky Cancer Registry to years beyond 2011 to reflect the changing practice patterns in EGFR-driven NSCLC, rather than simply rephrasing their discussion. If this is feasible, it should done.

Reviewer #2: Table 4: Since EGFR screening is associated with younger non-smoking women (most likely a surrogate for selecting appropriate patients for testing), is it possible that younger non-smoking women were more likely to have private insurance and lower poverty? Have you performed any statistical tests to see if these are associated? If so, it is possible that being a young non-smoker woman is the most important variable associated with testing and not necessary access to testing.

Discussion paragraph 5: The conclusion that that the improved survival with EGFR testing and erlotinib "is likely due to those patients receiving better overall healthcare, relating to care access, insurance coverage or poverty status" is flawed and not supported by your data. Overall survival is most likely better because the patients that received EGFR testing were more likely to have an EGFR mutation and thus obtained benefit from erlotinib. You state that this is not the case because only 10-15% would be positive for the mutation. This 10-15% is for the general public. It is most likely that those receiving EGFR testing in your population have a high chance of having an EGFR mutation given they they are predominately younger non-smoking women. Also, a population enriched with 10-15% of patients with EGFR mutations receiving erlotinib can still be responsible for the overall survival benefit. If you want to make a conclusion that access to care leads to better survival that is fine. But use the metropolitan vs rural and medicaid/medicare vs private insurance analysis instead of the EGFR/erlotinib analysis to support this conclusion.

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7. PLOS authors have the option to publish the peer review history of their article (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.

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Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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. Please note that Supporting Information files do not need this step.

EGFR testing and erlotinib use in non-small cell lung cancer patients in Kentucky

PONE-D-20-04879R2

Dear Dr. Kolesar,

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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Kind regards,

Randall J. Kimple

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: While having more recent Kentucky Cancer Registry data would be better, all concerns were addressed by the authors.

Reviewer #2: The authors have addressed all of my concerns and have appropriately revised the manuscript. There are no new concerns.

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7. PLOS authors have the option to publish the peer review history of their article (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