-->PONE-D-25-61423-->-->Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States-->-->PLOS One

Dear Dr. Denu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that your study has some merit but both reviewers indicate that there are significant flaws that need to be addressed before a final decision can be made. -->--> -->-->Specifically, both reviewers felt strongly that that the authors overstated their findings. Furthermore, some questions about methodology, clinical meaningfulness and overall presentation were raised. Please address all of these points in a revised version of the manuscript.

Please submit your revised manuscript by Apr 02 2026 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:-->

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We look forward to receiving your revised manuscript.

Kind regards,

Anette Duensing, M.D.

Academic Editor

PLOS One

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“This work was funded by Bayer HealthCare Pharmaceuticals, Inc. Notwithstanding those employed by Bayer, authors were not paid to participate. The funders, other than the named authors, did not play a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

We note that one or more of the authors is affiliated with the funding organization, indicating the funder may have had some role in the design, data collection, analysis or preparation of your manuscript for publication; in other words, the funder played an indirect role through the participation of the co-authors.

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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: No

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

Reviewer #1: Yes

Reviewer #2: No

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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 manuscript addresses an important but narrow real-world question: how regorafenib is being used in US patients with GIST outside of clinical trials, particularly regarding line of therapy and dosing. The topic is relevant, and the use of a large claims database is appropriate for utilization questions. However, the clinical inferences exceed what the data can support, and there are methodologic, interpretive, and presentation issues that substantially limit impact in its current form.

The manuscript would benefit from tightening its objectives, clarifying what can and cannot be concluded, and reducing causal language. As written, it risks overstating practice-changing implications from descriptive claims data.

Claims-based DOT and TTNT are weak surrogates for clinical benefit and should not be framed as efficacy proxies.

Recommendation:

Reframe the study explicitly as a treatment utilization and sequencing analysis, not an outcomes study. Avoid language implying benefit, tolerance, or superiority.

Overinterpretation of DOT and TTNT: DOT and TTNT are heavily confounded by:

o Physician preference

o Toxicity management strategies

o Access and insurance

o Planned treatment breaks

Statements suggesting longer DOT reflects better tolerance or response are speculative and unsupported.

Recommendation: Replace with neutral phrasing:

“Differences in DOT may reflect prescribing patterns, patient selection, or administrative factors rather than treatment effectiveness.”

Line of therapy classification is fundamentally incomplete and not reflect access to drugs through patient assistance programs.

This limitation should be moved from a minor limitation to a central interpretive caveat and reiterated in the Discussion conclusions.

The following statements are overreaching:

Despite guideline recommendations as an established third-line therapy, regorafenib may be used in earlier lines in the real world, perhaps for its ability to target a wide range of cancer pathways.- there is no data to substantiate this claim for the real world- and this may be misleading.

Discussion statement- The earlier use of regorafenib may be due to physician preference or patient- or market-specific drivers, such as mutation profiles, including KIT activation loop mutations (exon 17 or 18) or SDH deficient GIST which are more responsive to regorafenib and resistant to sunitinib- is completely unfounded with no data.

Does this comment truly represent the time period of the data or is this relevant to today?- potential inaccessibility of sunitinib for some patients, as it is now off patent and does not have any available financial assistance programs.

Reviewer #2: Line 88-89: "This lack of available data highlights a potential practice gap". This sentence is unclear. Perhaps the authors meant to say "The lack of available data limits our ability to determine practice patterns," or similar?

Line 107: Note "error" RE reference. Several other instances in manuscript.

Line 128: CCI score; to simplify for the reader, could you add what the categories mean by including something like: "Briefly, lower CCI score indicates fewer serious comorbidities..." and consider specifying why you split into cohorts of score 2-3 vs score 4+ (from table 1).

Line 138-139: Table 1 subgroups and stratification should line up with the categories listed here. Rather than putting "ie" I suggest detailing exactly what your subgroups are. Keep this consistent with text and figures. In the table for example, "pazopanib" is a header and it is not clear if this means pazopanib only vs any exposure to pazopanib. Further, since ripretinib was FDA approved during the study period (and since it is also an activation loop inhibitor, I suggest adding it as a subgroup. I also noted that sorafenib is listed in table 1, but here, avapritinib is listed. Finally, a big concern about these data is that many of the patients included in the study may have accessed TKI with patient assistance programs or as participants on clinical trials. I assume these data cannot capture this. Perhaps one sensitivity analysis could exclude any patients with a >3 month gap in therapies since we know that most patients with GIST are continuously on TKI therapy. This would hopefully remove any patients who were exposed to unknown TKI therapies.

Line 142: "Groups were also stratified by initial regorafenib dose..." Some clinicians start TKI at a lower dose and escalate as tolerated, and the initial RX may reflect this strategy. Would it be possible to analyze the dose that the patient received most during their time on treatment (acknowledging that some may be at a lower dose due to toxicity).

Line 172: how were the remaining cases categorized (the ones included do not add up to 100%)?

Table 1: typo in header "measured at any point in before index date period". Remove "in"?

Line 187: include “n” for each cohort in body of text (prior IM or SU vs IM+SU)

Line 190: Sentence fragment, please revise. Also include “n” for each cohort (LD vs RSD).

Line 205-206: Without clinical context, I do not think including that 3 patients underwent surgery adds any information. Consider removing.

Line 211-216: include “n” for each cohort (prior IM or SU vs IM+SU; LD vs RSD).

Line 217: Remove “slightly shorter”. These numbers are essentially the same so I suggest leaving out that description. You can just report the median TTNT for each cohort.

Line 221-226: The opening sentence is correct- although I still question whether it is clinically meaningful- but the second sentence RE LD vs RSD is overstated in my opinion. 103 vs 94.5 days are so similar and to highlight that patients on LD have longer DOT seems misleading.

Line 239-242: I suggest commenting on whether result is statistically significant and clinically meaningful to warrant additional evaluation. Further, therapies used in earlier lines often have better clinical outcomes than when used in later lines, yet they may not be better than the approved earlier-line therapies.

Line 245-246: Again, I suggest softening language here and mentioning that difference is similar and not clinically meaningful (1.5 weeks different).

Line 248: I did not see underrepresented status indicated in Table 1. Please define what is meant here.

Line 278-288: You may also mention that treatments received on clinical trials are not captured in these data.

Line 290-291: I think given the limitations of this data type, it is challenging to make any conclusions about utilization patterns.

Line 292-294: As mentioned many times, 1.5 weeks difference should not be highlighted as a true difference. Please revise.

Line 294-295: I’d suggest including more nuance if there is really a case for additional studies. Do you suggest a randomized trial evaluating regorafenib vs sunitinib, or bezuclastinib/sunitinib in 2nd line? Or regorafenib vs ripretinib for activation loop secondary mutations? This does not seem feasible and I’m not sure what additional studies should be done here.

Line 295-297: be sure to include US population; studies exist in other countries.

Line 297-298: I disagree with the conclusion that this adds nuance to the understanding of regorafenib treatment patterns and clinical outcomes. I am also not sure what “insufficiently characterized patient population” means.

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-->6. 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

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[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 ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->PONE-D-25-61423R1-->-->Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States-->-->PLOS One

Dear Dr. Denu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that the manuscript has improved but some small issues remain. We invite you to submit a revised version of the manuscript that addresses the points raised during this second review process.

Please submit your revised manuscript by May 29 2026 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Anette Duensing, M.D.

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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: (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

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

-->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: All comments appreciated. No further recommendations.

Appreciate the time and effort to make the changes.

Reviewer #2: Please update the abstract, (line 59) first sentence in the conclusion to conclude that TTNT *and* DOT were similar for LD and RSD.

Please correct the sentence in the abstract (line 54): "Patients who received prior imatinib or sunitinib alone

54 before regorafenib reported a numerically longer median DOT". ...The patients did not "report". You can say, for example, "The data showed that patients who received...had a numerically longer median DOT."

Please the language for the sentence in the abstract (line 56): "LD demonstrated a longer median DOT compared to RSD" and instead indicate that they are similar.

**********

-->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

**********

[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 ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Real-world regorafenib use among patients with advanced gastrointestinal stromal tumor in the United States

PONE-D-25-61423R2

Dear Dr. Denu,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

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,

Anette Duensing, M.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: