Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer

Christine S. Walsh; Mitchell Kamrava; Andre Rogatko; Sungjin Kim; Andrew Li; Ilana Cass; Beth Karlan; Bobbie J. Rimel

doi:10.1371/journal.pone.0252665

Peer Review History

Original SubmissionOctober 22, 2020
1 Mar 2021 Decision Letter - Sudeep Gupta, Editor PONE-D-20-32083 Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer PLOS ONE Dear Dr. Walsh, 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 respond to the reviewers’ comments and submit a revised manuscript for consideration. Please submit your revised manuscript by Apr 15 2021 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, Sudeep Gupta, M.D. Academic Editor PLOS ONE Additional Editor Comments: Please revise the manuscript according to reviewers comments and resubmit. Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year), b) a statement as to whether your sample can be considered representative of a larger population, c) a description of how participants were recruited, and d) descriptions of where participants were recruited and where the research took place. 3. Thank you for stating the following in the Financial Disclosure section: "Funded by Merck Investigator Studies Program (MISP) grant #52261 to C.W. http://engagezone.msd.com/ds_documentation.php. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you received funding from a commercial source: Merck. Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] 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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: Yes ****** 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 ****** 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 ****** 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: The manuscript entitled ‘Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer’ with the aim to evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. The manuscript requires further improvement. Comments Abstract Page 3 Line 41, NCT02608684 to be omitted. Statistical analysis Page 10 Line 190-193, 1 or 2-tailed test to be stated. Attrition rates to be considered in the sample size calculation. Page 11 Line 198-199, if most of the analysis were descriptive and no hypothesis testing done, the significance level not to be mentioned. Results All the tables require formatting according to the journal format. Table 1 & 2, n to be replaced with N. At least one decimal point for the percentages Likewise with the figures in the text. For Table 2, n (%) to be clearly denoted on top. 'Any G, G3-4, grade' to be clearly spelled out or denoted in the table footnote. Table 2 & 3, the name for the column (first row) 4, 6 and 8 to be stated or combined. Table 4 to be placed in results section. m to be denoted in table footnote. Page 22 Line 326, median to be stated. Range to be replaced with IQR with a single value. Figure 1, the flowchart requires improvement and to separate the allocation group and to be clearly structured according to the process. Figures 2, 3 and 4 difficult to be visualized and requires enlargement. Limitation of the study to be discussed. References list presentation to follow journal format. Reviewer #2: The authors provide us with a very well designed and carried out trial. It is evident that all the Ts have been crossed and Is dotted throughout the preparation and the conduction of this trial. The issue of the addition of immunotherapy to this tough subgroup of patients with ovarian cancer is of utmost importance and I commend the authors on the effort. The manuscript is very well written, the methods and results clearly explained and the discussion thorough. A few questions and remarks: 1. was PDL1 tested on the tumors and if so can this be reported? If not - please discuss why not. 2. was MSI evaluated on the tumors in all patients or IHC for MMR proteins performed? If so can this be reported? If not - please discuss why not. 3. Discussion - 427-438: this paragagraph is a duplicate of a simillar paragraph in the results section. It is important for the discussion but should be shorter and more concise now that it is discussed. ****** 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 [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. https://doi.org/10.1371/journal.pone.0252665.r001
Revision 1
10 Apr 2021 Author Response Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer Response to Editor and Reviewer Comments Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf The figures and supplementary files have been renamed to meet PLOS ONE’s style requirements. The figures have been renamed “Fig1.tif”, etc. The supplementary files have been renamed “S1 Protocol”, etc. 2. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year), b) a statement as to whether your sample can be considered representative of a larger population, c) a description of how participants were recruited, and d) descriptions of where participants were recruited and where the research took place. We have included this additional information in our methods. The trial was posted on clinicaltrials.gov (track changes manuscript, page 11, line 221). The recruitment date range was from 2/2016 to 11/2018 (page 12, line 223). Participants were recruited from patients receiving care at Cedars-Sinai Medical Center or were self-referred or referred from their physician at another institution (page 12, line 224-226). All research took place at Cedars-Sinai Medical Center (page 12, line 226-227). 3. Thank you for stating the following in the Financial Disclosure section: "Funded by Merck Investigator Studies Program (MISP) grant #52261 to C.W. http://engagezone.msd.com/ds_documentation.php. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you received funding from a commercial source: Merck. Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests We have updated the Competing Interests Statement and have included it within the cover letter. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Captions for Supporting Information files have been added at the end of the manuscript. There are no in-text citations to these materials. The supporting information files have been re-named to match the captions (track changes manuscript, p. 36). Reviewers' comments: Reviewer #1: The manuscript entitled ‘Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer’ with the aim to evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. The manuscript requires further improvement. Comments Abstract Page 3 Line 41, NCT02608684 to be omitted. Reference to the NCT number has been omitted (track changes manuscript, p. 3). Statistical analysis Page 10 Line 190-193, 1 or 2-tailed test to be stated. Attrition rates to be considered in the sample size calculation. The statistical analysis description was updated to reflect use of a one-tailed test and the subject replacement strategy for any participants that discontinued trial participation prior to receiving pembrolizumab with cycle 3. Attrition rates were not otherwise considered in the sample size calculation (track changes manuscript, p. 11). Page 11 Line 198-199, if most of the analysis were descriptive and no hypothesis testing done, the significance level not to be mentioned. Mention of the significance level has been omitted (track changes manuscript, p. 11). Results All the tables require formatting according to the journal format. All of the tables have been formatted according to the journal format. Table 1 & 2, n to be replaced with N. At least one decimal point for the percentages Likewise with the figures in the text. In Tables 1 & 2, N has been replaced with n. Percentages have been updated to include one decimal point in the tables and in the text. For Table 2, n (%) to be clearly denoted on top. 'Any G, G3-4, grade' to be clearly spelled out or denoted in the table footnote. “n (%)” has been added and “Any Grade” and Grade 3-4” have been spelled out at the top of tables 2 and 3. Table 2 & 3, the name for the column (first row) 4, 6 and 8 to be stated or combined. In Tables 2 &3, the cells in the first row have been merged per the reviewer’s suggestion. Table 4 to be placed in results section. m to be denoted in table footnote. Table 4 has been placed in the results section. “m” has been defined as “months” in the footnote (track changes manuscript, p. 28-29). Page 22 Line 326, median to be stated. Range to be replaced with IQR with a single value. This line has been edited to clarify this is a median duration of response. The range has been replaced with the interquartile range (track changes manuscript, p. 24). Figure 1, the flowchart requires improvement and to separate the allocation group and to be clearly structured according to the process. Figure 1 has been revised to clearly describe the allocation group and is structured according to the journal guidelines. Figures 2, 3 and 4 difficult to be visualized and requires enlargement. Figures 2, 3, and 4 have been created as high-quality tif files that are at least 300 dpi resolution per journal formatting guidelines. Limitation of the study to be discussed. We have modified our discussion to discuss the limitations of our study (track changes manuscript, p. 31-32). References list presentation to follow journal format. The reference list presentation has been updated to Vancouver style to follow the journal format (track changes manuscript, p. 34-36). Reviewer #2: The authors provide us with a very well designed and carried out trial. It is evident that all the Ts have been crossed and Is dotted throughout the preparation and the conduction of this trial. The issue of the addition of immunotherapy to this tough subgroup of patients with ovarian cancer is of utmost importance and I commend the authors on the effort. The manuscript is very well written, the methods and results clearly explained and the discussion thorough. A few questions and remarks: 1. was PDL1 tested on the tumors and if so can this be reported? If not - please discuss why not. Tumor PD-L1 immunohistochemistry was performed, and this data are reported in the revised manuscript. 75% of evaluable tumors demonstrated PD-L1 expression. There was no association between PD-L1 expression and response to treatment. A paragraph was added to materials and methods (track changes manuscript, p. 10) and to results (track changes manuscript, p. 26). 2. was MSI evaluated on the tumors in all patients or IHC for MMR proteins performed? If so can this be reported? If not - please discuss why not. Mismatch repair IHC was not performed as part of the clinical trial protocol. We re-reviewed original pathology reports to collect data on clinical MMR IHC testing and found testing was done on one patient, our exceptional responder. The manuscript reports intact MMR IHC results for this patient (track changes manuscript, p. 27). 3. Discussion - 427-438: this paragraph is a duplicate of a similar paragraph in the results section. It is important for the discussion but should be shorter and more concise now that it is discussed. The paragraph in the discussion has been modified and shortened to avoid redundancy with the prior paragraph in the results section (track changes manuscript, p. 31). Additional revisions: Author affiliations have been updated (track changes manuscript, p. 1-2). Minor edits were made in the introduction (track changes manuscript, p. 5) Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0252665.r002
20 May 2021 Decision Letter - Sudeep Gupta, Editor Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer PONE-D-20-32083R1 Dear Dr. Walsh 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Sudeep Gupta, M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): The manuscript is now suitable for publication. Reviewers' comments: https://doi.org/10.1371/journal.pone.0252665.r003
Formally Accepted
24 May 2021 Acceptance Letter - Sudeep Gupta, Editor PONE-D-20-32083R1 Phase II trial of cisplatin, gemcitabine and pembrolizumab forplatinum-resistant ovarian cancer Dear Dr. Walsh: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Sudeep Gupta Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0252665.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .