Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice

Sushmita Rath; Prahalad Elamarthi; Pallavi Parab; Seema Gulia; Ravindra Nandhana; Smruti Mokal; Yogesh Kembhavi; Prema Perumal; Jyoti Bajpai; Jaya Ghosh; Sudeep Gupta

doi:10.1371/journal.pone.0253722

Peer Review History

Original SubmissionFebruary 4, 2021
19 Apr 2021 Decision Letter - Albiruni Abdul Razak, Editor PONE-D-21-03932 Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice PLOS ONE Dear Dr. Gupta, 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 Jun 03 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. 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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: I Don't Know Reviewer #2: I Don't Know ****** 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Interesting report. I have several technical comments: 1. There are 16 actual references, but in the text there are 17 . Due to the same miscalculation I would recommend to change efference numbers on page 6 , line 99 to 11-15, instead of 11-14. Line 100 at the same page - 14-15, instead of 15-16 . Line 143 on page 9 - change reference 17 to 16 . Line 295 on page 21 - change 16 to 15 2. Table 2, on page 14 : Febrile neutropenia -there are no Grade 1 or 2 in this adverse event . Please reevaluate the numbers. 3. Table 4 on page 16 : The total number of patients receiving subsequent treatment is 77 , and not 101. 4.Line 220 on page 16 : You may consider to add "disease" when describing "Stable disease ". 5. Don't feel that the study provide enough information about Ribociclib safety, while only 10 patients reported. I don`t think that there is significant value for this small sample. If one decide to proceed with the same group of patients, I would recommend to address drug specific side effects in more detailed way. For example neutropenic fever and liver enzymes elevation for each on of the drugs, or ECG changes for Ribociclib population. Reviewer #2: This is a retrospective review of 101 patients treated with CDK4/6 inhibitors with a focus on safety and efficacy. There has been several similar real world reports on this, however the authors do not explicitly state what is novel about this study. While there may be scant data on this in India, 80% of these patients received this treatment in 2nd line setting or later, and 50% third line or later. 87% had visceral disease and 56% had ECOG 2-3. And almost 20% were offered best supportive care after progression on this treatment. This is a heavily treated population with poorer prognostic characteristics, a very different patient profile than that seen in the PALOMA trials. And yet treatment was reasonably well tolerated with only 3% discontinuing due to toxicity which is important. While this aspect is mentioned in the author summary, it should be the focus of the paper, as it was not apparently clear from the abstract and even the title. There are much fewer studies providing real world data on CDK4/6 inhibitors in later lines as seen here. Due to the differences between patient populations in this study and that seen in the PALOMA trials, there should be less of an emphasis on efficacy comparisons. It would be good to provide clarification on why this treatment was not offered in the 1st line / second line (was it approved at that point or was access on a compassionate basis?). 45% of patients experienced Grade 3/4 neutropenia, it would be interesting to conduct a subgroup analysis and report what percentage of these patients had bone metastases. A similar subgroup analysis reporting duration of PFS intervals in responders to previous endocrine therapy would be interesting, if there was any difference vs non responders. Overall the study was well conducted however needs to be clear in stating how this work is different to previously reported studies evaluating safety and efficacy of CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer patients. ****** 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.0253722.r001
Revision 1
29 May 2021 Author Response Reply to Editor’s and Reviewers’ comments We thank the Editor and reviewers for their painstaking review of our manuscript and their helpful suggestions. The incorporation of these suggestions has improved the quality of our manuscript. We hope that the revised version will be found suitable for publication. EDITOR'S SPECIFIC COMMENTS: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Reply: We rechecked our manuscript formatting and it now meets PLOS ONE's style requirements. 2. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records/samples were accessed; c) the source of the medical records/samples analyzed in this work (e.g. hospital, institution or medical center name). Reply: a) All data were not fully anonymized when we accessed the records. b)The patients’ medical records were accessed between January 2016 and June 2019. This was mentioned in the ‘Methods’ section. c)The medical records were analysed from the electronic medical records of Tata Memorial Centre, Mumbai. 3. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Reply: The Competing Interest statement of the authors have been added to the cover letter 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers Reply: There are federal Indian regulations on providing access to data for individuals outside the country. All such requests have to be cleared by the Indian Health Ministry Screening Committee. The de identified data set will be provided to any interested researcher outside India after obtaining the required approval from the Health Ministry Screening Committee. For researchers inside India the de identified data can be provided with hospital Ethics Committee approval. Reviewer 1 1. There are 16 actual references, but in the text there are 17 . Due to the same miscalculation I would recommend to change efference numbers on page 6 , line 99 to 11-15, instead of 11-14. Line 100 at the same page - 14-15, instead of 15-16 . Line 143 on page 9 - change reference 17 to 16 . Line 295 on page 21 - change 16 to 15 Reply: We apologize for this error. There are 17 actual references. Reference no.11 and 12 were clubbed together as 11 inadvertently. Therefore, none of the references require a change in number. 2. Table 2, on page 14 : Febrile neutropenia -there are no Grade 1 or 2 in this adverse event . Please re-evaluate the numbers. Reply: Agreed, we have recalculated the numbers and revised Table 2 accordingly. 3. The total number of patients receiving subsequent treatment is 77 , and not 101. Reply : Agreed, we have changed the total number of patients receiving subsequent treatment in Table 4. 4. You may consider to add "disease" when describing "Stable disease ". Reply : Agreed, we have added "disease" while describing Stable disease " in line 232 on page no 18. 5. Don't feel that the study provide enough information about Ribociclib safety, while only 10 patients reported. I don`t think that there is significant value for this small sample. If one decide to proceed with the same group of patients, I would recommend to address drug specific side effects in more detailed way. For example neutropenic fever and liver enzymes elevation for each on of the drugs, or ECG changes for Ribociclib population. Reply: We agree with the reviewer that a definite conclusion about Ribociclib safety cannot be made from our study since only 10 patients had received this drug. It is important to note that none of the patients who received Ribociclib had ECG changes. As suggested, we have now provided adverse events to palbociclib and ribociclib separately, and accordingly revised Table 2. Reviewer 2 1. This is a retrospective review of 101 patients treated with CDK4/6 inhibitors with a focus on safety and efficacy. There has been several similar real world reports on this, however the authors do not explicitly state what is novel about this study. While there may be scant data on this in India, 80% of these patients received this treatment in 2nd line setting or later, and 50% third line or later. 87% had visceral disease and 56% had ECOG 2-3. And almost 20% were offered best supportive care after progression on this treatment. This is a heavily treated population with poorer prognostic characteristics, a very different patient profile than that seen in the PALOMA trials. And yet treatment was reasonably well tolerated with only 3% discontinuing due to toxicity which is important. While this aspect is mentioned in the author summary, it should be the focus of the paper, as it was not apparently clear from the abstract and even the title. There are much fewer studies providing real world data on CDK4/6 inhibitors in later lines as seen here. Reply : We thank the reviewer for the pertinent comment. We have now elaborated on this unique aspect of our cohort in the ‘Discussion’ (page no. 24, para 5, lines 320-327) 2. Due to the differences between patient populations in this study and that seen in the PALOMA trials, there should be less of an emphasis on efficacy comparisons. It would be good to provide clarification on why this treatment was not offered in the 1st line / second line (was it approved at that point or was access on a compassionate basis?). Reply: Only a small fraction (20 %) of our patients received CDK4/6 inhibitors as first line treatment although various guidelines recommend their use as first line therapy in hormone receptor positive metastatic breast cancer. It is worth noting that although CDK4/6 inhibitors have been approved in first line setting based on improvement in PFS, OS benefit has been unequivocally proven only in second line scenario. Therefore, use of CDK4/6 inhibitors in second or later lines is associated with shorter duration of their use and lower cost compared to their use in first line. Most patients in our country are not covered by health insurance and have to spend out of their pocket for treatment. Treatment with CD4/6 inhibitors in 1st line setting was offered to our patients when deemed appropriate depending upon the disease burden or financial status. This has now been added to the ‘Discussion’ (page no. 24, para 6, lines 328-340) 3. 45% of patients experienced Grade 3/4 neutropenia, it would be interesting to conduct a subgroup analysis and report what percentage of these patients had bone metastases. A similar subgroup analysis reporting duration of PFS intervals in responders to previous endocrine therapy would be interesting, if there was any difference vs non responders. Reply: We thank the Reviewer for this suggestion. 75% of patients who experienced grade ¾ neutropenia had bone metastasis while 74% of patients who did not develop grade ¾ neutropenia had bone metastasis. Thus the presence of bone metastases seems to be not correlated with the occurrence of neutropenia. This has now been added to the Results (page 15, para 1, lines 199- 202). We performed a subgroup analysis based on endocrine sensitivity. There was no difference in median PFS between endocrine sensitive and resistant patients [7.9 months (95% CI 4.9-10.9) versus 8.2 months (95% CI 0.9-15.5), respectively]. These points have now been added to the ‘Results’ (page 19, para 1, lines 248-251). 4. Overall the study was well conducted however needs to be clear in stating how this work is different to previously reported studies evaluating safety and efficacy of CDK4/6 inhibitors in metastatic hormone receptor positive breast cancer patients. Reply: We thank the reviewer for the encouraging comment. Our study population is more heavily pre-treated and with poorer performance status compared to earlier studies. We have shown that poorer performance status, at the beginning of CDK4/6 inhibitor therapy, is associated with worse overall survival and not the line of therapy. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253722.r002
11 Jun 2021 Decision Letter - Albiruni Abdul Razak, Editor Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice PONE-D-21-03932R1 Dear Dr. Gupta, 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, Albiruni Abdul Razak, MB MRCPI Academic Editor PLOS ONE Additional Editor Comments (optional): Dear Authors, You have responded satisfactorily to the suggestions and comments by the reviewers. No further suggestions from me The only outstanding issue, to my mind, is the response to the Editor re: the need for Indian Ministry of Health approval for data release if the need ever arises. Academic Editor PLOS ONE. Reviewers' comments: https://doi.org/10.1371/journal.pone.0253722.r003
Formally Accepted
14 Jul 2021 Acceptance Letter - Albiruni Abdul Razak, Editor PONE-D-21-03932R1 Efficacy and safety of palbociclib and ribociclib in patients with estrogen and/or progesterone receptor positive, HER2 receptor negative metastatic breast cancer in routine clinical practice Dear Dr. Gupta: 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. Albiruni Abdul Razak Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0253722.r004

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