Cost-effectiveness of trastuzumab deruxtecan for previously treated HER2-low advanced breast cancer

Demin Shi; Xueyan Liang; Yan Li; Lingyuan Chen

doi:10.1371/journal.pone.0290507

Peer Review History

Original SubmissionFebruary 16, 2023
13 Jun 2023 Decision Letter - Mirosława Püsküllüoğlu, Editor PONE-D-23-04529Cost-effectiveness of Trastuzumab Deruxtecanfor Previously Treated HER2-Low Advanced Breast CancerPLOS ONE Dear Dr. chen, 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 Jul 28 2023 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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Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. 6. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This study evaluated the cost-effectiveness of trastuzumab deruxtecan (T-DXd) among HER2-Low advanced breast cancer (BC) patients, and the results showed that T-DXd is a cost-effective alternative to chemotherapy at willingness to pay threshold of $100,000/QALY. This discovery is intriguing and could have significant implications for the patients, clinicians and third-party payers. The methods are appropriate and results are reliable. However, I have several minor comments. 1. For subgroup analyses, why did you only focus on PFS, how about OS? How did the PFS variate? 2. For one-way sensitivity analyses among HER2- advanced BC patients (Supplementary Figure S2-C), the results showed that variation of the top 5 parameters might result in the ICER being over $100,000/QALY, which indicated that T-DXd was not cost-effective. How do we understand this result since you mentioned the results of this model are robust? 3. I did not find Figure 2 in the manuscript. 4. For the result of subgroup analysis, the manuscript stated “T-DXd was associated with lower HRs than chemotherapy in most of the subgroups”, how can conclude it from Table 3? 5. Is the T-DXd sole drug that is cost-effective for HER2-Low advanced BC patients? If not, what are the advantages of T-DXd? 6. I suggested that the coverage information of T-DXd in public healthcare systems such as Medicare should be added. Reviewer #2: The manuscript is technically sound. Only a few minor suggestions: Please clearly highlight the limitations of the study in the discussion section with some justifications There are some typo and grammatical errors so a proof reading is advised. Overall the paper is structured well. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Revision 1
7 Jul 2023 Author Response Dear Reviewers and Editors, Thank you for your extremely efficient and earnest work on our manuscript. The comments are all valuable and very helpful for revising and improving our paper. The main corrections in the manuscript and the response to the Referees' comments are listed below point by point: Reviewer(s)' Comments: Reviewer #1: This study evaluated the cost-effectiveness of trastuzumab deruxtecan (T-DXd) among HER2-Low advanced breast cancer (BC) patients, and the results showed that T-DXd is a cost-effective alternative to chemotherapy at willingness to pay threshold of $100,000/QALY. This discovery is intriguing and could have significant implications for the patients, clinicians and third-party payers. The methods are appropriate and results are reliable. However, I have several minor comments. 1. For subgroup analyses, why did you only focus on PFS, how about OS? How did the PFS variate? Reply: We conducted subgroup analyses to examine the variability in outcomes from different subgroups of patients with advanced HER2+ BC that were reported in the trials of DESTINY-Breast04. Due to the subgroup results of OS was not provided, we did not perform the subgroup analysis focus on OS. In the DESTINY-Breast04 trial, a consistent benefit was observed for trastuzumab deruxtecan across analyzed subgroups, trastuzumab deruxtecan showed superior activity over standard chemotherapy options in patients with HER2-low advanced breast cancer in most subgroups except for other race. Furthermore, the unstratified HR for PFS was shown in Table 3. For most subgroups in this study, the ICERs were greatly influenced by HRs, and trastuzumab deruxtecan performed better when the risks of death were lower. 2. For one-way sensitivity analyses among HER2- advanced BC patients (Supplementary Figure S2-C), the results showed that variation of the top 5 parameters might result in the ICER being over $100,000/QALY, which indicated that T-DXd was not cost-effective. How do we understand this result since you mentioned the results of this model are robust? Reply: Due to we considered a wider range of the base-case values (± 20%) for the parameters and ICER being very close to $100,000/QALY, the results showed that variation of the top 5 parameters might result in the ICER being over $100,000/QALY. In all cases, a suitable distribution was determined based on different parameters. In terms of cost parameters, proportion and probability, and baseline characteristics, gamma, beta, and normal distributions were assigned, respectively. We selected the justified distribution and sensitivity analysis undertaken to assess the robustness of estimates to this choice. In the past, the most common form of sensitivity analysis was to undertake a one-way analysis. Here estimates for each parameter are varied one at a time in order to investigate the impact on study results. A common way to present the results of a one-way analysis is in a ‘tornado diagram’. The impact that variation in each parameter has on the study result is shown by the width of the respective band. These diagrams are normally arranged so that the parameter in which variation has the biggest impact on the study result is at the top. A variant of one-way sensitivity analysis is to undertake a threshold analysis. Here the critical value(s) of a parameter or parameters central to the decision are identified. For example, a decision-maker might specify an increase in cost, or an ICER, above which the program would not be acceptable. Then the analyst could assess which combinations of parameter estimates could cause the threshold to be exceeded. Alternatively, the threshold values for key parameters that would cause the program to be too costly or not cost-effective could be defined. The decision-makers could then make a judgment about whether particular thresholds were likely to be breached or not. Hence, the conclusion of this study is that the result is robust. 3. I did not find Figure 2 in the manuscript. Reply: We have reuploaded Figure 2. 4. For the result of subgroup analysis, the manuscript stated “T-DXd was associated with lower HRs than chemotherapy in most of the subgroups”, how can conclude it from Table 3? Reply: The results were illustrated in Table 3, and the unstratified HR for PFS (95% CI) showed the results that T-DXd was associated with lower HRs than chemotherapy in most of the subgroups. 5. Is the T-DXd sole drug that is cost-effective for HER2-Low advanced BC patients? If not, what are the advantages of T-DXd? Reply: The aim of this study was to evaluate the cost-effectiveness of T-DXd vs. chemotherapy for previously treated HER2-low advanced BC, and the comparison of this study was T-DXd and chemotherapy, and no other drugs were evaluated. From a third-party payer's perspective in the United States, the findings of the cost-effectiveness analysis revealed that, at the current price, T-DXd is a cost-effective alternative to chemotherapy for patients with prior HER2-low advanced BC, at WTP threshold of $100,000/QALY, and this is the advantage of T-DXd. 6. I suggested that the coverage information of T-DXd in public healthcare systems such as Medicare should be added. Reply: Thank you for your suggestion. We have added that information in the section of discussion. The results of the one-way sensitivity analysis suggested that T-DXd cost was a sensitive variable. The price of T-DXd remains the most sensitive variable, and reducing the price of T-DXd is important to increase its feasibility. On August 5, 2022, the Food and Drug Administration approved trastuzumab deruxtecan for adult patients with HER2-low advanced BC who had received prior chemotherapy in a metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. However, T-DXd is not included in Medicare Part B in the United States. If Medicare Part B covers T-DXd and patients pay the Medicare Part B deductible, Medicare beneficiaries will have a certain percent co-insurance cost for T-DXd. The government announced American Patients First and aimed to construct a blueprint for cutting drug prices and reducing out-of-pocket payments in the United States [39, 40]. The availability of innovative treatments requires significant reductions in price and financial assistance. Reviewer #2: The manuscript is technically sound. Only a few minor suggestions: Please clearly highlight the limitations of the study in the discussion section with some justifications There are some typo and grammatical errors so a proof reading is advised. Overall the paper is structured well. Reply: Thank you for your suggestion. We have provided and highlight the limitations of the study in the discussion section with justifications. We have corrected the typo and grammatical errors in our manuscript and English has been edited and proofread by editage. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0290507.r002
10 Aug 2023 Decision Letter - Mirosława Püsküllüoğlu, Editor Cost-effectiveness of Trastuzumab Deruxtecan for Previously Treated HER2-Low Advanced Breast Cancer PONE-D-23-04529R1 Dear Dr. Chen 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, Mirosława Püsküllüoğlu, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0290507.r003
Formally Accepted
15 Aug 2023 Acceptance Letter - Mirosława Püsküllüoğlu, Editor PONE-D-23-04529R1 Cost-effectiveness of Trastuzumab Deruxtecan for Previously Treated HER2-Low Advanced Breast Cancer Dear Dr. chen: 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. Mirosława Püsküllüoğlu Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0290507.r004

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