Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France

Round 1

Reviewer 1 Report (Previous Reviewer 3)

Thank you for making the necessary changes. I recommend that the authors must cite the reference (PMID: 35759736). in the reference in Line 84 on Page 12 (Discussion section). Immunotherapy is fast becoming front-line standard of care for metastatic melanoma even with BRAF mutation. Hence, making that statement without citing a reference will not be useful for the manuscript.

Author Response

Thank you for this comment we have added the reference

Reviewer 2 Report (Previous Reviewer 2)

Author Response

Thank you verry much for this review

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

1.    The selection of the sample looks suspicious to me. "The 26 hospitals were selected based on their expertise in the treatment of MM, their infrastructure (a biobank was mandatory), and will to participate. "
2.    The authors took a French health insurance perspective. What are the available health insurance plans in France? Does French health insurance equal the national health insurance plan paid by the government? Is the government paying for all the treatment options under investigation?
3.    The cost of care should be specified -"Costs were assessed from the French health insurance perspective and were indicated in €2019, as previously described40. A monthly cost per treatment and per line was reported." The authors self-cited their previous publications but lacked a specification on what type of costs was considered in the current study. 
4.    "The cost-effectiveness analysis required adapting the code from tutorial of Williams et al.38,39 to incorporate the propensity score obtained by GBM, by taking into account the adjustment on multiple covariates. " I believe our audience is happy to see the code in the supplementary document. This study adopts advanced statistical analyses incorporating CEA and propensity score matching to adjust for the baseline characteristics. I am curious how that was achieved too.
5.    Did the authors implement the Markov model in R software?
6.    Did the authors discount costs and effects for the 5-year and 10-year sensitivity analyses? Reference 37 is not written in English, making it impossible for other non-French readers to access.
7.    What is the time horizon for the base case?
8.    It's hard for readers to follow the details from the self-cited publications. For example, "The MSM is based on regression models where each transition from one state to the other directly uses individual patient data from the MelBase cohort." The clarity will be improved if the authors show us the structure of the Markov model (if they are using it), model structure, input parameters, utility, and costs more systematically. 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

1. In 2.3 Data section, although propensity score was used to balance the two comparison groups, is there any other unmeasured confounder, residual confounding?

2. In 2.5 Utility estimates section, the author mentioned Utility scores per line and per treatment were obtained from individual patient data collected in MelBase cohort using the three-level EuroQol five-dimensional (EQ-5D 3L) questionnaire. Questionnaires were filled out by patients themselves and assessed at inclusion, every 3 months and at each change of melanoma therapy, until death. How was the response rate of the questionnaire, did all patients fill the questionnaire at inclusion, every 3 months and at each change of melanoma therapy?

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

The authors have presented a study of the cost-effectiveness of using multiple therapies in the French context for patients diagnosed with advanced melanoma. Although this is an exciting study, some important questions must be answered here. 

1. In today's date and age, chemotherapy is practically out of the door for patients with advanced melanoma as a first-line treatment. Barring very few unique case scenarios, this reviewer would be hard-pressed to imagine any melanoma expert recommending chemotherapy first. Hence, I would ask the authors why this has been chosen as a comparator arm. Although they acknowledge this issue in their limitation, I think for the lucidity of the manuscript, this part of the analysis should be in the subtext or at least presented last. 

2. Although I understand the importance of cost and financial toxicity of drug treatments, is there a way to understand and assess the impact of a patient's extended life span on the general society? For example, if a young entrepreneur is diagnosed with BRAF WT advanced melanoma and is treated with immunotherapy first, although in the general scheme of things he is receiving a lesser cost-effective treatment, his extended survival could mean more job creation and eventually a better impact on the society as a whole. Is there a way to assess this impact and factor in the cost-effectiveness?

3. More data is emerging from a scientific perspective that Immunotherapy with Ipi and Nivo first gives a better survival compared to BRAF/ MEK inhibitors first in patients with stage IV melanoma, at least from a scientific perspective (DREAMSeq and SECOMBIT trial). How does this manuscript view itself in terms of what will be the impact of understanding the cost-effectiveness of such an approach?

Author Response

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Author Response File: Author Response.docx