Cost-Effectiveness of Pyrotinib Plus Capecitabine versus Lapatinib Plus Capecitabine for the Treatment of HER2-Positive Metastatic Breast Cancer in China: A Scenario Analysis of Health Insurance Coverage
Round 1
Reviewer 1 Report
This is an informative paper for the Chinese health care situation. A link to other countries or a comparison to cost-effectiveness of other second line treatments is missing and would improve the content of the paper. This especially when pyrotinib is planned to be submitted for approval in other countries then China.
Abstract: In the title of the paper and at first in the abstract, it is said that pyrotinib is compared to lapatinib. In the conclusion of the abstract, it is pyrotinib versus lapatinib plus capecitabine. In the introduction it is in the end Pyr+Cap versus Lap+Cap. Please be consequent. Furthermore, please explain in the introduction why Pyr is compared to Lap and not another second line treatment. Is Lap+Cap standard of care in China?
Line 35: “chief diagnosed cancer” is a strange way of describing that BC has taken the lead. Alternative: “has replaced lung cancer as the most often diagnosed cancer”.
Line 38: it is not the “female BC ….. getting younger” but women get BC at a younger age.
Line 68-69: “Pyrotinib, a second-generation irreversible….” should be “Pyrotinib, is a second-generation irreversible…..
Line 69-67: independently developed -> independently of what?
Line 78-82: please include results on PFS and if available OS
Line 86 “of which were generally tolerated and easily manageable.” -> “which were generally well(?) tolerated and…..”
Material and Methods.
Patients and treatments: It is somewhat unclear whether the analysis is based on outcomes from clinical trials (Because the clinical data was obtained from the published report of clinical trials) or there was a new trial going on? (The demographic characteristics of the study were similar to those of the PHOEBE-3 and NCT02422199 trials[26,27]. Eligible patients were 18 to 70 years of age, had pathologically confirmed HER2-positive)
Utility values: Are no differences in utilities expected between Pyr and Lap?
Results.
Base case: it is somewhat confusion to write of a “gain of 1.85 QALYs” for Pyr-B and “While….additional 0.53 QALYs” in Pyr-A, somehow suggesting a difference between the two in QALYs, while there is none. This also for the Abstract. As the difference in the ICER only comes from the difference in the costs for Pyr, I suggest to describe this differently putting the focus on the cost differences.
Time horizon:
I do not understand the “extrapolation” scenarios for time horizon as in methods it is said for the model that “the time horizon was set to be a lifetime”. So 5 and 10 years is less then lifetime and not an extrapolation?
Line 276-277: what do you mean by “the average age of BC”should it be BC patients?
Line 283-284: When the price of Pyr-A diminished it was more “effective”? How can that be? By lowering a price, a drug becomes more effective?
Line 285-287: sentence unclear, please rephrase
Line 294: “a Chinese innovative anti-cancer drug had been approved in China…” should be “a Chinese innovative anti-cancer drug approved in China…”
Discussion.
General: it would be good for the international reader to somewhere see ICERs expressed in US$ of €.
Line 306: “being economic” you mean “being cost-effective”?
Line 318: “has been proved” maybe better use “has been proven”
Line 346-347: How can “possible implications” be “consistent with a research hypothesis”, and what was this hypothesis? As it has not been described in the introduction
Line: 348-249: “it was further confirmed the distinct advantages of its inclusion in NRDL for patients,” change into: “the distinct advantages of its inclusion in NRDL for patients was further confirmed”
Line 368-369: what do you mean by domestic and foreign?
Line 377: “which far beyond payment burden.” Should be “which is far beyond payment burden”.
Appendix B scatter plots:
If possible, please use (at least for the x-axis (QALYs)) the same range and scale. Now both scatter plots look in there scape quite different. As the effect of QALY should be the same for both regiments in Pyr the distribution of the dots on the X-axis should be similar in range. And while in Pyr-A the range for costs is between circa 268.000-308.000 (delta 40.000), for Pyr-B delta is circa 30’000(?) both shapes of the scatters should be similar. The different look only comes because of different ranges in axis.
Author Response
Response to Reviewer 1
[General Comment] This is an informative paper for the Chinese health care situation. A link to other countries or a comparison to cost-effectiveness of other second line treatments is missing and would improve the content of the paper. This especially when pyrotinib is planned to be submitted for approval in other countries then China.
Response: Thank you very much.
[Point 1] In the title of the paper and at first in the abstract, it is said that pyrotinib is compared to lapatinib. In the conclusion of the abstract, it is pyrotinib versus lapatinib plus capecitabine. In the introduction it is in the end Pyr+Cap versus Lap+Cap. Please be consequent.
Response 1:
Thank you so much for your suggestions. According to your suggestions, we have modified our text as follows:
The expression of the treatment strategies have been unified as pyrotinib plus capecitabine (pyrotinib regimen) and lapatinib plus capecitabine (lapatinib regimen) in the manuscript. (see Page1,line 2-3/line 15-16/line 28; Page7,Table2-the expression of treatments; Page8, line 286/line 289/line 294-296; Page9, line 299-301/ line 305-306; Page10, line316-317; Page11, line322-323; Page12, line372)
[Point 2] Furthermore, please explain in the introduction why Pyr is compared to Lap and not another second line treatment. Is Lap+Cap standard of care in China?
Response 2:
The reason why chose lapatinib was as follows. First, both pyrotinib and lapatinib belong to tyrosine kinase inhibitors, which are similar in structure and target sites. Second, they are standard treatment drugs recommended by CSCO, and they are also suitable for second-line treatment of advanced HER2-positive BC after tolerance of trastuzumab. Background characteristics were comparable between the two drugs. Moreover, in China, recommended optional drugs for second-line treatment of HER2-positive metastatic BC were scarce. T-DM1, another guideline recommended drug, is an antibody-drug conjugate. Its mechanism of action is different from that of pyrotinib and lapatinib. At the same time, there have been international pharmacoeconomic studies on T-DM1, so in our study it is excluded. Third, though there were several clinical trials on the efficacy and safety of pyrotinib and lapatinib, the research on pharmacoeconomics between two drugs is lacking.(see Page 2, line 96-97; Page 3, line98-112)
The answer to "Is Lap+Cap standard of care in China?" should be "yes". Lapatinib plus capecitabine is one of the standard therapies recommended by CSCO, and it was the only first-class recommended therapy until 2020.
[Point 3] Line 35:"chief diagnosed cancer" is a strange way of describing that BC has taken the lead. Alternative: "has replaced lung cancer as the most often diagnosed cancer".
Response 3: We have modified our text as advised. (see Page1, line 38)
[Point 4] Line 38: it is not the "female BC ….. getting younger" but women get BC at a younger age.
Response 4: We have modified our text as advised. (see Page1, line 41-42)
[Point 5] Line 68-69:"Pyrotinib, a second-generation irreversible...." should be "Pyrotinib, is a second-generation irreversible...
Response 5: We have modified our text as advised. (see Page2, line 72)
[Point 6] Line 69-72:independently developed→independently of what?
Response 6:
Here "independently developed" means pyrotinib is an independent research and development drug. In other words, pyrotinib is an innovative drug developed by the Chinese indigenous pharmaceutical company (Jiangsu Hengrui Medicine Co.,Ltd.). The company has all of its proprietary intellectual property and manufacturing technology. We have modified our text accordingly. (see Page2, line 73-75)
[Point 7] Line 78-82: please include results on PFS and if available OS
Response 7: We have added some data in the manuscript as advised. (see Page 2,line 82-84/ line 87-90)
[Point 8] Line 86 "of which were generally tolerated and easily manageable." -> "which were generally well(?) tolerated and….."
Response 8: We have modified our text as advised. (see Page2, line 94-95)
[Point 9] Material and Methods. Patients and treatments: It is somewhat unclear whether the analysis is based on outcomes from clinical trials (Because the clinical data was obtained from the published report of clinical trials) or there was a new trial going on? (The demographic characteristics of the study were similar to those of the PHOEBE-3 and NCT02422199 trials[26,27]. Eligible patients were 18 to 70 years of age, had pathologically confirmed HER2-positive)
Response 9:
Our research was based on the outcomes of published clinical trials, which were registered as ClinicalTrials.gov, NCT03080805 and NCT02422199. The demographic characteristics of the two clinical trials were similar and could be summarized as follows. First, eligible patients were 18 to 70 years of age, had pathologically confirmed HER2-positive relapsed or metastatic BC, and had previously been treated with trastuzumab. Second, they all received up to two prior lines of chemotherapy and they were 50-year-old on average.
We have also explained in the manuscript to clear that the research was based on the existing clinical trials rather than a new trial going on. (see Page 3, line 126-129)
[Point 10] Utility values: Are no differences in utilities expected between Pyr and Lap？
Response 10:
Yes, the pyrotinib and lapatinib groups has the same utility values. There was no specific study on the health utility value of patients who taking pyrotinib and lapatinib globally. Instead, relevant studies usually focused on measuring the health utility value of a certain disease. Since both pyrotinib and lapatinib were used to treat HER2-positive metastatic breast cancer, we employed the utility values of metastatic breast cancer to indicate the health utility value of patients taking pyrotinib and lapatinib. The health utility values could be considered to be representative, for the reason that the utility evidence was consistent with the research population---the utility evidence was from China, and our study was based on Chinese population.
We have added the explanation in the manuscript. (see Page 6, line 231)
[Point 11] Results. Base case: it is somewhat confusion to write of a "gain of 1.85 QALYs" for Pyr-B and "While….additional 0.53 QALYs" in Pyr-A, somehow suggesting a difference between the two in QALYs, while there is none. This also for the Abstract. As the difference in the ICER only comes from the difference in the costs for Pyr, I suggest to describe this differently putting the focus on the cost differences.
Response 11:
Thank you for your kind reminders. We have modified the results and the abstract to make the results clearer. Compared with lapatinib regimen, the QALYs of pyrotinib-A and pyrotinib-B are both 0.53, but the incremental costs of them are different, which leads to significant differences in ICER. (see Page 1, line 23-26; Page 7, line 261-268/ Table 2)
[Point 12] Time horizon: I do not understand the "extrapolation" scenarios for time horizon as in methods it is said for the model that "the time horizon was set to be a lifetime". So 5 and 10 years is less then lifetime and not an extrapolation?
Response 12:
Yes, I agree with you. Indeed, a lifetime horizon includes 5 and 10 years of disease course. 5 and 10 years are not an extrapolation, it is an error expression in manuscript. Patients with breast cancer usually live for an average of 27 years. The initial purpose of set it in the background of 5 and 10 years was to find out whether the economic benefits of pyrotinib before and after being enrolled in NRDL have changed compared with those of lapatinib within a relatively short time. For example, the difference in ICER is not so significant. As a result, the observation time of 5 and 10 years have the same findings as that of lifetime. In order to correct the misunderstanding, we have deleted the "extrapolation analysis" in the manuscript.
We have modified our text accordingly. (see Page11, line 328-334)
[Point 13] Line 276-277: what do you mean by "the average age of BC" should it be BC patients?
Response 13: Yes. We have modified as "the average survival time of BC patients ". (see Page11, line 329-330)
[Point 14] Line 283-284: When the price of Pyr-A diminished it was more "effective"? How can that be? By lowering a price, a drug becomes more effective?
Response 14:
This part was not clearly stated, which led to ambiguity. We would like to express that when the price of Pyr-A diminished by half, the cost-effectiveness of Pyr-A plus CAP would be improved under the condition of unchanged QALYs. To put it simply, the ICER of Pyr-A regimen would be improved. Because according to the formula ICER= Cost/QALYs, the lower the price, the better the ICER, and it was more advantageous compared with the WTP threshold.
We have modified our text accordingly. (see Page 11, line 336-344)
[Point 15] Line 285-287: sentence unclear, please rephrase
Response 15:
We have modified our text as follows: In the setting where pyrotinib was enrolled in NRDL, lapatinib regimen would not be cost-effective even if lapatinib with 100% price reduction according to the results of the comparison between the pyrotinib-B and lapatinib regimens. (see Page 11, line 344-348)
[Point 16] Line 294: "a Chinese innovative anti-cancer drug had been approved in China…" should be "a Chinese innovative anti-cancer drug approved in China…"
Response 16: We have modified our text as advised. (see Page 12, line 355)
[Point 17] General: it would be good for the international reader to somewhere see ICERs expressed in US$ of €.
Response 17:
In the manuscript, the monetary values in Chinese Yuan Renminbi (RMB) have been converted into United States dollars (US$) based on the average exchange rate in 2021 (1 RMB = 0.15502 US$).
We have modified our text as advised. (see Page 1, line 23-26; Page 4, line 177-181; Page 5, line 192/ Table 1; Page6 Table1/ line 212; Page 7, line 261-268/ Table 2; Page 8-9, Figure 3-4; Page 9, line 306-310; Page 10, Figure 5; Page 11, line 339/ Table 3/ Figure6; Page 12, line 368; Page 14-17, Table A2/ Table A3/ Figure A1)
[Point 18] Line 306: "being economic" you mean "being cost-effective"?
Response 18:
Yes. We felt sorry that the improper use of the word leads to the deviation of understanding. What we would like to express is that the meaning of cost performance in Chinese understanding. However, in English comprehension, economic and cost-effectiveness are irrelevant.
We have modified our text accordingly. (see Page 12, line 365-371)
[Point 19] Line 318: "has been proved" maybe better use "has been proven"
Response 19: We have modified our text as advised. (see Page 12, line 397)
[Point 20] Line 356-357: How can "possible implications" be "consistent with a research hypothesis", and what was this hypothesis? As it has not been described in the introduction
Response 20:
The research hypothesis has been supplemented in the introduction section. Specifically, though the impact of the national medical insurance price negotiation on the economics of certain innovative anti-cancer medicine in China is unknown. Therefore, we hypothesized that the national drug price negotiation reduced the price of pyrotinib, thus increasing the cost-effectiveness of the treatment containing this innovative anti-cancer medicine without modifying clinical efficacy.
And due to lack of pharmacoeconomic evaluation studies on pyrotinib have been developed worldwide. Our study is helpful to verify the economic value of pyrotinib. Considering the significant changes in pyrotinib price before and after the national price negotiation, the distinct advantages of its inclusion in NRDL for patients was further confirmed. It also provided evidence and guidance for national negotiation of drug price renewal in reverse. We have modified in the manuscript accordingly. (see Page 3, line 112-117; Page 13, line 426-431)
[Point 21] Line: 348-249: "it was further confirmed the distinct advantages of its inclusion in NRDL for patients," change into: "the distinct advantages of its inclusion in NRDL for patients was further confirmed"
Response 21: We have modified our text as advised. (see Page 13, line 428-429)
[Point 22] Line 368-369: what do you mean by domestic and foreign?
Response 22:
The expression "domestic and foreign" may not be appropriate, actually, what I mean is global. Pyrotinib is a drug developed locally in China. Although it is one of the recommended therapeutic drugs for advanced BC patients in China, it has not been widely used all over the world. The analysis of this study was only based on the Chinese population, lacking evidence from other populations, so there was no comparison between BC patients from different countries. It could be one of the limitations of the study.
We have modified our text as accordingly. (see Page 13, line 447-453)
[Point 23] Line 377: "which far beyond payment burden." Should be "which is far beyond payment burden".
Response 23: This sentence has been replaced. Because another reviewer suggested making the conclusion clearer.(see Page 13, line 462-464)
[Point 24] Appendix B scatter plots: If possible, please use (at least for the x-axis (QALYs)) the same range and scale. Now both scatter plots look in there scape quite different. As the effect of QALY should be the same for both regiments in Pyr the distribution of the dots on the X-axis should be similar in range. And while in Pyr-A the range for costs is between circa 268.000-308.000 (delta 40.000), for Pyr-B delta is circa 30’000(?) both shapes of the scatters should be similar. The different look only comes because of different ranges in axis.
Response 24: We have modified our text as advised. (see Page 16-17, Figure A1)
Author Response File: 
Author Response.docx
Reviewer 2 Report
The research question is essentially to measure the cost-effectiveness of pyrotinib versus lapatinib for the treatment of HER2-positive metastatic breast cancer in China.
I think there is no source information in lines 10-12, please explain. particularly this sentence “Recent clinical trials showed that pyrotinib has promising antitumor activity and acceptable tolerability for those patients. Because it seems to me that this study is entirely based on its findings. If this source is valid then this research is relevant in the field.
As this study is done considering the socio-economic condition of a country, therefore, I think it is acceptable in that context based on another previous study.
Since this paper tries to highlight the issue of comparative cost considering the socio-economic status of a specific country, I think it is better to be a little clearer about the data collection of the study and also mention the limitations of the study.
The conclusion can be made clearer and more beautiful if the author mentions the limitations of the research results, i.e. about its generalizability.
The references are appropriate. The reference depends on generalizability. Since this research has tried to highlight the issue of comparative cost considering the socio-economic status of a country, thus, it can be accepted.
Author Response
Response to Reviewer 2
[General Comment] The research question is essentially to measure the cost-effectiveness of pyrotinib versus lapatinib for the treatment of HER2-positive metastatic breast cancer in China.
Response: Thank you very much.
[Point 1] I think there is no source information in lines 10-12, please explain. particularly this sentence “Recent clinical trials showed that pyrotinib has promising antitumor activity and acceptable tolerability for those patients. Because it seems to me that this study is entirely based on its findings. If this source is valid then this research is relevant in the field.
Response 1:
Our research was mainly based on results of published clinical trials, which were registered as ClinicalTrials.gov, NCT03080805 and NCT02422199 [1-2]. Both of their findings showed that pyrotinib has promising antitumor activity and acceptable tolerability for patients with HER2-positive metastatic BC. On the one hand, pyrotinib has better drug resistance and effectively prolongs PFS. Specifically, both trials demonstrated that pyrotinib plus capecitabine has better efficacy than lapatinib plus capecitabine, with longer PFS (18.1 months vs. 7.0 months and 12.5 months vs. 6.8 months, respectively) and higher overall response rates (78.5% vs. 57.1% and 67% vs. 52%, respectively) after prior trastuzumab. On the other hand, the main adverse reaction of pyrrolidine is diarrhea, which is controllable and mostly occurs in the first medication cycle.
We have modified our text as accordingly. (see Page 1, line 14; Page 3, line 126-129)
References:
[1]Xu, B.; Yan, M.; Ma, F.; Hu, X.; Feng, J.; Ouyang, Q.; Tong, Z.; Li, H.; Zhang, Q.; Sun, T.; et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. The Lancet Oncology 2021, 22, 351-360, doi:10.1016/s1470-2045(20)30702-6.
[2]Ma F, O.Q., Li W, Jiang Z, Tong Z, Liu Y, Li H, Yu S, Feng J, Wang S, Hu X, Zou J, Zhu X, Xu B. Pyrotinib or Lapatinib Combined With Capecitabine in HER2–Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, andor Trastuzumab A Randomized, Phase II Study. J Clin Oncol 2019, 37, 2610-2619, doi:10.1200/JCO.19.00108.
[General Comment] As this study is done considering the socio-economic condition of a country, therefore, I think it is acceptable in that context based on another previous study.
Response: Thank you for your comment.
[Point 2] Since this paper tries to highlight the issue of comparative cost considering the socio-economic status of a specific country, I think it is better to be a little clearer about the data collection of the study and also mention the limitations of the study.
Response 2:
Thank you so much for your suggestions. This study was based on the existing literature and the socio-economic status of a specific country. Data collection is important and necessary. For data collection, there was no separate paragraph for “Data Collection”, but in the "Materials and Methods" section, there are specific descriptions of data collection in the part of cost data, utility values, etc. Moreover, the manuscript further supplemented the description of data collection. As follows:
Firstly, cost data. Our research adopted direct medical costs, including the costs of drugs, AEs treatment, subsequent treatment, and regular laboratory examination. The drug treatment costs were mainly incurred by pyrotinib, lapatinib, and capecitabine. The usage and dosage of three drugs were consistent with the instructions. According to the unit drug price obtained from the hospital drug database and theirs usage and dosage, the costs of drug treatment were calculated. The AEs treatment costs, which not only contained agents but also included the hospitalization expenses, were calculated through expert consultation of eight BC clinicians from different hospitals. Subsequent treatment costs were calculated according to the follow-up treatment program and its proportion of the PHOEBE clinical trial, combined with clinical expert opinions and the average bid-winning prices of required therapeutic drugs in various provinces of China in 2021. Furthermore, the laboratory examination costs, including blood routine tests, urine routine tests, liver, kidney function tests and so on, were calculated based on the actual investigation cost of various inspection items in hospitals. Secondly, adverse events. According to PHOEBE clinical trial, the most common grade 3 to 4 AEs of patients with HER2-positive metastatic BC were diarrhea and hand-foot syndrome. The probability of patients experiencing Grade≧3 AEs were also derived from PHOEBE clinical trial. Additionally, utility values. Major health state utility scores were derived from relevant published kinds of literature based on the Chinese population, using the scale of EQ-5D. (see Page 5,line 194-198; Page 6,line 224-235/line 231)
We have added modification of limitations in the section of Discussion. (see Page 13, Line 447-453)
[Point 3] The conclusion can be made clearer and more beautiful if the author mentions the limitations of the research results, i.e. about its generalizability.
Response 3:
Thank you so much for your suggestions. We have modified the section of Limitation as advised: Finally, due to the lack of other population information, it is a pity that no comparison of second-line drugs comprising pyrotinib between domestic and foreign was conducted. Although pyrotinib is one of the recommended therapeutic drugs for advanced BC patients in China, it has not been widely used all over the world. The analysis of this study was only based on the Chinese population, lacking evidence from other populations, so there was no comparison between BC patients from different countries. (see Page 14, Line 459-465)
[General Comment] The references are appropriate. The reference depends on generalizability. Since this research has tried to highlight the issue of comparative cost considering the socio-economic status of a country, thus, it can be accepted.
Response: Thank you for your comment.
Author Response File: Author Response.docx
