Cost-effectiveness of pertuzumab and trastuzumab biosimilar combination therapy as initial treatment for HER2-positive metastatic breast cancer in Singapore

Li-Jen Cheng a, Lydia Loke a, Elaine Hsuen Lim b, Fiona Pearcea, Mohamed Ismail Abdul Aziza and Kwong Nga


Background: This study evaluates the cost-effectiveness of pertuzumab with trastuzumab biosimilar and docetaxel as initial treatment for HER2-positive metastatic breast cancer (MBC) in Singapore.
Methods: A partitioned survival model with three health states was developed to evaluate the cost- effectiveness of trastuzumab biosimilar and docetaxel with or without pertuzumab from a healthcare system perspective over a 15-year time horizon for patients with HER2-positive MBC. Key clinical inputs were derived from the CLEOPATRA trial. Health state utilities were derived from the literature and direct medical costs were obtained from local public healthcare institutions.
Results: The base-case resulted in an incremental cost-effectiveness ratio (ICER) of SGD366,658 (USD272,244) per quality-adjusted life-year (QALY) gained. One-way sensitivity analyses showed that the ICER was sensitive to utilities in the progression-free state, price of pertuzumab and time horizon. When the price for trastuzumab reference biologic (branded) was applied, the ICER was even higher (SGD426,996 [USD317,045]/QALY).
Conclusion: Although trastuzumab biosimilar reduced the cost of the pertuzumab combination regimen, the ICER remained high and was not cost effective in Singapore’s context. As pertuzumab contributed 80% of the overall combination treatment cost, price reductions for pertuzumab will be required to improve the cost-effectiveness of combination treatment to an acceptable level.

1. Background

Targeted combination therapies, comprising a ‘backbone ther- apy’ and an ‘add-on’ therapy, are increasingly used in cancer care as they enable parallel inhibition of targets, resulting in a more effective and durable blockade [1]. However, they can pose a budget challenge for payers especially when multiple patented products are used together. Likewise, studies have shown that clinically effective ‘add-on therapies’ are often not cost-effective even at zero price especially when survival gain increases the time spent on the expensive treatment combi- nation [2,3].
One such example is the addition of pertuzumab to trastu- zumab and docetaxel for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC). Despite significant progression-free survival (PFS) and overall survival (OS) improvements (PFS: HR = 0.62; p < 0.001; OS: HR = 0.68; p < 0.001) seen in the landmark CLEOPATRA trial [4–6], pertuzumab was not cost-effective even at zero price when used as combination therapy in the UK context [2]. Survival gains from pertuzumab in the progression-free state increased active treatment costs outweighing the quality- adjusted life-years (QALYs) gained from the increased survival, leading to an unfavorable cost-effectiveness outcome. In Singapore, both pertuzumab and trastuzumab ranked among the top five drugs with the highest total expenditure at public healthcare institutions in 2019 which raises the question whether they are cost effective on a healthcare sys- tem level. The healthcare financing system in Singapore is based on a philosophy of shared responsibility and comprises a combination of government subsidies, compulsory indivi- dual health care savings accounts, risk-pooling via voluntary private and mandatory government health insurance plans, and out-of-pocket contributions from patients [7]. Government subsidies cover 50–75% of drug costs and play a significant role in ensuring patient access to effective drugs. Drug subsidy decisions are informed by multiple factors, such as unmet need, clinical effectiveness, safety, cost-effectiveness and budget impact [8]. Although there is no explicit cost- effectiveness threshold in Singapore, incremental cost- effectiveness ratios (ICERs) for drugs used to treat cancer which have been previously recommended for subsidy in Singapore generally ranged below SGD45,000 (USD33,413) per QALY gained [9,10]. The recent availability of trastuzumab biosimilars, which are less expensive than trastuzumab reference biologic, is expected to provide an opportunity to improve the affordabil- ity and financial impact of pertuzumab combination therapy for MBC. However, the impact of trastuzumab biosimilar on the cost-effectiveness of pertuzumab combination therapy remains unexplored. The aim of this study is to evaluate the cost-effectiveness of adding pertuzumab to trastuzumab biosimilar and docetaxel for first-line treatment of HER2- positive MBC in Singapore. Results from this study will be helpful to inform local funding decisions for HER2-positive MBC alongside other relevant considerations. 2. Methods 2.1. Model structure A partitioned-survival model was developed in Microsoft Excel 2016 (Microsoft Corp, Redmond, WA) by referencing pre- viously validated oncology models [3,11,12]. The analysis was performed from the Singapore healthcare system’s perspective. The model consisted of 2 health states, progression free (PF) and progressive disease (PD), and an absorbing state for death (Figure 1). At the beginning of the simulation, all patients were in the PF health state, during which they received trastuzumab biosimilar and docetaxel with or without pertuzumab and remained in that health state until they progressed to the PD health state or died. Upon disease progression, patients received subsequent treatments and were assumed to stay in the PD health state for the remaining time horizon or die. Transitions between health states were determined by the distribution of patients across health states observed in any given cycle. The proportions of the cohort in each state were estimated using parametric survival curves for PFS and OS. The proportion of patients in the PF health state was based on estimated PFS; the proportion of patients in the PD health state for any given cycle was calculated as the difference between OS and PFS curves per cycle. The area under the curve (AUC) was used to calculate the sum of the mean sojourn time in the PF and PD health states. A time horizon of 15 years was selected in the base-case analysis following advice from local clinicians. Based on a reported 10-year survival of 12.8% observed in women with primary stage IV breast cancer [13] and an 8-year OS rate of 37% reported in the pertuzumab arm of the CLEOPATRA trial [6], the time horizon was considered sufficiently long enough to capture all survival benefits and costs accrued in the pertuzumab arm. A cycle length of 1 week was chosen in the model to capture relevant changes in the health states, with a half-cycle correction applied to adjust for the timing of events. 2.2. Patients and interventions The modeled population was women with HER2 over- expression who were treatment-naïve for metastatic disease. Drug treatments and doses were consistent with the CLEOPATRA trial, which compared efficacy and safety out- comes of trastuzumab and docetaxel with or without pertu- zumab in the first-line setting in patients with HER2-positive MBC. In the trial, patients in the comparator arm could cross- over to receive pertuzumab treatment (12%). Results from the trial demonstrated the superiority of the pertuzumab- containing combination which led to a 16.3-month improve- ment in median OS after a median follow-up of 99.9 months. In the model pertuzumab was administered at a loading dose of 840 mg in the first cycle and decreased to 420 mg in subsequent cycles. Similarly, trastuzumab was given at a loading dose of 8 mg/kg in the first cycle, followed by 6 mg/kg in subsequent cycles. Docetaxel was given at a dose of 75 mg/m2. All 3 drugs were given intravenously every 3 weeks until disease progression or unacceptable toxi- city. Upon progression, patients were assumed to receive subsequent lines of therapies, supportive or palliative care, or die. 2.3. Data 2.3.1. Clinical efficacy data Data from the CLEOPATRA trial was used to inform the prob- ability of patients remaining in each health state [6]. To simu- late a 15-year time horizon, PFS and OS Kaplan Meier (KM) data based on the intention-to-treat population were extra- polated using standard parametric survival distributions. As patient level data were not available, data from the survival curves were first extracted using a web-based digitizer pro- gram (WebPlotDigitizer version 4.2) [14]. The statistical meth- ods developed by Guyot et al (2011) [15] were adopted to reconstruct patient-level data underlying the survival curves. Regression methods were then conducted using R statistical software (‘flexsurvreg’ packages) to fit parametric functions (i.e. exponential, Weibull, log-logistic, log-normal, Gompertz and generalized gamma distributions) to the survival curves. As the proportional hazard assumption was violated based on diagnostic plots of ln(-ln S(t)) over ln(t), parametric functions were derived by fitting parametric functions onto the OS and PFS KM curves in the two arms separately. Visual observation also showed that the curves did not provide a good fit to both the observed OS and PFS KM data. A two-piece model was chosen in which data from KM curves were used up to the selected inflexion points, after which parametric functions were fitted to the remaining KM data to extrapolate the long- term survival over the remaining time horizon. To determine the best inflexion points for the two-piece setting, the Chow’s test was used to generate a number of candidate time points, and parametric survival curves were fitted to the remaining KM data after each candidate time point [16]. The most appro- priate inflexion points and distributions for the extrapolation were selected based on goodness of fit statistics (Akaike infor- mation criterion, AIC) and visual inspection of the parametric curves against the KM data (Table S2). In the base-case analysis, for the pertuzumab arm, week 180 and week 206 were identified as the most appropriate inflexion points for OS and PFS curves respectively; for the placebo arm, week 278 and week 137 were selected. Based on AIC results, for the pertuzumab arm, the loglogistic and expo- nential distributions were found to be the best fitting models for OS and PFS curves respectively; for the placebo arm, the exponential and lognormal distributions were chosen (Figure 2). Extrapolations of OS were also adjusted for age-specific all- cause mortality, using a competing risk approach in which the estimate with a higher risk of death was selected to calculate the adjusted survival. Data on all-cause mortality were taken from the Department of Statistics, Singapore [17]. All model inputs are summarized in Table 1. 2.3.2. Utility values In the base-case analysis, health state utility values chosen for the PF (0.72) and PD (0.44) health states were consistent with other published economic evaluations of advanced or meta- static breast cancer [3,18–20]. Values were taken from a primary utility study by Lloyd et al (2006) [21], which derived state utilities by using the standard gamble method and visual analogue scale from the UK general public. Health state uti- lities were assumed to not be treatment-specific. Disutilities for adverse events (AEs) were not modeled, because reported AEs in the trial were not considered to have a substantial impact on a patient’s quality of life. 2.3.3. Cost In line with the healthcare system’s perspective, only direct healthcare costs borne by the patient, government, insurance payers and public healthcare institutions (PHIs) were incorpo- rated in the model, including costs of the drugs, consultation visits, computerized tomography scans, blood tests and term- inal care. Costs for managing adverse events were not con- sidered due to their low incidence reported in the trial. All costs were presented in Singapore dollars (SGD) and were estimated from local utilization data and average unit costs obtained from survey of healthcare professionals in the PHIs. Time on first-line therapy was estimated using PFS curves from the CLEOPATRA trial as disease progression was the most common reason for treatment discontinuation (~80%). Patients occupying the PD health state were assumed to receive up to 4 lines of subsequent treatments, with the option of best supportive care as 5th line therapy. The dura- tion of patients receiving subsequent-line treatments for any given cycle was calculated as the difference between the areas under the PFS and OS curves per cycle. The types and dis- tribution of 2nd line treatments were informed by the CLEOPATRA trial, while the proportion of patients remaining on second line therapy was calculated based on the EMILIA trial [22]. The EMILIA trial was a randomized trial, comparing the efficacy and safety of T-DM1 with lapatinib plus capecita- bine as 2nd line treatment for HER2-positive MBC. As lapatinib and capecitabine combination therapy was the most common 2nd line regimen in the CLEOPATRA trial, the PFS curve for lapatinib and capecitabine from the EMILIA trial was selected as a proxy for the average time on treatment across all 2nd line treatments (Supplementary Figure S1). The types and distribu- tion of 3rd and subsequent line treatments were derived from a survey of local clinical experts (Supplementary Table S1). 2.3.4. Outcomes Outcomes of interest were progression-free life years (PFLYs), overall life years (LYs), quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Future costs and health outcomes were discounted at a rate of 3% per annum [23]. 2.4. Sensitivity and scenario analyses A one-way sensitivity analysis (OWSA) was conducted over the range of predefined values of the point estimates for specific model parameters (i.e. ±20% or feasible range). Results were plotted as a Tornado diagram according to the extent of the parameter’s impact on the ICER. A multivariate probabilistic sensitivity analysis (PSA) was performed, using second-order 15,000 Monte Carlo simulation. Uncertainty of model inputs was explored by simultaneously performing random sampling of the parameters from assigned distributions. Utility values were modeled as beta distributions, whereas the health care costs were assumed to be certain. Parameters characterizing PFS and OS were sampled from multivariate normal distribu- tions using the Cholesky decomposition matrix [24]. A cost- effectiveness acceptability curve (CEAC) was generated to pre- sent the probability of pertuzumab combination treatment being cost-effective at each willingness-to-pay (WTP) threshold. A series of scenario analyses were performed to test the robustness of the model results to different assumptions about parametric functions chosen for PFS and OS extrapola- tions, and treatment costs. The scenario analyses included using: (1) the most optimistic PFS extrapolation for the pertu- zumab arm – lognormal distribution; (2) the most optimistic OS extrapolation for the pertuzumab arm – Gompertz distri- bution; (3) the trastuzumab reference biologic (branded) price. An additional scenario analysis was conducted to assess the effect of different hypothetical price discounts for pertuzumab on the cost-effectiveness of pertuzumab combination therapy. 3. Results 3.1. Base case analysis In the base-case analysis, compared to trastuzumab biosimilar and docetaxel combination therapy, the combination of per- tuzumab, trastuzumab biosimilar and docetaxel yielded more LYs and QALYs gained (5.09 LYs; 3.14 QALYs) at higher mean estimated costs (SGD417,064) over a 15-year time horizon (Table 2). The estimated ICER for the addition of pertuzumab to trastuzumab biosimilar and docetaxel was SGD366,658 (USD272,244)/QALY (incremental costs SGD268,207 (USD199,144); incremental QALYs 0.73). 3.2. Sensitivity analyses The OWSA results indicated that the ICER was most sensitive to variations in utility values in the PF health state, pertuzu- mab selling price and time horizon (Figure 3). Overall, all the ICERs remained above SGD298,000(USD221,265)/QALY when model parameters were varied within their uncertainty ranges. The average costs and QALYs over the 15,000 simulations from the PSA (mean probabilistic ICER: SGD365,202 (USD271,163) per QALY) were generally congruent with the deterministic base-case results. The CEACs demonstrated that combination therapy with pertuzumab, trastuzumab biosimi- lar and docetaxel was preferred only when the WTP was above SGD370,000 (USD274,725) per QALY (Figure 4). 3.3. Scenario analyses Trastuzumab reference biologic (branded) is more than five times expensive than trastuzumab biosimilar. When the price for the trastuzumab reference biologic (branded) was applied instead of the price for trastuzumab biosimilar, the ICER was less favorable for combination therapy with pertuzumab, trastuzumab and docetaxel (SGD426,996 [USD317,045]/QALY) compared to the base case (Table 2). Pricing analyses showed that the ICERs were highly sensitive to the hypothetical price discounts assumed for pertuzumab instead. A 10% price reduction led to a corresponding reduction of SGD23,000 (USD17,078) in the base-case ICER, suggesting that reducing the pertuzumab price substantially improved the cost- effectiveness of pertuzumab combination therapy. However, the ICERs remained consistently high even when the price of pertuzumab was reduced by 90% (SGD84,482[USD62,728]/ QALY). There was only a small variation in the cost- effectiveness results for the most optimistic extrapolation functions assigned for the PFS and OS in the pertuzumab arm. 4. Discussion The addition of pertuzumab to trastuzumab and docetaxel is standard first-line treatment of HER2-positive MBC. Nevertheless, targeted combination therapies remain a budget challenge for payers and are often not cost- effective. With the recent availability of trastuzumab biosimi- lars in Singapore, its cost has been significantly reduced and it has become more affordable for patients; however, the cost- effectiveness of the combination regimen was unknown and required further exploration to support funding decisions. To our best knowledge, this is the first study evaluating the cost- effectiveness of pertuzumab in combination with a trastuzumab biosimilar for HER2-positive MBC. Our analyses found that compared with the ICER (SGD426,996 [USD317,045] per QALY gained) for pertuzu- mab combination treatment with trastuzumab reference biologic, the ICER for combination treatment with trastuzu- mab biosimilar was greatly improved (SGD366,658 [USD272,244] per QALY gained). Nonetheless, the ICER remained high and pertuzumab combination treatment is unlikely to be considered a cost-effective option for HER2- positive MBC in Singapore. The high ICER was largely due to the cost difference incurred in the PF state, which explained 98% of the total incremental costs. While the incremental cost was significantly reduced by trastuzumab biosimilar by nearly SGD40,000 (USD29,700), it still outweighed the QALYs (0.73) gained due to the longer time spent on pertuzumab combination therapy. The OWSA results showed that increasing the PF state utility and the time horizon or lowering the discounting rate for outcomes led to lower ICERs. However, even with these variations, the ICERs remained consistently high, substantiat- ing that trastuzumab price reductions alone were insufficient to reduce the ICER to an acceptable level. Further analyses revealed that the ICER was only significantly reduced when further price reductions were also applied to pertuzumab which contributed 80% of the overall treatment cost of the combination regimen. Several economic evaluations have assessed the cost- effectiveness of pertuzumab with trastuzumab and docetaxel for HER2-positive MBC based on the CLEOPATRA trial [5]. For example, Durkee et al evaluated the cost- effectiveness of pertuzumab in the US setting [25] and Diaby et al performed cost-effectiveness analyses of four HER2 targeted treatment sequences in different countries [26–28]. All studies were informed by shorter follow-up data from the CLEOPATRA trial (4 years). As compared with the present study, the estimated incremental QALY gains were smaller although the incremental LYG were larger, probably due to shorter follow-up data, different modeling and extra- polation approaches and utility assumptions. All analyses found pertuzumab combination therapy not cost-effective with PSA results also showing zero probability of the com- bination regimen being cost effective at commonly accepted WTP thresholds. Unlike previous economic evaluations, our model used the end-of-study results from the CLEOPATRA trial which had a median follow-up of 8 years. The longer follow-up reduced uncertainties in the Kaplan-Meier survival curve extrapolations. Furthermore, published economic evaluations simulated hypothetical patients with HER2-positive MBC using a Markov model, in which transition probabilities were derived by calibration [25]. However, in the absence of individual patient level data, the partitioned survival analysis approach applied in this study may be considered more appropriate and is commonly seen in health technology assessments of cancer treatments [29,30]. Our analysis has some limitations. First, our model was informed by Kaplan-Meier curves from the CLEOPATRA trial, in which patients received trastuzumab reference biologic (Herceptin). While there are no clinical trials evaluating the efficacy of pertuzumab with trastuzumab biosimilar, extensive bioequivalence studies have demonstrated that a trastuzumab biosimilar has similar physicochemical characteristics, biological activity, safety, efficacy and immunogenicity compared with its reference biologic [31]. In vitro studies have also shown that trastuzumab biosimilar-pertuzumab and Herceptin-pertuzumab combinations have similar binding and biological activities [32]. Taken together, the clinical efficacy and safety of trastuzumab biosimilar-pertuzumab and Herceptin-pertuzumab combina- tions can be considered comparable. Second, as detailed information regarding the type of subsequent treatments administered upon disease progres- sion were not included in the CLEOPATRA trial and the lack of published real-world data on local treatment patterns, we modeled subsequent treatment costs based on advice from local clinicians elicited via surveys. Although the impact of different subsequent treatment mixes on treatment costs and effectiveness is unknown, it is unlikely to have a large impact on the ICER given the same subsequent treatment mix was used in both treatment arms after 2nd line therapy. Last, health state utilities were obtained from a UK study due to a lack of direct utility data from the CLEOPATRA trial or local studies. Even though the study elicited patients’ quality of life (QoL) data from a MBC population, the results were not stratified by breast cancer subtype, adding uncertainty to the estimated ICERs. Nevertheless, a recent health utility study of patients with MBC in the Netherlands found no significant differences (p = 0.499) between patients with different breast cancer subtype [33]. Sensitivity analyses performed in this study also helped to ensure the robustness of our conclusions. 5. Conclusion Although trastuzumab biosimilar reduced the overall cost of combination therapy, our study demonstrated that the cost associated with better PFS and thus longer-term use of adding pertuzumab outweighed the QALYs gain. At current prices, pertuzumab combination therapy was unlikely to be a cost-effective treatment option for HER2-positive MBC in Singapore. As pertuzumab contributed 80% of the overall treatment cost of the combination regimen, price reduc- tions for pertuzumab will be required to improve its cost- effectiveness to an acceptable level. Results from this study will be useful to inform local funding decisions for pertuzu- mab combination therapy alongside other factors including clinical effectiveness, safety and budget impact considerations. References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Dankó D, Blay JY, Garrison LP. Challenges in the value assessment, pricing and funding of targeted combination therapies in oncology. Health Policy. 2019;123(12):1230–1236. 2. Davis S NICE DSU Report. Assessing technologies that are not cost-effective at zero price. 2014. •• This report describes in detail why clinicially effective combination therapies are often not cost-effective. 3. Phua LC, Lee SC, Ng K, et al. Cost-effectiveness analysis of atezoli- zumab in advanced triple-negative breast cancer. BMC Health Serv Res. 2020;20(1):581. 4. Baselga J, Cortés J, Kim SB, et al., Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366(2): 109–119. •• Results from pivotal trial. 5. Swain SM, Baselga J, Kim SB, et al., Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015; 372(8): 724–734. •• Results from pivotal trial. 6. Swain SM, Miles D, Kim SB, et al., Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020; 21(4): 519–530.
•• Results from pivotal trial.
7. Pearce F, Lin L, Teo E, et al. Health technology assessment and its use in drug policies: Singapore. Value Health Reg Issues. 2019;18:176–183.
8. Drug evaluation methods and process guide v2.0 agency for care effectiveness. Singapore: Ministry of Health; [2020Aug12]. Available from:
9. Abiraterone for treating metastatic prostate cancer. Technology guidance. agency for care effectiveness. Singapore: Ministry of Health; [2020Oct1]. Available from
10. Blinatumomab for treating relapsed or refractory B-precursor acute lymphoblastic leukaemia. Technology guidance. agency for care effectiveness. Singapore: Ministry of Health; [2020Sept1]. Available from
11. Aziz MIA, Tan LE, Tan WHG, et al. Cost-effectiveness analysis of pembrolizumab monotherapy versus chemotherapy for previously untreated advanced non-small cell lung cancer. J Med Econ. 2020;23(9):952–960.
12. Tan PT, Aziz MIA, Pearce F, et al. Cost effectiveness analysis of afatinib versus pemetrexed-cisplatin for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small- cell lung cancer from the Singapore healthcare payer’s perspective. BMC Cancer. 2018;18(1):352.
13. Eng LG, Dawood S, Sopik V, et al. Ten-year survival in women with primary stage IV breast cancer. Breast Cancer Res Treat. 2016;160 (1):145–152.
14. Rohatgi A WebPlotDigitizer Version 4.2 [cited 2020 Oct 19] [Available from: http://arohatgi.ifo.
15. Guyot P, Ades A, Ouwens MJ, et al. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12(1):9.
16. Chow GC. Tests of equality between sets of coefficients in two linear regressions. Econometrica. 1960;28(3):591–605.
17. Department of Statistics, Complete life tables for Singapore Resident Population, 2016–2017. 2018 [accessed on 2018 Nov 30]. Available from: lation/-/media/Files/publications/population/lifetable16–17
18. Galve-Calvo E, González-Haba E, Gostkorzewicz J, et al. Cost- effectiveness analysis of ribociclib versus palbociclib in the first- line treatment of HR+/HER2– advanced or metastatic breast cancer in Spain. Clinicoecon Outcomes Res. 2018;10:773–790.
19. Garrison LP, Babigumira J, Tournier C, et al. Cost-effectiveness analysis of pertuzumab with trastuzumab and chemotherapy com- pared to trastuzumab and chemotherapy in the adjuvant treat- ment of HER2-positive breast cancer in the United States. Value Health. 2019;22(4):408–415.
20. Sabale U, Ekman M, Thunström D, et al. Economic evaluation of fulvestrant 500 mg compared to generic aromatase inhibitors in patients with advanced breast cancer in Sweden. Pharmacoecon Open. 2017;1(4):279–290.
21. Lloyd A, Nafees B, Narewska J, et al. Health state utilities for metastatic breast cancer. Br J Cancer. 2006;95(6):683–690.
22. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367 (19):1783–1791.
23. Drug evaluation methods and process guide. Agency for care effectiveness, Singapore. 2019. [Version 2.0 updated December 2019] [accessed on 2020 Oct 19]. Available from: www.
24. Cholesky Decomposition: International Encyclopedia of the Social Sciences; [cited 2020 May 29]. Available from: www.encyclopedia. com/social-sciences/applied-and-social-sciences-magazines/cholesky- decomposition.
25. Durkee BY, Qian Y, Pollom EL, et al., Cost-effectiveness of pertuzu- mab in human epidermal growth factor receptor 2-positive meta- static breast cancer. J Clin Oncol. 2016; 34(9): 902–909.
• A different approach to evaluate the cost-effectiveness of pertuzumab.
26. Diaby V, Adunlin G, Ali AA, et al., Cost-effectiveness analysis of 1st through 3rd line sequential targeted therapy in HER2-positive meta- static breast cancer in the United States. Breast Cancer Res Treat. 2016; 160(1): 187–196.
• A different approach to evaluate the cost-effectiveness of pertuzumab.
27. Diaby V, Ali AA, Williams KJ, et al., Economic evaluation of sequen- cing strategies in HER2-positive metastatic breast cancer in Mexico: a contrast between public and private payer perspectives. Breast Cancer Res Treat. 2017; 166(3): 951–963.
• A different approach to evaluate the cost-effectiveness of pertuzumab.
28. Diaby V, Alqhtani H, van Boemmel-wegmann S, et al. A cost-effectiveness analysis of trastuzumab-containing treatment sequences for HER-2 positive metastatic breast cancer patients in Taiwan. Breast. 2020;49:141–148.
• A different approach to evaluate the cost-effectiveness of pertuzumab.
29. Woods B, Sideris E, Palmer S NICE DSU technical support docu- ment 19: partitioned survival analysis for decision modelling in health care: a critical review.2017 cited 2020 Sept 20]. Available from: Partitioned-Survival-Analysis-final-report.pdf.
30. Cranmer H, Shields GE, Bullement A. A comparison of partitioned survival analysis and state transition multi-state modelling approaches using a case study in oncology. J Med Econ. 2020;23 (10):1176–1185.
31. Health sciences authority- health products regulation group. Guidance on Therapeutic Product Registration in Singapore – Guidance on registration of biosimilar products. 2016.
32. Pimentel F, Toledo J, Goncalves J, et al.editors. Comparative evaluation of a trastuzumab biosimilar or originator trastuzu- mab in association with pertuzumab: binding and biological activities in cell culture-based assays. PS-05-08. San Antonio Breast Cancer Symposium 2019.San Antonio, Texas, USA.
33. Claessens AKM, Ramaekers BLT, Lobbezoo DJA, et al. Quality of life in a real-world cohort of advanced breast cancer patients: a study of the SONABRE Registry. Qual Life Res. 2020;29 (12):3363–3374.