Authors' objectives: 1-To assess and compare the effectiveness, safety and economic implication as well as organisational or societal issues of Pertuzumab, Trastuzumab, Lapatinib, Trastuzumab Biosimilar in combination of chemotherapy in neoadjuvant setting for HER2-positive breast cancer. 2-To determine whether to use single or dual-targeted therapies in combination with chemotherapy in neoadjuvant setting for HER2-positive breast cancer.

Authors' results and conclusions: Targeted therapy had shown to improve the pathologic complete response rates in HER2-positive early and locally advanced breast cancer population particularly with the treatment of dual-targeted therapy. Combination of pertuzumab plus trastuzumab plus chemotherapy (with or without anthracyclines) significantly improved pCR compared with single-targeted therapy followed by combination of lapatinib plus trastuzumab plus chemotherapy (with or without anthracyclines). In addition, for both types of interventions (addition of pertuzumab or lapatinib), combination chemotherapy (with or without anthracyclines) was significantly better than mono chemotherapy. From indirect meta-analysis, they found that there was no difference in pCR between the two groups with and without anthracyclines. However, according to the SUCRA rank, the group without anthracyclines took the highest percentage of pCR for both additions of pertuzumab or lapatinib. The used of trastuzumab biosimilar plus chemotherapy (with or without anthracyclines) was also ranked higher than combination of pertuzumab plus trastuzumab plus docetaxel. There was a good level of retrievable evidence that showed the rates of PFS, DFS, EFS and OS were higher in dual-targeted therapy (for addition of pertuzumab or lapatinib) than single-targeted therapy. In terms of safety, grade 3 to 5 treatment-related side effects were significantly higher in patients who received pertuzumab-arms (neutropenia), lapatinib-arms (diarrhea and skin disorders) and chemotherapy with commonly reported side effects of diarrhea and skin disorders. For incidence of cardiac events, there was no significant difference observed in all treatment arms. Trastuzumab biosimilar had comparable side-effects to trastuzumab. Based on two cost-effectiveness analyses studies, mono chemotherapy (pertuzumab plus trastuzumab plus taxol) was more effective with the highest health benefits (10.73 QALYs) and less costly (USD415,833) compared to combination chemotherapy (taxol plus carboplatin plus pertuzumab plus trastuzumab or taxol plus pertuzumab plus trastuzumab plus anthracyclines). However, de-escalated strategies found that combination of trastuzumab plus taxol became the most cost-effective option in both HR-positive and HR-negative patients. One cost minimisation analysis showed SC trastuzumab resulted in savings of RM7,561 every patient to the MOH and RM7,820 every patient to the society in comparison with IV trastuzumab. From the decision analytic modelling that has been conducted, addition of six cycles of neoadjuvant trastuzumab biosimilar (Herzuma) or neoadjuvant pertuzumab/ trastuzumab on top of standard neoadjuvant chemotherapy considered as a cost-effective strategy for high-risk early breast cancer with HER2 positive, yielding an ICER of RM16,471.59 and RM96,013.20 per QALY gained, which is within the suggested value of cost-effectiveness threshold by WHO (1-3 times GDP per capita). However, if suggested cost-effectiveness threshold for Malaysia is taken into consideration which is ≤1 GDP per capita, addition of single targeted therapy may be the most cost-effective strategy. Definition of one Malaysian GDP per capita per QALY gained is USD10, 500 ~ RM43,884.75. Based on one-way sensitivity analysis performed, these components have shown to be sensitive parameters for ICER determination: discount rate, recurrence state transitional probability values, and cost of targeted therapies.

Authors' recommendations: Targeted therapy in combination with chemotherapy is recommended to be used in early and locally advanced breast cancer. Combination of chemotherapy plus trastuzumab biosimilar is the most cost-effective option for Malaysian population. However, dual-targeted therapy may be used to achieve the highest effectiveness treatment, if cost reduction of the dual targeted therapy of at least 50% could be negotiated.

Authors' methods: Electronic databases were searched through the Ovid interface: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions(R)-1946 to March 26, 2021. Additional articles were identified from reviewing the references of retrieved articles. Data on the effectiveness, safety and outcomes of using targeted therapies were presented in tabulated format with narrative summaries. Meta-analysis using RevMan 5.0 was conducted for this Health Technology Assessment for selected outcomes: pathological complete response (pCR) rate and safety data. The data was pooled when heterogeneity, I2 was less than 80%. Risk ratio (RR), Odds ratio (OR) were calculated using fixed-effect model with 95% Confidence Interval (CI). Statistical significance was set at p< 0.05 for all outcomes. A literature-based hybrid model (Decision tree and Markov cohort simulation) was developed using Microsoft 365 Excel Workbook® to estimate the lifetime costs and quality adjusted life years (QALYs) of using targeted agents in combination with neoadjuvant chemotherapy in early HER2+ breast cancer. This type of model was chosen for its ability to extrapolate efficacy data from short-term clinical trials in early HER2+ breast cancer to longer term cost-effectiveness results.

Authors' identified further research: More long-term study using pertuzumab is warranted as current long-term evidence heavily with lapatinib as dual targeted therapy. In future, we might include study on other types of tyrosine kinase inhibitor such as neratinib and afitinib.

Project Status: Completed

Year Published: 2021

URL for published report: https://www.moh.gov.my/moh/resources/Penerbitan/MAHTAS/HTA/ES_-_Targeted_Therapies_in_Combination_with_Neoadjuvant_Chemotherapy_for_Her2-Positive_Breast_Cancer_and_Economic_Evaluation.pdf

Requestor: Ministry of Health, decision-making committee

URL for additional information: https://www.moh.gov.my/moh/resources/Main%20Banner/2021/Nov/Targeted_Therapies-portal.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Malaysia

Organisation Name: Malaysian Health Technology Assessment

Contact Address: Malaysian Health Technology Assessment Section, Ministry of Health Malaysia, Federal Government Administrative Centre, Level 4, Block E1, Parcel E, 62590 Putrajaya Malaysia Tel: +603 8883 1229

Contact Name: htamalaysia@moh.gov.my

Contact Email: htamalaysia@moh.gov.my

Copyright: Malaysian Health Technology Assessment Section (MaHTAS)