Authors' objectives: Breast cancer is the most common cancer in Swiss women. About 15-20% of women with breast cancers have an overexpression of the human epidermal growth factor receptor 2 (HER2), which is associated with uncontrolled cell growth. Inhibition of HER2 receptors can be the focus of targeted treatment. In Switzerland, the HER2-targeted pharmaceuticals trastuzumab and pertuzumab are approved for the treatment of HER2-positive early breast cancer, either starting before surgery (neoadjuvant) or after surgery (adjuvant). The present health technology assessment (HTA) addresses the question whether a reduced treatment duration of 6 months or less of trastuzumab or trastuzumab combined with pertuzumab is non-inferior in terms of clinical efficacy and has the potential of reducing adverse effects (AEs) and treatment costs compared with a treatment duration of 12 months.

Authors' results and conclusions: Results: In the systematic review related to the clinical efficacy and safety, 6 RCTs with 11,603 women between 21 and 86 years of age – PHARE, E2198, HORG, Short-HER, SOLD, and PERSEPHONE – were included. The evaluated reduced durations for trastuzumab treatment were 6 months (3 RCTs), 12 weeks (1 RCT), and 9 weeks (2 RCTs). All RCTs evaluated trastuzumab treatment in the adjuvant setting. No RCTs were identified for different treatment durations for trastuzumab and pertuzumab in combination. The primary findings of the assessment of clinical efficacy and safety were the following: Overall survival (OS): Considering a non-inferiority margin of HR 1.543 (corresponding to a 3% absolute difference for an assumed 5-year OS of 94.2%), OS with 6 months or less of trastuzumab treatment is likely non-inferior to 12 months of trastuzumab treatment (HR 1.13, 95% CI 0.99 to 1.28, p<0.0001 for non-inferiority, I2 = 0%, 6 RCTs, 11,603 participants, moderate certainty of evidence). Disease-free survival (DFS): Considering a non-inferiority margin of HR 1.266 (corresponding to a 3% absolute difference for an assumed 5-year DFS of 87.7%), the evidence is inconclusive (i.e., inferiority cannot fully be ruled out) whether DFS with 6 months or less of trastuzumab treatment is non-inferior to 12 months of trastuzumab treatment (HR 1.14, 95% CI 0.98 to 1.32, p=0.22 for non-inferiority, I2 = 37%, 6 RCTs, 11,603 participants, low certainty of evidence). Health-related quality of life (HRQoL): HRQoL with 6 months or less of trastuzumab treatment may be similar or higher compared with 12 months of trastuzumab treatment, but the evidence is very uncertain (1 RCT, 4,088 participants, very low certainty of evidence). Congestive heart failure: The risk is likely lower with ≤6 vs. 12 months of trastuzumab treatment (RR 0.65, 95% CI 0.42 to 1.00, p=0.051, I 2 = 0%, 3 RCTs, 5,788 participants, moderate certainty of evidence). Left-ventricular ejection fraction (LVEF) 10%: The risk is likely lower with ≤6 vs. 12 months of trastuzumab treatment (RR 0.76, 95% CI 0.63 to 0.92, p=0.004, I 2 = 0%, 3 RCTs, 7,532 participants, moderate certainty of evidence). Any severe (grade ≥3) AE: The risk may be lower with ≤6 vs. 12 months of trastuzumab treatment (RR 0.89, 95% CI 0.72 to 1.09, p=0.25, I2 = 88%, 2 RCTs, 6,007 participants, low certainty of evidence). Trastuzumab discontinuation due to any AE: The risk is likely lower with ≤6 vs. 12 months of trastuzumab treatment (RR 0.37, 95% CI 0.27 to 0.50, p<0.0001, I2 = 61%, 3 RCTs, 6,807 participants, moderate certainty of evidence). The findings of the assessment of clinical efficacy and safety for the comparison of 6 months compared with 12 months of trastuzumab treatment were overall similar to the results presented for the comparison of ≤6 months vs. 12 months of trastuzumab treatment, except that the evidence regarding congestive heart failure was considered very uncertain. All cost-effectiveness studies identified in the systematic review reported that ≤6 months of trastuzumab treatment is less expensive than 12 months of treatment. The effects on quality-adjusted life-years (QALYs) were discordant, with 5 studies suggesting that ≤6 months of trastuzumab led to more QALY gained, and 2 studies concluding that ≤6 months of trastuzumab led to less QALY gained than 12 months of trastuzumab. The de novo cost-effectiveness analysis conducted for Switzerland suggested that 6 months of trastuzumab treatment resulted in lower costs (CHF -15,047 per patient) compared to 12 months of treatment. At the same time, 6 months of trastuzumab treatment led to a total decrease of 0.62 QALY per patient. Consequently, an incremental cost-effectiveness ratio (ICER) of CHF 24,242 saved per QALY lost was estimated. The results were in the lower-left quadrant of the cost-effectiveness plane. In this situation, low ICERs indicate that the amount of money saved per QALY lost is rather small. The probabilistic sensitivity analysis suggested that the results were highly uncertain: while most (57%) of the ICER results still indicated that 6 months led to lower costs but also to a decrease in QALYs (i.e., lower-left quadrant of the cost-effectiveness plane), a considerable proportion (43%) of the ICER results indicated that 6 months led to lower costs and to an increase in QALYs compared to 12 months trastuzumab (i.e., lower-right quadrant). The budget impact analysis suggested that switching from 12 months to 6 months of trastuzumab treatment would lead to a decrease in total costs ranging between CHF 13.6 million in 2024 and CHF 14.1 million in 2028. Regarding ethical, legal, social and organisational issues (ELSO), there is very little literature in relation to the specific question of reducing the duration of cancer treatment. Application of the principles of biomedical ethics in a normative analysis reveals that shortening the course of trastuzumab is largely compatible with the principles of beneficence, nonmaleficence, and justice. No serious ELSO issues were found in the literature. A few ethical issues emerging from the analysis concern uncertainties with respect to non-inferiority in DFS, potential harms to a subset of patients, informing patients about these potential harms, and respecting patient’s autonomy with regard to treatment choice. Conclusion: OS with 6 months or less of trastuzumab treatment is likely non-inferior to 12 months of treatment, whereas the evidence for non-inferiority is inconclusive for DFS. While the evidence is very uncertain regarding HRQoL, the risk of cardiac AEs and trastuzumab discontinuation due to any AE is likely lower and the risk of any severe (grade ≥3) AEs may be lower with ≤6 months of treatment. The economic base case analysis suggested, that 6 months compared to 12 months of trastuzumab treatment leads to lower costs but also to a decrease in QALYs. However, the probabilistic sensitivity analyses revealed that results were highly uncertain (i.e., 6 months of treatment may also lead to an increase in QALYs). Due to a lack of evidence, the comparison of 6 months or less of adjuvant combination treatment with trastuzumab and pertuzumab compared to 12 months of combination treatment could not be assessed in this HTA.

Authors' methods: For the assessment of clinical efficacy and safety, a systematic review was conducted. Eligible studies were randomised controlled trials (RCTs) that compared a treatment duration of 6 months or less (≤6 months) of trastuzumab or trastuzumab combined with pertuzumab with a treatment duration of 12 months in HER2-positive early breast cancer. Non-inferiority meta-analyses were conducted for the outcomes of overall survival (OS) and disease-free survival (DFS). Furthermore, meta-analyses were conducted for AEs, and data was summarised narratively regarding the direction and size of any observed effects if pooling was not possible. The risk of bias was assessed based on the Cochrane risk of bias 2 tool. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, and summary statements were formulated according to GRADE guidance. The economic assessment consisted of a systematic review of existing health economic evidence, the development of a de novo Markov model-based cost-effectiveness analysis and a budget impact analysis for Switzerland. To address ethical, legal, social, and organisational issues relating to the different treatment durations, an exploratory literature search was conducted. The main issues identified were reported descriptively.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/trastazumab.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0062thtr-hta-protocol.pdf.download.pdf/HTA%20protocol.pdf

Year Published: 2024

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0067thtr-hta-report.pdf.download.pdf/h0067thtr-hta-report.pdf

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health