LBA11 - Individual patient data meta-analysis of 5 non-inferiority RCTs of reduced duration single agent adjuvant trastuzumab in the treatment of HER2 positive early breast cancer

Background

We planned an individual patient data (IPD) meta-analysis of non-inferiority (NI) RCTs to determine if a duration of less than the standard of 12 months (m) of adjuvant trastuzumab is non-inferior for treatment outcomes in HER-2 positive early breast cancer patients.

Methods

A systematic review identified five NI RCTs, and trial groups agreed a meta-analysis collaboration. PERSEPHONE, PHARE and HORG compared 12m v 6m; SOLD and Short-HER compared 12m v 9weeks[w]. Primary outcome was invasive disease-free survival (IDFS). Secondary outcomes were distant relapse-free survival (DRFS); overall survival (OS) and breast cancer specific survival (BCSS). Analysis was intention-to-treat (ITT). Random effects modelling evaluated prognostic effects of patient and tumour characteristics, treatment and trial. Heterogeneity between studies was assessed using the Cochran’s Q statistic. For the comparison of 12m v less (n≈11,500 pts), a 1-sided 2.5% significance was used. For the analyses of 12m v 6m (n≈8,000 pts) and 12m v 9w (n≈3,500 pts), 1-sided 5% significance was utilised.

Results

To date, IPD has been obtained from 4 trials and published data has been used from PHARE. For ITT analysis of the primary outcome of IDFS, non-inferiority limits for absolute 2% margins were calculated as 1.19 for all 5 trials, 1.20 for 3 trials comparing 12m v 6m and 1.25 for 2 trials comparing 12m v 9w. For 12m v less (all 5 trials combined), 5-year IDFS rates were 88.46% and 86.87% respectively. The adjusted HR for treatment was 1.14 (95% credibility interval (CI) 0.88-1.47), non-inferiority p=0.37. For 12m v 6m, 5-year IDFS rates were 89.26% and 88.56% respectively. The adjusted HR for treatment was 1.07 (90% CI 0.98-1.17), non-inferiority p=0.02. For 12m v 9w, 5-year IDFS rates were 91.40% and 89.22% respectively. The adjusted HR for treatment was 1.27 (90% CI 1.07-1.49), non-inferiority p=0.56. Cochran’s Q is 5.5 for all 5 trials, 0.91 for the 3 trials comparing 12m v 6m and 1.1 for the 2 trials comparing 12m v 9w.

Conclusions

Six months trastuzumab is non-inferior to 12months, although nine weeks is not.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Part-funded by NIHR Senior Investigator Award to Professor Janet Dunn, University of Warwick Clinical Trials Unit.

Disclosure

H.M. Earl: Financial Interests, Personal, Invited Speaker, Invited speaker on topic of duration of adjuvant trastuzumab and the Persephone Trial: Asian Society of Continuing Medical Education and Intas Pharmaceuticals. P.F. Conte: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board, For alpelisb trial: Novartis; Financial Interests, Personal, Expert Testimony, Drug approval with AIFA: Roche; Financial Interests, Institutional, Research Grant: Merck KGaAa,; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Roche. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Synton Biopharmaceuticals. H. Joensuu: Financial Interests, Personal, Advisory Board: Maud Kuistila Foundation; Financial Interests, Personal, Advisory Board: Neutron Therapeutics; Financial Interests, Personal, Advisory Board: Orion Pharma; Financial Interests, Personal, Full or part-time Employment, Until Aug 31, 2020: Orion Pharma; Financial Interests, Personal, Stocks/Shares: Orion Pharma; Financial Interests, Personal, Stocks/Shares: Sartar Therapeutics. D. Cameron: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: SeaGen; Financial Interests, Institutional, Advisory Board: Synthon; Financial Interests, Institutional, Advisory Board: Zymeworks; Non-Financial Interests, Institutional, Principal Investigator, Non-financial, Funding and drug for participation in Novartis study.: Novartis; Financial Interests, Institutional, Advisory Role, Consultancy role: Novartis. D.W. Miles: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Exact Science; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Gilead. A.M. Wardley: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer-Ingleheim; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Easai; Financial Interests, Personal, Writing Engagements, From contracted research and related (unremunerated): Eli Lilly; Financial Interests, Personal, Advisory Board, Remunerated: Eli Lilly; Financial Interests, Personal, Invited Speaker, Remunerated: Eli Lilly; Financial Interests, Personal, Advisory Board: Genomic Health/Exact Sciences; Financial Interests, Personal, Other, Scientific Review Committee. Expenses paid: INCa; Financial Interests, Personal, Other, Travel support - conference: MSD; Financial Interests, Personal, Advisory Board: MDS; Financial Interests, Personal, Writing Engagements, Papers from contracted research and related. Unremunerated writing: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker, Papers from contracted research: Novartis; Financial Interests, Personal, Other, Joint working project access to secondary breast cancer in Greater Manchester. Unremunerated: Novartis/iQIVA; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Other, Outreach Research and Innovation Group (not for profit): Public Health England; Financial Interests, Personal, Writing Engagements, Papers from contracted research. Unremunerated writing: Roche; Financial Interests, Personal, Invited Speaker, Several: Roche; Financial Interests, Personal, Advisory Board, Numerous remunerated advisory boards: Roche; Financial Interests, Personal, Advisory Board: Simon-Kucher; Financial Interests, Personal, Other, Internal company training on breast cancer: Takeda; Financial Interests, Personal, Member of the Board of Directors, Company for private medical income and payment of advisory engagements: Andrew Wardley Limited; Financial Interests, Personal, Full or part-time Employment, As of 11 January 2021: AstraZeneca; Financial Interests, Personal, Member of the Board of Directors: Manchester Cancer Academy; Financial Interests, Institutional, Member of the Board of Directors, Not for profit organisation to improve cancer care across the UK and internationally: Outreach Research & Innovation Group Limited; Financial Interests, Personal, Other, SAB: Athenex; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Personal and Institutional, Other, Steering Committee Member: Eli Lilly; Financial Interests, Institutional, Principal Investigator: Medivation; Financial Interests, Institutional, Principal Investigator: NIHR; Financial Interests, Institutional, Research Grant: NIHR; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Pfizer, Local; Financial Interests, Institutional, Principal Investigator: Roche; Non-Financial Interests, Leadership Role, Strategy Director 2018-2021: ACP; Non-Financial Interests, Leadership Role, Breast Research Group Member, Early Breast cancer sub-group 2014-21 Chair 2020-2021: NCRI; Non-Financial Interests, Advisory Role, 2013-2021: NHSE Chemotherapy Clinical reference group; Non-Financial Interests, Advisory Role, 2013-2021: PHE Chemotherapy Clinical Intelligence Group; Non-Financial Interests, Other, Committee member, NICE liaison, until 2020: UKBCG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Leadership Role, 2013 to 2021 EBC subgroup; lead for development of HER2-RADiCAL trial: NCRI; Non-Financial Interests, Member, Until 2021: UKBCG; Other, Raised protected public interest Disclosures - into former employer The Christie Hospital: NHSI. All other authors have declared no conflicts of interest.