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Proffered Paper session - Breast cancer, early stage

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

Date

17 Sep 2021

Session

Proffered Paper session - Breast cancer, early stage

Presenters

Helena Earl

Citation

Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741

Authors

H.M. Earl1, L. Hiller2, J.A. dunn3, P.F. Conte4, R. D'Amico5, V. Guarneri6, H. Joensuu7, T. Huttunen8, V. Georgoulias9, J. Abraham10, D. Cameron11, D.W. Miles12, A.M. Wardley13, G. Romieu14, M. Debled15, C. Faure-Mercier16, H. Lindman17, J. Fraser18, D. Cox19, X. Pivot20

Author affiliations

  • 1 Department Of Oncology, Addenbrooke's Hospital - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, CB2 0QQ - Cambridge/GB
  • 2 Warwick Clinical Trials Unit, University of Warwick, CV4 7AL - Coventry/GB
  • 3 Warwick Clinical Trials Unit,, University of Warwick, CV4 7AL - Coventry/GB
  • 4 Surgery, Oncology And Gastroenterology, University of padova, Padova/IT
  • 5 Department Of Medical And Surgical Sciences, University of Modena and Reggio Emilia, 41124 - Modena/IT
  • 6 Department Of Surgery, Oncology And Gastroenterology Dept., Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 7 Oncology Dept, Helsinki University Central Hospital (HUCH), 00260 - Helsinki/FI
  • 8 Management, EstiMates, 20810 - Turku/FI
  • 9 Medical Oncology, University Hospital of Heraklion, 712 01 - Heraklion/GR
  • 10 Department Of Oncology, Cambridge University Hospitals NHS Foundation Trust - Addenbrooke's Hospital, CB2 0QQ - Cambridge/GB
  • 11 Oncology, Edinburgh Cancer Centre Western General Hospital, EH4 2XU - Edinburgh/GB
  • 12 Medical Oncology, Mount Vernon Cancer Centre, HA6 2RN - Northwood/GB
  • 13 Ceo & Medical Director, Outreach Research Innovation Group Limited, M20 2YY - Manchester/GB
  • 14 Medical Oncology, ICM Regional Cancer Institute of Montpellier, 34090 - Montpellier/FR
  • 15 Medical Oncology, Institut Bergonié, 33076 - Bordeaux/FR
  • 16 Clinical Research, INCa - Institut National du Cancer, 92513 - Boulogne-Billancourt/FR
  • 17 Oncology, University Hospital Uppsala/Akademiska Sjukhuset, 751 85 - Uppsala/SE
  • 18 Breast Team, BWSCC - Beatson West of Scotland Cancer Centre - NHS Greater Glasgow and Clyde, G12 0YN - Glasgow/GB
  • 19 Oncology, Centre Léon Bérard, 69008 - Lyon/FR
  • 20 Medical Oncology Dept., ICANS - Institut de Cancérologie Strasbourg Europe, 67200 - Strasbourg/FR
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Resources

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Abstract LBA11

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.

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