Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

Abstract

Aim: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.

Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.

Results: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.

Conclusions: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.

Trial registration: clinicaltrials.gov Identifier NCT01358877.

Keywords: Adjuvant therapy; HER2-positive early breast cancer; Pertuzumab; STEPP (Subpopulation Treatment Effect Pattern Plot); TILs (tumour infiltrating lymphocytes); Trastuzumab.

Conflict of interest statement

Conflict of interest statement Richard D. Gelber: Research grants to institutions from Roche, Novartis, Pfizer, AstraZeneca, Merck. Xin Victoria Wang: None for this work. Bernard F. Cole: None for this work. David Cameron: Non-personal (all income to institution). Advisory/consultancy work with Roche, Novartis, Synthon, Seattle Genetics, Daiichi-Sankyo. Research funding during the life of APHINITY trial – Novartis and Roche. Stock ownership, expert testimony, directorships – NONE. Fatima Cardoso: Consultancy role for Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Debiopharm, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, IQVIA, MacroGenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, touchIME. Vivianne Tjan-Heijnen: Grants and personal fees from Pfizer, grants and personal fees from Roche, grants and personal fees from Novartis, grants and personal fees from E Lilly, grants from Eisai, grants and personal fees from Daiichi Sankyo, personal fees from Accord. Ian Krop: Research support (paid to his institution) from Genentech/Roche and Pfizer, has received fees from Novartis and Merck for Data Monitoring Board participation and has received consulting fees from Bristol Meyers Squibb, Daiichi/Sankyo, Macro-Genics, Context Therapeutics, Taiho Oncology, Genentech/Roche, Seattle Genetics, Celltrion and AstraZeneca. Sherene Loi: Research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics and Bristol Meyers Squibb. She has been a Scientific Advisory Board Member of Akamara Therapeutics. She is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. Roberto Salgado: Non-financial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology and Roche; advisory board fees for Bristol Myers Squibb; no COI related to this project. He is supported by a grant from the Breast Cancer Research Foundation (grant No. 17-194). Astrid Kiermaier: Employee and stockowner at F. Hoffmann-La Roche. Elizabeth Frank: None for this work. Debora Fumagalli: My institution received support from F. Hoffmann-La Roche Ltd/Genentech, Inc. for the conduct of APHINITY. My institution also receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi and Pfizer for the conduct of clinical trials. Carmela Caballero: My institution received support from F. Hoffmann-La Roche Ltd/Genentech, Inc. for the conduct of APHINITY. My institution also receives support from F. Hoffmann-La Roche Ltd/Genentech, AstraZeneca, Novartis, Servier, Tesaro, Sanofi and Pfizer for the conduct of clinical trials. Evandro Azambuja: Honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs, Lilly and Pierre Fabre; travel grants from Roche/GNE and GSK/Novartis; research grants to my institution from Roche/GNE, AstraZeneca, GSK/Novartis and Servier. Marion Procter: M.P.'s institution received funding from Roche in respect to the APHINITY trial. Emma Clark: Employee of Roche Products Ltd. Shares in F. Hoffmann-La Roche. Issued patent: uses for and article of manufacture including HER2 dimerisation inhibitor pertuzumab, 13/649591. Eleonora Restuccia: Employment by F. Hoffmann-La Roche and stocks in F. Hoffmann-La Roche/Genentech. Sarah Heeson: Employment by Roche Products Ltd and shares in F. Hoffmann-La Roche. Jose Bines: Dr. Bines reports personal fees from Roche during the conduct of the study. Sibylle Loibl: Dr. Loibl reports grants, non-financial support and other from Roche during the conduct of the study; grants and other from AbbVie, non-financial support and other from Amgen, grants and other from AstraZeneca, other from Bayer, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi Sankyo, other from EirGenix, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Prime/Medscape, non-financial support and other from Puma, other from Samsung, non-financial support and other from Seagen, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending and a patent Digital Ki67 Evaluator with royalties paid. Martine Piccart-Gebhardt: Board Member (Scientific Board): Oncolytics. Consultant (honoraria): AstraZeneca, Camel-IDS, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Seattle Genetics, Immutep, Seagen, NBE Therapeutics, Frame Therapeutics. Research grants to my Institute: AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. Speakers bureau/stock ownership: none.

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