TY - JOUR
T1 - 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
AU - APHINITY Steering Committee and Investigators
AU - Gelber, Richard D.
AU - Victoria Wang, Xin
AU - F. Cole, Bernard
AU - Cameron, David A
AU - Cardoso, Fatima
AU - Tjan-Heijnen, Vivianne
AU - Krop, Ian
AU - Loi, Sherene
AU - Salgado, Roberto
AU - Kiermaier, Astrid
AU - Frank, Elizabeth
AU - Restuccia, Eleonora
AU - Heeson, Sarah
AU - Bines, Jose
AU - Loibl, Sibylle
AU - Piccart-Gebhart, Martine
N1 - Funding Information:
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 ).
Funding Information:
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.
Funding Information:
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.
Funding Information:
The conduct of the APHINITY study was sponsored and funded by Roche. The STEPP analyses reported here were conducted per a research proposal submitted to and approved by the APHINITY Steering Committee. No specific additional funding was used to conduct the STEPP analyses.Richard D. Gelber: Research grants to institutions from Roche, Novartis, Pfizer, AstraZeneca, Merck.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.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.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.
Funding Information:
The conduct of the APHINITY study was sponsored and funded by Roche . The STEPP analyses reported here were conducted per a research proposal submitted to and approved by the APHINITY Steering Committee. No specific additional funding was used to conduct the STEPP analyses.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/3/18
Y1 - 2022/3/18
N2 - 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.
AB - 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.
KW - Adjuvant therapy
KW - HER2-positive early breast cancer
KW - Pertuzumab
KW - STEPP (Subpopulation Treatment Effect Pattern Plot)
KW - TILs (tumour infiltrating lymphocytes)
KW - Trastuzumab
U2 - 10.1016/j.ejca.2022.01.031
DO - 10.1016/j.ejca.2022.01.031
M3 - Article
SN - 0959-8049
VL - 166
SP - 219
EP - 228
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -