Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial

Abstract

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial.

Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents.

Design, setting, and participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019.

Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide.

Main outcomes and measures: Pathologic complete response and 3-year EFS and DRFS.

Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS.

Conclusions and relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study.

Trial registration: ClinicalTrials.gov Identifier: NCT01042379.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Yee reported receiving grants from National Institutes of Health (NIH), NIH/National Cancer Institute (NCI), and Quantum Leap Healthcare Collaborative during the conduct of the study; and grants from Boehringer Ingelheim and Martell Diagnostics, personal fees for serving on advisory boards from Puma Biotechnology, Lilly/Daiichi Sankyo, and Tempus, and serving on a scientific advisory board (uncompensated) for and holding stock in ApoGen Biotechnologies outside the submitted work. Dr DeMichele reported receiving salary support for study chair of clinical trial working group from Quantum Leap Healthcare Collaborative and grants and salary support from NCI during the conduct of the study. Dr Yau reported receiving grants from NIH/NCI during the conduct of the study. Dr Isaacs reported receiving grants from Georgetown University Cancer Center during the conduct of the study; and grants from Tesaro; personal fees from Genentech, AstraZeneca, Novartis, Puma Biotechnology, Seattle Genetics, Pfizer, and Context Therapeutics; and royalties from Wolters-Kluwer, McGraw-Hill, and Elsevier; and personal fees from Physician Education Resource outside the submitted work. Dr Symmans reported having founder equity in serving as unpaid scientific advisor to Delphi Diagnostics, Inc, outside the submitted work, and having a patent to measure residual cancer burden issued and licensed and a patent to predict sensitivity to endocrine therapy for breast cancer pending and licensed with Delphi Diagnostics, Inc. Dr Albain reported receiving grants from Seattle Genetics and personal fees from Puma Biotechnology, Genentech/Roche, and Pfizer during the conduct of the study, and receiving personal fees from Genomic Health and Novartis outside the submitted work. Dr B. Chen reported grants and nonfinancial support (supply of drugs) from Foundation for the NIH (FNIH) and Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Magliocco reported receiving grants from Roche and Genentech and receiving personal fees from and being an employee and shareholder of Protean BioDiagnostics outside the submitted work. Dr Chien reported receiving institutional support from Quantum Leap Healthcare Collaborative during the conduct of the study and receiving institutional support from Merck, Seattle Genetics, Amgen, and Puma Biotechnology outside the submitted work. Dr Stringer-Reasor reported receiving grants from Susan G Komen and V Foundation and personal fees from Eli Lilly and Company, Immunogenics, and BCI outside the submitted work. Dr Pusztai reported receiving grants and personal fees from AstraZeneca, Seattle Genetics, and Merck during the conduct of the study; and grants and personal fees from Bristol-Myers Squibb and Pfizer and personal fees from Novartis, Roche Genentech, h3bio, and Almac outside the submitted work. Dr Boughey reported grants from FNIH and Quantum Leap Healthcare Collaborative during the conduct of the study; grants from Eli Lilly and Company outside the submitted work; and a patent to methods and materials for treating cancer pending. Dr Lu reported receiving personal fees for serving on advisory boards from Daiichi, Novartis, Pfizer, and Puma Biotechnology outside the submitted work. Dr Lang reported receiving grants from Angle Parsortix and personal fees from Genomic Health outside the submitted work. Dr Han reported receiving institutional research funding from Quantum Leap Healthcare Collaborative during the conduct of the study and personal fees for speakers bureaus from Eli Lilly and Company outside the submitted work. Dr Clark reported receiving grants from Novartis outside the submitted work. Dr Nanda reported receiving grants from Immunomedics, OBI, Odonate Therapeutics, Seattle Genetics, and Corcept Therapeutics; grants and personal fees from AstraZeneca, Celgene, Daiichi, Genentech, Merck, and Pfizer; and personal fees from Aduro Biotech, Athenex, Clovis, G1 Therapeutics, MacroGenics, Puma Biotechnology, and Syndax Pharmaceuticals outside the submitted work. Dr Khan reported receiving grants from Novartis outside the submitted work. Dr Edmiston reported receiving grants from Safeway Foundation during the conduct of the study. Dr Chui reported being a full-time employee of Genentech and owning Roche stock. Dr Park reported receiving personal fees from Genentech and Pfizer outside the submitted work. Dr Liu reported receiving grants from Eisai, Novartis, Seattle Genetics, and Tesaro; grants and nonfinancial support (travel costs) from Genentech, Grail, and Merck; and nonfinancial support (travel costs) from AstraZeneca, Genomic Health, Ionis, Pfizer, and Syndax Pharmaceuticals outside the submitted work. Dr Olopade reported being a cofounder of CancerIQ and serving on a scientific advisory board for Tempus outside the submitted work. Dr Leyland-Jones reported receiving speakers fees from Genentech, Bayer, Puma Biotechnology, and Exelixis; serving as a board member for AKESOgen; and consulting fees from NedBio outside the submitted work. Dr Tripathy reported receiving grants and personal fees from Novartis and personal fees for serving on a steering committee from Pfizer during the conduct of the study; and receiving consulting fees from Genomic Health and GlaxoSmithKline outside the submitted work. Dr Rugo reported receiving grants to UCSF for clinical trials support from Genentech/Roche, Pfizer, Merck, Novartis, Eli Lilly and Company, OBI, Odonate Therapeutics, Daichi, Eisai, Macrogenics, Immunomedics, and consulting fees from Puma Biotechnology, Samsung, and Celltrion outside the submitted work; and receiving travel support to academic meetings from Mylan, Pfizer, Merck, AstraZeneca, and Novartis. Dr Schwab reported receiving other from Samumed outside the submitted work. Dr Helsten reported receiving grants from AbbVie, Eli Lilly and Company, Novartis, Genentech, Synthon, Bayer, Merrimack, and Pfizer outside the submitted work. Dr Beckwith reported receiving grants and nonfinancial support (supply of drugs) from FNIH and Quantum Leap Healthcare Collaborative during the conduct of the study. Dr Hylton reported receiving grants from NIH NCI during the conduct of the study. Dr van’t Veer reported receiving personal fees from, holding stock in, and being a cofounder of Agendia NV outside the submitted work. Dr Melisko reported receiving funding for trial conduct from Quantum Leap Healthcare Collaborative during the conduct of the study; and personal fees from Agendia and institutional research support for clinical trials from Puma Biotechnology, Novartis, Seattle Genetics, Nektar, KCRN Research, and AstraZeneca outside the submitted work. Dr Buxton reported receiving grants from Breast Cancer Research Foundation, Amgen, Genentech, Merck, Plexxikon, and Synta Pharmaceuticals; philanthropic support from Safeway Foundation, William K. Bowes Foundation, and Give Breast Cancer The Boot/UCSF; and nonfinancial support from Puma Biotechnology and AbbVie during the conduct of the study; and receiving grants from Amgen, Eli Lilly and Company, Janssen, and Bayer and personal fees from Berry Consultants, LLC, outside the submitted work. Dr Paoloni reported receiving personal fees from Arcus Biosciences outside the submitted work. Dr S. Asare reported receiving grants from Merck, Amgen, Puma Biotechnology, AbbVie, Genentech, and Synta Pharmaceuticals during the conduct of the study. Dr Sanil reported being an employee of Berry Consultants, a private consulting company with clients in the pharmaceutical and medical device industry. Dr Esserman reported receiving grants from and serving as a board member (uncompensated) for Quantum Leap Healthcare Collaborative and receiving grants from NIH/NCI during the conduct of the study; and receiving personal fees and travel costs from Medical Advisory Panel for Blue Cross/Blue Shield outside the submitted work. Dr D. Berry reported being co-owner of Berry Consultants, LLC, a company that designs adaptive clinical trials for pharmaceutical and medical device companies, NIH cooperative groups and grantees, patient advocacy groups, and international consortia. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

EFS indicates event-free survival; OS, overall survival.

Figure 2.. Kaplan-Meier Survival Curves

Kaplan-Meier survival curves for event-free survival (EFS) (A), and distant recurrence–free survival (DRFS) (B), in populations achieving pathologic complete response (pCR) at surgery (gray) and those with residual disease at time of surgery (orange). Kaplan-Meier survival curves for EFS among patients achieving pCR (C) and those who did not (D), stratified by hormone receptor (HR) and ERBB2 subtype (HR+ ERBB2+: light blue; HR+ ERBB2−: dark blue; HR− ERBB2−: gray; HR− ERBB2+: orange).