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Chemotherapy De-Escalation Using an 18F-FDG PET/CT–Based, Pathologic Response–Adapted Strategy in HER2-Positive Early Breast Cancer: The PHERGain Trial

Background: Several de-escalation approaches are under investigation in patients with HER2-positive early breast cancer (EBC). We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab (HP) using 18F-FDG PET/CT (FDG-PET) and the possibility of chemotherapy de-escalation using a response–adapted strategy. 
 
Methods: PHERGain is a randomised, open-label phase 2 trial conducted in 45 centres from seven European countries. Patients aged ≥18 years with FDG-PET–evaluable, centrally confirmed HER2-positive EBC were randomly allocated (1:4) to receive docetaxel (T), carboplatin (C), and HP (arm A) or HP±endocrine therapy (arm B). Randomisation was stratified by hormone receptor status. Centrally reviewed FDG-PET was performed with pre-randomisation and after two treatment cycles. Arm A patients completed six cycles regardless of FDG-PET results. Arm B/FDG-PET–responders continued HP±endocrine therapy for six cycles; arm B/FDG-PET–nonresponders switched to six cycles of TCHP. Co-primary endpoints were the percentage of arm B/FDG-PET–responders with pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) and 3-year invasive disease-free survival (iDFS) of arm B patients. 
 
Findings: Between 26 June 2017 and 24 April 2019, 356 patients were randomly assigned to arm A (n=71) or arm B (n=285). pCR occurred in 41 patients in arm A (57.7%, 95% Confidence Interval (CI) 47.4–69.4%) and 101 in arm B (35.4%, 95% CI 29.9–41.3%). Among arm B patients, 227 (79.6%) were FDG-PET–responders, 86 (37.9%, 95% CI 31.6–44.5%) of whom obtained pCR. No new safety signals were identified. Global health status declined ≥10% in 65.0% and 35.5% of patients in arms A and B, respectively. 
 
Interpretation: FDG-PET identified HER2-positive EBC patients likely to benefit from chemotherapy-free dual HER2 blockade with HP and a reduced impact on global health status. Depending on iDFS results, this strategy could select patients not requiring chemotherapy. 
 
Trial Registration: This trial is registered with EudraCT (‎2016-002676-27) and ClinicalTrials.gov (NCT03161353). 
 
Funding Statement: The study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with F. Hoffmann-La Roche Ltd, which funded the study and provided the study drugs. MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol. 
 
Declaration of Interests: JMP-G reports to have a consulting role for Roche and Lilly, and travel expenses from Roche. GG reports research funding to the Institution from Roche and that an immediate family member received personal fees from Roche outside the submitted work. MRB reports to have a consulting role for Novartis, Pfizer, MSD, and to be part of speaker bureau for Pfizer, Novartis, Roche, Lilly, Astrazeneca. AS reports to have a consulting role for Roche and EISAI, to be part of speaker bureau for Roche and EISAI, expert testimony for ESIAI and Roche, and travel expenses from Roche and Pfizer. BB reports to have a consulting role for Genentech and MSD, to be part of speaker bureau for Genentech, and travel expenses from Pfizer. SE-de-R reports to have a consulting role for Roche, Pierre-Fabre, Eisai, research funding from Synthon and Roche, and travel expenses from Roche, Pierre-Fabre, and Daiichi Sankyo. AP reports honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, to have a consulting role for Amgen, Roche, Novartis, Pfizer, Brystol-Myers Squibb, Boehringer, PUMA Biotechnology, Oncolytics Biotech, Daiichi Sankyo, Abbvie, NanoString Technologies, research funding to the Institution from Roche, Novartis, Incyte, PUMA Biotechnology, to have intellectual property (PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY; WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence), travel expenses from Daiichi Sankyo, other relationship with Oncolytics, Peptomyc S.L., and that an immediate family member is an employee of Novartis. MC reports to have a consulting role for Pierre-Fabre, Pfizer, OBI Pharma, Celldex, AstraZeneca, and honoraria from Novartis. NA reports to have a consulting role for Pfizer, Novartis, Roche, AstraZeneca, and Lilly, and travel expenses from Pfizer, Novartis, Roche, and AstraZeneca. MS-C reports honoraria from MEDSIR, Syntax for Science, and Nestle, to have a consulting role for MEDSIR, Syntax for Science, and Nestle, to be part of speaker bureau for MEDSIR, Syntax for Science, Roche, research funding from MEDSIR, Syntax for Science, and Roche, and travel expenses from MEDSIR, Syntax for Science, and Roche. AM is a full-time employee of MEDSIR. JC reports to have a consulting role for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, and Clovis Oncology, honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, and Daiichi Sankyo, research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London, and intellectual property for MEDSIR. AL-C reports leadership for Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD, intellectual property for MEDSIR and Initia-Research, to have a consulting role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, and GSK, to be part of speaker bureau for Lilly, AstraZeneca, and MSD, research funding from Roche, Foundation Medicine, and Pierre-Fabre, Agendia, and travel expenses from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. LC, NR, NM, CA, FD, and KK have nothing to declare. 
 
Ethics Approval Statement: This study was performed in accordance with guidelines of the International Conference on 205 Harmonization and ethical principles outlined in the Declaration of Helsinki. Written informed 206 consent was obtained before enrolment, and all participants agreed to study-specific procedures. 207 Approvals from appropriate regulatory authorities and ethics committees were obtained.