PHERGain (NCT03161353): Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy
Lancet. 2024 Apr 3. IF: 168.9
3-year invasive disease-free survival with chemotherapy de-escalation using an (18)F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.
Pérez-García JM, Cortés J, Ruiz-Borrego M, Colleoni M, Stradella A, Bermejo B, Dalenc F, Escrivá-de-Romaní S, Calvo Martínez L, Ribelles N, Marmé F, Cortés A, Albacar C, Gebhart G, Prat A, Kerrou K, Schmid P, Braga S, Di Cosimo S, Gion M, Antonarelli G, Popa C, Szostak E, Alcalá-López D, Gener P, Rodríguez-Morató J, Mina L, Sampayo-Cordero M, Llombart-Cussac A; PHERGain Trial Investigators.
International Breast Cancer Center (IBCC), Barcelona, Spain; Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain; Institut Català D'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; Translational Genomics and Targeted Therapies Group, IDIBAPS, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Universidad Europea de Madrid, Madrid, Spain; Oncology Biomedical Research National Network (CIBERONC-ISCIII), Madrid, Spain; University Hospital Ramón y Cajal, Madrid, Spain; University Hospital Virgen del Rocío, Sevilla, Spain; Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain; Universidad de Valencia, Spain; Hospital Arnau de Vilanova, Universidad Católica de Valencia, Valencia, Spain; Hospital Universitario A Coruna, A Coruna, Spain; UGC Oncología Intercentros, Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Málaga, Spain; Hospital Universitari Sant Joan de Reus, Reus, Spain; European Institute of Oncology IRCCS, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy; Oncopole Claudius Regaud- IUCT, Toulouse, France; Tenon Hospital IUC-UPMC, Sorbonne University, Paris, France; INSERM U938 (Cancer Biology and Therapeutics), Paris, France; University Hospital Mannheim, Heidelberg University, Mannheim, Germany; Institut Jules Bordet, Hopital Universitaire de Bruxelles (HUB), Université Libre de Bruxelles (ULB), Brussels, Belgium; Barts Cancer Institute, Queen Mary University of London, UK; Barts Hospital NHS Trust, London, UK; Unidade de Mama, Instituto CUF de Oncologia, Lisbon, Portugal; NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy.
METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing.
FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43.3 months (range 0.0-63.0). In group B, the 3-year iDFS rate was 94.8% (95% CI 91.4-97.1; p=0.001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs.
INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy.
FUNDING: F Hoffmann-La Roche
PMID: 38582092
DOI: 10.1016/S0140-6736(24)00054-0
Lancet. 2024 Apr 3. IF: 168.9
Safe de-escalation of chemotherapy in HER2-positive early breast cancer.
Earl HM.
University of Cambridge, Cambridge, UK.
PMID: 38582093
DOI: 10.1016/S0140-6736(24)00535-X
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