• José Manuel Pérez-García, Javier Cortés, Manuel Ruiz-Borrego, Marco Colleoni, Agostina Stradella, Begoña Bermejo, Florence Dalenc, Santiago Escrivá-de-Romaní, Lourdes Calvo Martínez, Nuria Ribelles, Frederik Marmé, Alfonso Cortés, Cinta Albacar, Geraldine Gebhart, Aleix Prat, Khaldoun Kerrou, Peter Schmid, Sofia Braga, Serena Di Cosimo, Maria Gion, Gabriele Antonarelli, Crina Popa, Emilia Szostak, Daniel Alcalá-López, Petra Gener, Jose Rodríguez-Morató, Leonardo Mina, Miguel Sampayo-Cordero, Antonio Llombart-Cussac, and PHERGain Trial Investigators.
• International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona 08022, Spain; Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain.
• Lancet. 2024 Apr 27; 403 (10437): 164916591649-1659.

BackgroundPHERGain 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.MethodsPHERGain 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.FindingsBetween 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.InterpretationAmong 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.FundingF Hoffmann-La Roche.Copyright © 2024 Elsevier Ltd. All rights reserved.

43 keywords...

hide…