Chemotherapy de-escalation using an (18)F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): a multicentre, randomised, open-label, non-comparative, phase 2 trial.
Por:
Perez-Garcia, J, Gebhart, G, Borrego, M, Stradella, A, Bermejo, B, Schmid, P, Marme, F, Escriva-de-Romani, S, Calvo, L, Ribelles, N, Martinez, N, Albacar, C, Prat, A, Dalenc, F, Kerrou, K, Colleoni, M, Afonso, N, Di Cosimo, S, Sampayo-Cordero, M, Malfettone, A, Cortes, J, Llombart-Cussac, A and PHERGain Steering Comm Trial Inve
Publicada:
1 jun 2021
Ahead of Print:
18 may 2021
Categoría:
Oncology
Resumen:
BACKGROUND: Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using (18)F-fluorodeoxyglucose ((18)F-FDG)-PET ((18)F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy. METHODS: We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I-IIIA, invasive, operable breast cancer (=1·5 cm tumour size) with at least one breast lesion evaluable by (18)F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m(2) intravenous), carboplatin (area under the concentration-time curve 6 mg/mL per min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed (18)F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of (18)F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. (18)F-FDG-PET responders in group B continued this treatment for six further cycles; (18)F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of (18)F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353), and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3-6·0). 227 (80%) of 285 patients in group B were (18)F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6-44·5; p<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively INTERPRETATION: (18)F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy. FUNDING: F Hoffmann-La Roche.
Filiaciones:
Perez-Garcia, J:
Int Breast Canc Ctr, Quiron Grp, Barcelona 08022, Spain
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Gebhart, G:
Inst Jules Bordet Univ Libre Bruxelles, Brussels, Belgium
Borrego, M:
Hosp Univ Virgen Rocio, Med Oncol Dept, Seville, Spain
Stradella, A:
Hosp Llobregat, Inst Catala Oncol, Barcelona, Spain
Bermejo, B:
Hosp Clin Univ Valencia, Valencia, Spain
Schmid, P:
Queen Mary Univ London, Barts Expt Canc Med Ctr, Barts Canc Inst, London, England
Barts Hosp NHS Trust, London, England
Marme, F:
Heidelberg Univ, Med Fac Mannheim, Univ Hosp Heidelberg, Heidelberg, Germany
Escriva-de-Romani, S:
Vali dHebron Inst Oncol, Barcelona, Spain
Calvo, L:
Hosp Univ A Coruna, UGC Oncol Interctr, La Coruna, Spain
Ribelles, N:
Hosp Univ Reg & Virgen Victoria Malaga, Malaga, Spain
Inst Invest Biomed Malaga, Med Oncol Serv, Malaga, Spain
Martinez, N:
Univ Hosp Ramon y Cajal, Med Oncol, Madrid, Spain
Albacar, C:
Hosp Univ St Joan de Reus, Dept Med Oncol, Reus, Spain
Prat, A:
Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain
IDIBAPS, Translat Genom & Targeted Tberapies Grp, Barcelona, Spain
Univ Barcelona, Dept Med, Barcelona, Spain
Dalenc, F:
Toulouse Canc Res Ctr, Inst Claudius Regaud, INSERM, IUCT Oncopole, Toulouse, France
Kerrou, K:
Sorbonne Univ, Tenon Hosp IUC UPMC, AP HP, Nucl Med & Pet Ctr Dept, Paris, France
Colleoni, M:
IRCCS European Inst Oncol, Div Med Senolo Gy, Milan, Italy
Afonso, N:
Ctr Hosp Univ Porto, Porto, Portugal
Di Cosimo, S:
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Fdn IRCCS Ist Nazl Tumori, Dept Appl Res & Technol Dev, Biomarkers Unit, Milan, Italy
Sampayo-Cordero, M:
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Malfettone, A:
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Cortes, J:
Int Breast Canc Ctr, Quiron Grp, Barcelona 08022, Spain
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Vali dHebron Inst Oncol, Barcelona, Spain
:
Med Scientia Innovat Res, Barcelona, Spain
Med Scientia Innovat Res, Ridgewood, NJ USA
Univ Catolica, Hosp Arnau Vilanova, Valencia, Spain
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