Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer
Authors: Huober Jens , Weder Patrik , Ribi Karin , Thürlimann Beat , Thery Jean-Christophe , Li Qiyu , Vanlemmens Laurence , Guiu Séverine , Brain Etienne , Grenier Julien , Dalenc Florence , Levy Christelle , Savoye Aude-Marie , Müller Andreas , Membrez-Antonioli Véronique , Gérard Marie-Aline , Lemonnier Jérôme , Hawle Hanne , Dietrich Daniel , Boven Epie , Bonnefoi Hervé ,   Swiss Group for Clinical Cancer Research, Unicancer Breast Group, and Dutch Breast Cancer Research Group, Popescu Razvan , Schreiber Alexander , Caspar Clemens , Cescato- Wenger Corinne , Rochlitz Christoph , Condorelli Rosaria , Rabaglio-Poretti Manuela , Borner Markus , Mengis Bay Catherine , Jost Lorenz M. , von Moos Roger , Fehr Mathias , Bodmer Alexandre , Zaman Khallil , Seifer Bettina , Calderoni Antonello , Aebi Stefan Paul , Uhlmann Nussbaum Catrina , Riniker Salome , Bolliger Barbara , Ackermann Christoph , Dedes Konstantin , Bihan Céline , Capitain Olivier , Arsene Olivier , Simon Hélène , Rastkhah Mansour , Coudert Bruno , Mousseau Mireille , Venat- Bouvet Laurance , Lamy Régine , Brunel Véronique , Goncalves Anthony , Largillier Rémy , Spaeth Dominique , Vannetzel Jean- Michel , Ferrero Jean- Marc , Ricci Francesco , Rosca Cristina , Baron Marc , Campone Mario , Jacquin Jean- Philippe , Serra Sebastian , Del Piano Francesco , Dramais Marcel Dominique , Ovign Irma , Smorenburg Carolien , Konings Inge , Houtsma Daniel , Kessels Lonneke , van Warmerdam Laurance , de Graaf Hiltje , Kroep Judith , Agterof Mariette , van Rossum- Schornagel Quirine , Van Leeuwen Elise , Benavent Valérie , Pilop Christiane , Lemonier Jerôme , Martin Anne Laure , Ölschlegel Christiane , Gérard Marie- Aline , Gnant Michael , Loibl Sybille , Tondini Carlo 
Published: August 2023

ImportanceIn ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved.ObjectiveTo assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes.Design, Setting, and ParticipantsThis was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022.InterventionsPatients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B).Main Outcomes and MeasuresOverall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL).ResultsA total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B.Conclusions and RelevanceThe findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach.Trial RegistrationClinicalTrials.gov Identifier: NCT01835236