Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2–positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2–positive breast cancer with different CD16A allelic variants are warranted.

INTRODUCTION

Margetuximab-cmkb is an Fc-engineered anti–human epidermal growth factor receptor 2 (anti-HER2) immunoglobulin G monoclonal antibody that targets the same epitope as trastuzumab, with similar antiproliferative effects.^1,2 Compared with trastuzumab, margetuximab was designed to increase binding affinity (in vitro) for activating Fcγ receptor (FcγR) CD16A (FcγRIIIa) and decrease binding affinity for inhibitory FcγR CD32B (FcγRIIb).^1-3 Margetuximab has improved binding affinity for both polymorphic allelic variants (158V or 158F) of CD16A, binds CD16A-158F with higher affinity than trastuzumab binds CD16A-158V, and enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab.^1-4

Primary analysis of progression-free survival (PFS) by central review of the phase 3 study SOPHIA (ClinicalTrials.gov identifier: NCT02492711)⁵ led to the US Food and Drug Administration approval of margetuximab with chemotherapy in patients with HER2+ metastatic breast cancer (BC) who have received ≥ 2 prior anti-HER2 regimens, at least one of which was for metastatic disease.⁶ Here, we report the final overall survival (OS) analysis after 385 deaths, with updated safety information.

PATIENTS AND METHODS

Study Design and Participants

Study design, eligibility criteria, treatment plan, and statistical analyses are detailed in a prior publication⁵ and are summarized in Appendix Figure A1 (online only). Sequential primary end points were PFS by central review followed by OS. These two end points were tested in a hierarchical manner, with PFS being tested first with full allocation of two-sided α = .05. OS was tested at two-sided α = .05 only when a statistically significant difference in PFS was obtained (ie, PFS test P < .05). Final analysis of PFS took place when 257 PFS events had occurred in the randomly assigned population. Final OS analysis was triggered when 385 events had occurred. Investigator-assessed PFS was a secondary end point. Additional planned end points included investigator-assessed objective response rate, safety, and exploratory evaluation of FcγR allelic variation on efficacy. Trial conduct was in accordance with Good Clinical Practice and Principles in the Declaration of Helsinki. An independent ethics committee approved the Protocol (online only) at each participating site. All patients provided written informed consent.

RESULTS AND DISCUSSION

Study Population

Baseline characteristics, previously published,⁵ show that all patients had received prior trastuzumab, all but one had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine (Table 1).⁵ Patient disposition is summarized in Appendix Figure A2 (online only). At the data cutoff date for this analysis (June 14, 2021), 8 (3.0%) of 266 patients in the margetuximab group and 5 (1.9%) of 270 patients in the trastuzumab group remained on study, including three patients remaining exclusively on margetuximab and one patient remaining exclusively on trastuzumab. Patients received a median of seven cycles of margetuximab plus chemotherapy versus six cycles of trastuzumab plus chemotherapy, with a median treatment duration of 20.7 months (0.7-61.4) for the margetuximab group and 19.4 months (0.1-64.5) for the trastuzumab group.

TABLE 1.

Demographic and Baseline Disease Characteristics in the Intention-to-Treat Population (N = 536)

Efficacy

At data cutoff, with a median follow-up of 20.2 months among all intention-to-treat (ITT) patients (0.1-64.5), 385 deaths had occurred (194 [73%] in the margetuximab group and 191 [71%] in the trastuzumab group). The median OS in the ITT population was not statistically different between the two treatment groups: 21.6 months with margetuximab versus 21.9 months with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620; Fig 1A).

FIG 1.

(A) Final OS in the ITT population and (B-E) planned prespecified^a exploratory OS analysis, per CD16A genotype^b by treatment group, June 14, 2021, cutoff. (A) Kaplan-Meier estimates of OS in the ITT population (n = 536). Kaplan-Meier estimates of OS by treatment group in (B) CD16A-158F carriers (FF or FV; n = 437; 86%), (C) CD16A-158FF homozygotes (n = 192; 38%), (D) CD16A-158FV heterozygotes (n = 245; 48%), and (E) CD16A-158VV homozygotes (n = 69; 14%). ^aNon–α-allocated analysis. ^bA total of 506 of 536 ITT patients genotyped (94%). HR, hazard ratio; ITT, intention-to-treat; NA, not available (because cannot be calculated); OS, overall survival.

A planned, prespecified non–α-allocated subgroup analyses of OS by chemotherapy backbone, HER2 status, showed no difference in survival between margetuximab and trastuzumab (Fig 2). Prespecified non–α-allocated subgroup analyses of OS by FcγR genotype were also conducted: genotyping was available for 506 patients (94%). Although no association was observed between CD32A or CD32B genotypes and survival benefit, OS subgroup analysis by CD16A genotype suggested a possible improvement in OS in favor of margetuximab in the CD16A-158FF patients, along with a possible improvement in OS in favor of trastuzumab in the CD16A-158VV patients. In 437 patients (86%) who carried the CD16A-158F low-affinity allele (F carriers), margetuximab prolonged the OS by 2.5 months compared with trastuzumab (Fig 1B). Median OS was 23.3 months with margetuximab versus 20.8 months with trastuzumab (HR, 0.86; 95% CI, 0.69 to 1.08; Fig 1B). Among 192 CD16A-158FF patients (38%), margetuximab prolonged the OS by 4.4 months compared with trastuzumab. Median OS was 23.6 months with margetuximab versus 19.2 months with trastuzumab (HR, 0.72; 95% CI, 0.52 to 1.00; Fig 1C). In 245 CD16A-158FV patients (48%), the median OS was 21.3 months with margetuximab versus 22.0 months with trastuzumab (HR, 0.96; 95% CI, 0.71 to 1.30; Fig 1D). By contrast, in the 69 CD16A-158VV patients (14%), the median OS was 22.0 months with margetuximab versus 31.1 months with trastuzumab (HR, 1.77; 95% CI, 1.01 to 3.12; Fig 1E). Additional efficacy results are shown in Appendix Figure A3 (online only), Appendix Table A1 (online only), and are presented in Appendix 2 (online only), Supplemental Efficacy Results.

FIG 2.

Planned prespecified^a exploratory OS subgroup analyses (cutoff, June 14, 2021)^b. Median OS, HRs, and 95% CIs are shown by subgroup. ^aNon-α-allocated analysis. ^bA total of 506 of 536 ITT patients genotyped (94%). ^cCD32B-232TT not included in the forest plot because n = 9 is too small (five on margetuximab and four on trastuzumab) to make the analysis meaningful. HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridization; OS, overall survival.

Safety

As of June 14, 2021, the safety population included 264 patients in the margetuximab group and 266 patients in the trastuzumab group (Appendix Table A2, online only). Common adverse events (AEs) occurring in ≥ 20% of patients, regardless of causality, were fatigue, nausea, diarrhea, and neutropenia in both groups, as well as vomiting and pyrexia (margetuximab group) and anemia (trastuzumab group; Appendix Table A3, online only). Grade 3 or greater AEs in at least 5% of patients were neutrophil count decreased and anemia in both groups, as well as fatigue (margetuximab group) and febrile neutropenia (trastuzumab group; Appendix Table A3). Discontinuations from study treatment because of AEs were 4% (10 patients) in each treatment group (Appendix Table A2). There were six deaths because of AEs, none of which were considered treatment-related: four patients (2%) in the margetuximab group and two patients (1%) in the trastuzumab group (Appendix Table A2). Additional safety results are presented in Appendix 2, Supplemental Safety Results.

In SOPHIA, the final OS analysis after 385 deaths in the ITT population did not demonstrate a survival advantage for margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in patients with pretreated HER2+ advanced BC.

The prespecified non–α-allocated evaluation of FcγR allelic variation on efficacy including an analysis of CD16A genotypes (FF, FV, and VV) suggested a possible improvement in OS in favor of margetuximab in the CD16A-158FF patients, along with a possible improvement in OS in favor of trastuzumab in the CD16A-158VV patients. Of note, there was an imbalance in poor prognostic characteristics between the two treatment groups in the CD16A-158VV patients⁵ although there is no other clear explanation for why margetuximab did not provide a greater clinical benefit in these patients. In this study, the proportion of CD16A-158FF patients versus CD16A-158VV patients was 38% versus 14%, similar to other studies of HER2 agents in HER2+ BC.^7-13 Margetuximab improved median PFS (27% relative risk reduction) and objective response rate assessed by the investigator over trastuzumab, at the time of this final OS analysis.

The safety profile of margetuximab plus chemotherapy assessed at the time of this final OS analysis of SOPHIA confirmed an acceptable profile comparable with trastuzumab plus chemotherapy, similar to previous reports⁵ and consistent with the US Food and Drug Administration–approved label for margetuximab.⁶ Infusion-related reactions occurred at a higher frequency in the margetuximab plus chemotherapy arm but were manageable with premedications. Left ventricular dysfunctions occurred at a similar frequency in both arms. Left ventricular dysfunction requiring delay or cessation of margetuximab/trastuzumab administration occurred in fewer patients receiving margetuximab than in patients receiving trastuzumab.

In conclusion, PFS advantage with margetuximab plus chemotherapy observed in the previous analysis⁵ and confirmed in this analysis did not translate into a significant difference in OS in the ITT population of SOPHIA. However, margetuximab plus chemotherapy is an available treatment option for patients with pretreated HER2+ advanced BC. Studies of margetuximab in patients with HER2+ BC with different CD16A allelic variants are warranted, including MARGOT (ClinicalTrials.gov identifier: NCT04425018), a randomized phase 2, neoadjuvant investigator-initiated study on the efficacy of margetuximab versus trastuzumab (both plus pertuzumab and paclitaxel) in patients with stage II–III HER2+ BC carrying the CD16A-158F low-affinity allele.

APPENDIX 1. Group Information for the SOPHIA Study (ClinicalTrials.gov identifier: NCT02492711)

Austria—Daniel Egle, MD (Universitätsklinik Innsbruck, Innsbruck), Alois Lang, MD, and Holger Rumpold, MD (Landeskrankenhaus Rankweil, Vorarlberg). Belgium—Sevilay Altintas, MD, PhD (UZ Antwerpen—Oncologie, Edegem), Annelore Barbeaux, MD (CHR Verviers East Belgium, Verviers), Jean-Francois Baurain, MD, PhD (Cliniques Universitaires Saint-Luc—Oncology, Bruxelles), Marleen Borms, MD (AZ Groeninge—Campus Loofstraat, Kortrijk), Nele Claes, MD (AZ Sint-Jan Brugge—Oostende AV—Campus Sint-Jan, Brugge), Caterina Confente, MD (INDC Entité Jolimontoise—CH de Jolimont-Lobbes, Haine-Saint-Paul), Ines Deleu, MD (AZ Nikolaas—Campus Sint-Niklaas Moerland, Sint-Niklaas), Luc Dirix, MD, PhD (GZA Ziekenhuizen—Campus Sint-Augustinus, Wilrijk), Christel Fontaine, MD (UZ Brussel—Campus Jette, Bruxelles), Marie-Pascale Graas, MD (CHC MontLégia, Liège), Stephanie Henry, MD, Donatienne Taylor, MD, and Peter Vuylsteke, MD (CHU UCL Namur—Site Sainte-Elisabeth, Namur), Jeroen Mebis, MD, PhD (Jessa Ziekenhuis—Campus Virga Jesse, Hasselt), Renaud Poncin, MD (Clnique Saint Pierre Ottignies, Ottignies), Isabelle Spoormans, MD (AZ Damiaan, Oostende). Canada—Orit Freedman, MD, FRCP(C), MSc (RS McLaughlin Durham Regional Cancer Centre, Lakeridge Health, Oshawa), Skander Ghedira, MD (Dr Leon Richard Oncology Centre, Moncton), Ravi Ramjeesingh, MD, PhD (The Atlantic Clinical Cancer Research Unit, Halifax). Czech Republic—Zdenek Kral, MD, CSc (Fakultni nemocnice Brno, Brno), Bohuslav Melichar, MD, PhD (Fakultni nemocnice Olomouc, Olomouc), Katarína Petráková, MD, PhD (Masaryk Memorial Cancer Institute, Brno), Jana Prausova, MD, PhD, MBA (Fakultni nemocnice v Motole, Praha 5). Denmark—Vesna Glavicic, MD (Næstved Sygehus, Næstved), Erik H. Jakobsen, MD (Vejle Hospital, Vejle), Julia Kenholm, MD (Regionshospitalet Herning (Herning Centralsygehus), Herning), Sven Langkjer, MD, PhD (Aarhus Universitets Hospital, Aarhus C). Finland—Johanna Mattson, MD, PhD (Helsinki University Central Hospital—Meilahden Sair, Helsinki), Minna Tanner, MD, PhD, MSc (Tampere University Hospital, Tampere). France—Thomas Bachelot, MD, PhD (Centre Leon Berard, Lyon Cedex 08), Etienne Brain, MD, PhD (Institut Curie—Hopital Rene Huguenin, Saint-Cloud), Mario Campone, MD, PhD (Centre de Lutte Contre le Cancer—Institut de Cancer, Saint Herblain), Bruno Coudert, MD, and Audrey Hennequin, MD (Centre Georges Francois Leclerc, Dijon), Veronique Dieras, MD, MSc (Centre De Lutte Contre Le Cancer—Institut Curie, Paris), Jean-Marc Ferrero, MD (University Côte d'Azur, Centre Antoine Lacassagne, Nice), Cyril Foa, MD, and Robert Herve, MD (Hôpital Privé Clairval, Marseille), Christelle Levy, MD (Centre François Baclesse, Institut Normand du Sein, Caen Cedex 5), Marie-Ange Mouret-Reynier, MD (Centre Jean Perrin, Clermont-Ferrand Cedex 1), Francesco Ricci, MD, PhD (Centre De Lutte Contre Le Cancer—Institut Curie, Paris). Germany—Bahriye Aktas, MD, PhD, and Oliver Hoffmann, MD, PhD (Universitaetsklinikum Essen—Klinik fuer Frauenheilkunde, Essen), Nikola Bangemann, MD (Campus Charité Mitte, Berlin), Malgorzata J. Banys-Paluchowski, MD, and Gerhard Gebauer, MD, MBA (Katholisches Marienkrankenhaus gGmbH—Frauenklinik, Hamburg), Wolfgang Eiermann, MD (Interdisziplinäres Onkologisches Zentrum München, München), Peter A. Fasching, MD (Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen), Aristoteles Giagounidis, MD (Marien Hospital Düsseldorf, Düsseldorf), Eva-Maria Grischke, MD (Universitaetsklinikum Tuebingen, Tuebingen), John Hackmann, MD (Marien Hospital, Witten), Meinolf Karthaus, MD (Städtisches Krankenhaus München—Neuperlach, München), Anita Prechtl, MD (Praxis für Frauenheilkunde, München), Andreas Schneeweiss, MD (University Hospital Heidelberg, Heidelberg), Pauline Wimberger, MD (Medizinische Fakultät Carl Gustav Carus, Dresden). Israel—Noa Efrat, MD (Kaplan Medical Center, Rehovot), David Geffen, MD, and Margarita Tokar, MD (Soroka University Medical Center, Beer Sheva), Goldberg Hadassah, MD (Galilee Medical Center, Nahariya), Natalya Karminsky, MD, PhD (The Edith Wolfson Medical Center, Holon), Bella Kaufman, MD (Chaim Sheba Medical Center, Breast Oncology Institute, Ramat Gan), Iryna Kuchuk, MD (Meir Medical Center, Kfar Saba), Michelle Leviov, MD (Clalit Health Services—Lin Medical Center, Haifa), Larisa Ryvo, MD, and Ido Wolf, MD (Tel Aviv Sourasky Medical Center, Tel Aviv), Beatrice Uziely, MD (Hadassah Medical Center, Jerusalem), Rinat Yerushalmi, MD (Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva). Italy—Antonio Ardizzoia, MD (Presidio Ospedaliero “Alessandro Manzoni”, Lecco), Rossana Berardi, MD (Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona), Antonio Bernardo, MD, and Lorenzo Pavesi, MD (Istituti Clinici Scientifici Maugeri, Pavia), Laura Biganzoli, MD (Nuovo Ospedale di Prato Santo Stefano, Prato), Roberto Bordonaro, MD (Presidio Ospedaliero Garibaldi-Nesima, Catania), Marco Colleoni, MD (European Institute of Oncology, Milan), Giuseppe Curigliano, MD, PhD (European Institute of Oncology, University of Milano, Milan), Mauro D'Amico, MD (Ente Ospedaliero Ospedali Galliera, Genova), Bruno Daniele, MD, and Vincenza Tinessa, MD (Azienda Ospedaliera San Pio, Presidio Gaetano Rummo, Benevento), Michelino De Laurentiis, MD, PhD (Istituto Nazionale Tumori “Fondazione Pascale,” Naples), Alfredo Falcone, MD (Azienda Ospedaliero-Universitaria Pisana Santa Chiara, Pisa), Gabriella Farina, MD, and Nicla Maria La Verde, MD (Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milano), Guido Francini, MD (Azienda Ospedaliero Universitaria Senese, Siena), Antonio Frassoldati, MD (Azienda Ospedaliero-Universitaria “Arcispedale Sant'Anna,” Ferrara), Daniele Generali, MD (Presidio Ospedaliero di Cremona, Cremona), Donatella Grasso, MD, and Paolo Pedrazoli, MD (Fondazione IRCCS Policlinico San Matteo, Pavia), Vito Lorusso, MD (Istituto Oncologico Giovanni Paolo II, Bari), Gabriele Luppi, MD (Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena), Paolo Marchetti, MD (Azienda Ospedaliero-Universitaria Sant'Andrea, Roma), Filippo Montemurro, MD (Instituto di Candiolo, Candiolo), Antonino Musolino, MD, PhD, MSc (University of Parma—University Hospital of Parma, Parma), Andrea Rocca, MD (Istituto Scientifico Romagnolo per lo Studio e la Cura die Tumori, Meldola), Elena Rota Caremoli, MD (Azienda Ospedaliera Papa Giovanni XXIII, Bergamo), Enzo Ruggeri, MD (Ospedale Belcolle, Viterbo), Armando Santoro, MD (Istituto Clinico Humanitas, Rozzano), Giuseppe Tonini, MD (Policlinico Universitario Campus Bio-Medico, Roma). Korea—Seock-Ah Im, MD, PhD (Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul), Young-Hyuck Im, MD, PhD (Samsung Medical Center, Seoul), Sung-Bae Kim, MD, PhD (Asan Medical Center, Seoul), Joo Hyuk Sohn, MD, PhD (Severance Hospital, Yonsei University Health System, Seoul). the Netherlands—Maaike de Boer, MD, PhD (Maastricht University Medical Center, GROW-School of Oncology and Developmental Biology, Maastricht), Franciscus Erdkamp, MD (Stichting Zuyderland Medisch Centrum, Sittard-Geleen), Daniel Houtsma, MD, and Johanna Portielje, MD, PhD (Haga Ziekenhuis, Leiden), Robbert van Alphen, MD (Elisabeth-Tweesteden Ziekenhuis, Tilburg). Poland—Barbara Bauer-Kosinska, MD (Mazowiecki Szpital Onkologiczny, Wieliszew), Dorota Garncarek-Lange, MD, PhD (Wojewódzki Szpital Specjalistyczny we Wrocławiu, Wroclaw), Bartosz Itrych, MD, and Tomasz Sarosiek, MD, PhD (Magodent Sp. z o.o. Szpital Elblaska, Warszawa), Tomasz Jankowski, MD, PhD (Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli, Lublin), Zbigniew Nowecki, MD, PhD (Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie—Państwowy Instytut Badawczy, Warszawa), Tadeusz Pieńkowski, MD, PhD (Radomskie Centrum Onkologii, Warszawa), Piotr Wysocki, MD, PhD (Spzoz Szpital Uniwersytecki w Krakowie, Uniwersyteckie Lecznictwo Szpitalne, Krakow). Portugal—Miguel Abreu, MD (Instituto Português Oncologia Francisco Gentil do Porto, Porto), Fatima Cardoso, MD, and Maria Rita Dionisio, MD (Champalimaud Clinical Center—Champalimaud Foundation, Lisbon), Luis Costa, MD, PhD (Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon). Puerto Rico—Mirelis Acosta, MD (Fundacion de Investigacion de Diego, San Juan). Spain—José Alés Martínez, MD, PhD (Hospital Nuestra Señora de Sonsoles, Avila), Begoña Bermejo de las Heras, MD, PhD (Hospital Clínico Universitario de Valencia, Valencia), Beatriz Cirauqui, MD (Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, Badalona), Javier Cortes Castan, MD, PhD (IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona—Vall d'Hebron Institute of Oncology, Barcelona), Joan Dorca Ribugent, MD (ICO-Hospital Universitari de Girona Dr Josep Trueta, Girona), María Fernández Abad, MD, PhD (Hospital Universitario Ramón y Cajal, Madrid), Laura García Estévez, MD, and Elena Sevillano Fernández, MD (Hospital Madrid Norte Sanchinarro, Madrid), José García Sáenz, MD (Hospital Clínico San Carlos, Madrid), Joaquin Gavilá Gregori, MD (Fundación Instituto Valenciano de Oncología, Valencia), Antonio Gonzalez Martin, MD, PhD, and Raúl Márquez Vázquez, MD (MD Anderson Center Madrid, Madrid), Santiago González Santiago, MD (Hospital San Pedro de Alcántara, Cáceres), José Juan Illarramendi Manas, MD (Hospital de Navarra, Pamplona), Mireia Melé Olivé, MD (Hospital Universitari Sant Joan de Reus, Reus), Serafín Morales Murillo, MD (Hospital Universitari Arnau de Vilanova, Lleida), Laura Palomar Abad, MD, and Ana Santaballa Bertrán, MD (Hospital Universitari i Politècnic La Fe, Valencia), José Pérez García, MD, PhD (Hospital Quirón Barcelona, Barcelona), José Ponce Lorenzo, MD (Hospital General Universitario de Alicante, Alicante), Manuel Ruiz Borrego, MD (Hospital Universitario Virgen del Rocio, Sevilla), Cristina Saura Manich, MD, PhD (Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona), Miguel Angel Segui Palmer, MD, PhD (Hospital Universitari Parc Tauli, Sabadell), Sonia Servitja Tormo, MD, PhD (Hospital del Mar, Barcelona). the United Kingdom—Pavel Bezecny, MD, DVM, MRCP (Blackpool Victoria Hospital, Blackpool), Steve Chan, MBBS, DM, FRCR, FRCP (Nottingham University Hospital, Nottingham), Amandeep Dhadda, MBChB, MSc, MRCP, FRCR (Castle Hill Hospital, Hull), Janine Graham, MBChB, MRCP (South Tees NHS Foundation Trust, Middlesbrough), Catherine Harper-Wynne, MBBS, MRCP, MD, CCST, FRCP (Maidstone Hospital—Kent Oncology Centre, Maidstone), Martin Hogg, MBBS, MRCP (Royal Preston Hospital, Blackburn), Chiara Intrivici, MD, PhD (United Lincolnshire Hospitals NHS Trust, Boston, MA), Janine Mansi, MBBS, MRCP, FRCP, MD (Guys and Saint Thomas NHS Foundation Trust, London); Christopher J. Poole, MBBChir, MRCP, FRCP (University Hospital Coventry, Coventry). the United States—Apurv Agrawal, MD (New Jersey Hematology Oncology Associates, Brick, NJ), Eugene Ahn, MD, and Dennis Citrin, MBChB, MRCP, PhD (Cancer Treatment Centers of America at Midwestern Reg, Zion, IL), Sramila Aithal, MD (Eastern Regional Medical Center Inc, Philadelphia, PA), Eleni Andreopoulou, MD, and Linda Vahdat, MD, MBA (Breast Center at Weill Cornell Medicine, New York, NY), Shakeela Bahadur, MD (Banner MD Anderson Cancer Center, Gilbert, AZ), Samuel Bailey, MD, and Hassan Ghazal, MD (ARH Cancer Clinic, Hazard, KY), Reema Batra, MD (Sharp Memorial Hospital, San Diego, CA), Chiara Battelli, MD, PhD (New England Cancer Specialists, Scarborough, ME), Thaddeus Beeker, MD, and Michael Meshad, MD (Southern Cancer Center, Mobile, AL), Christiana M. Brenin, MD (University of Virginia Cancer Center, Charlottesville, VA), Ursa Brown-Glaberman, MD (University of New Mexico Comprehensive Cancer Center, Albuquerque, NM), Adam Brufsky, MD, PhD, FACP (University of Pittsburgh Medical Center, Pittsburgh, PA), Daniel Bruetman, MD, and Ebenezer Kio, MD (IU Health Goshen Center For Cancer Care, Goshen, IN), Jennifer Carney, MD, MA (Kaiser Permanente Hawaii Moanalua Medical Center, Honolulu, HI), Helen Chew, MD (UC Davis Medical Center—UC Davis Comprehensive Cancer, Sacramento, CA), Marc Citron, MD (ProHealth Care Associates, LLP, Lake Success, NY), Melody Cobleigh, MD (Rush University Medical Center, Chicago, IL), Suzanne Cole, MD (Mercy Clinic Oncology and Hematology, Oklahoma City, OK), Jessica Croley, MD (Saint Joseph Hospital, Lexington, KY), Christopher Croot, MD (Jewish Medical Center Northeast, Louisville, KY), Brooke Daniel, MD (Tennessee Oncology PLLC, Chattanooga, TN), Robert Dichmann, MD (Central Coast Medical Oncology, Santa Maria, CA), Alfred DiStefano, MD (Arlington Cancer Center, Arlington, TX), Tracy Dobbs, MD (Tennessee Cancer Specialists, PLLC—Dowell Springs, Knoxville, TN), Robert Droder, MD, and Arielle Lee, MD (HOPE Cancer Center of East Texas, Tyler, TX), Erin Ellis, MD (Swedish Cancer Institute, Seattle, WA), John Erban, MD, and Rachel Buchsbaum, MD (Tufts Medical Center Cancer Center, Boston, MA), Louis Fehrenbacher, MD, and Jennifer Suga, MD (Kaiser Permanente Medical Center, Vallejo, CA), Trevor Feinstein, MD (Piedmont Cancer Institute, PC, Atlanta, GA), Erin Fleener, MD (Saint Joseph Health Cancer Center, Bryan, TX), William Fusselman, MD (Physicians Clinic of Iowa, Cedar Rapids, IA), Nashat Gabrail, MD (Gabrail Cancer Center Research, Canton, OH), Christopher Gallagher, MD (MedStar Washington Hospital Center, Washington, DC), William J. Gradishar, MD, FASCO, FACP (Northwestern University, Chicago, IL), Deena Graham, MD (Hackensack University Medical Center—John Theurer Cancer Center, Hackensack, NJ), Maria Grosse-Perdekamp, MD (Carle Cancer Center, Urbana, IL), Barbara Haley, MD (University of Texas Southwestern Medical Center, Dallas, TX), Kathleen Harnden, MD, and Mary Wilkinson, MD (Inova Schar Cancer Institute, Fairfax, VA), Lowell Hart, MD, FACP (Florida Cancer Specialists & Research Institute, Fort Myers, FL), John Hrom, MD (Hattiesburg Clinic, PA, Hattiesburg, MS), Sara Hurvitz, MD, FACP (UCLA Hematology Oncology, Ventura, Los Angeles, CA), Nicholas Iannotti, MD, FACP (Hematology/Oncology Associates of the Treasure Coast, Port Saint Lucie, FL), Sujith Kalmadi, MD (Ironwood Cancer & Research Center, Chandler, AZ), Edward Kaplan, MD (Hematology Oncology of the North Shore, Skokie, IL), Peter A. Kaufman, MD, and Gary Schwartz, MD (Dartmouth-Hitchcock Norris Cotton Cancer Center, Lebanon, NH), Mary Kemeny, MD, FACS (Queens Hospital Center, Jamaica, NY), Stephen Kendall, MD (Utah Cancer Specialist, Salt Lake City, UT), Elisa Krill-Jackson, MD, FACP (Mount Sinai Comprehensive Cancer Center, Miami Beach, FL), Bradley Lash, MD (Guthrie Medical Group, PC, Corning, NY), Andrew Brown, MD, and Anna Litvak, MD (Cancer Center of Saint Barnabas Medical Center, Livingston, NJ), Philip Lowry, MD (Guthrie Medical Group, PC, Sayre, PA), Kit Lu, MD (UPMC Pinnacle Health Cancer Institute, Harrisburg, PA), Cynthia Lynch, MD (Western Regional Medical Center, Inc, Goodyear, AZ), Ajit Maniam, MD (Pacific Cancer Medical Center, Inc, Anaheim, CA), Monte Martin, MD (Flaget Cancer Center, Bardstown, KY), Samuel McCachren, MD, Suratha Murali, MD, MS, and Wenqing Zhang, MD, PhD (Thompson Cancer Survival Center, Knoxville, TN), Diana Medgyesy, MD, FACP, and Ann Stroh, DO (Poudre Valley Health Care, Inc, Fort Collins, CO), Susan Melin, MD (Wake Forest University Baptist, Winston Salem, NC), Raul Mena, MD (East Valley Hematology and Oncology Medical Group, Burbank, CA), Kathy Miller, MD (Indiana University Health Melvin and Bren Simon Cancer Center, Indianapolis, IN), Aldemar Montero, MD (Gwinnett Medical Center—Center for Cancer Care, Lawrenceville, GA), Mahvish Muzaffar, MD (ECU—Leo W Jenkins Cancer Center, Greenville, NC), Bichlien Nguyen, MD (Long Beach Memorial Medical Center, Bakersfield, CA), Damien Hansra, MD, and Mary Ninan, MD (Southeastern Regional Medical Center, Newnan, GA), Yelena Novik, MD, FACP (New York University Clinical Cancer Center, New York, NY), Brian O'Connor, MD (Frederick Memorial Hospital, Frederick, MD), Ira Oliff, MD (Orchard Healthcare Research Inc, Skokie, IL), Raul Oyola, MD (Northwest Georgia Oncology Centers, PC, Marietta, GA), Mark D. Pegram, MD (Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Stanford, CA), Alejandra Perez, MD (University of Miami Sylvester Comprehensive Cancer Center, Plantation, FL), Timothy J. Pluard, MD (Saint Luke's Cancer Institute, Kansas City, MO), David Riseberg, MD (Mercy Medical Center, Baltimore, MD), Angel Rodriguez, MD (Austin Cancer Center, Austin, TX), Hope S. Rugo, MD, FASCO (University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA), Lupe Salazar, MD (University of Washington—Seattle Cancer Care Alliance, Seattle, WA), Nikita Shah, MD (UF Health Cancer Center at Orlando Health, Orlando, FL), Sagun Shrestha, MD (Southwestern Regional Medical Center Inc, Tulsa, OK), Bethany Sleckman, MD (Mercy Hospital Saint Louis, Saint Louis, MO), Robert Somer, MD (Cooper University Hospital, Camden, NJ), Scott Sonnier, MD (Touro Infirmary Hospital, Marrero, LA), Elizabeth Tan-Chiu, MD (FL Cancer Research Institute, Plantation, FL), Saritha Thumma, MD (Cancer Care Northwest, PS, Spokane, WA), Michaela Tsai, MD (Virginia Piper Cancer Institute, Minneapolis, MN), Sonia Varghese, MD, MBBS (Mercy Clinic Oncology and Hematology, Dallas, TX), Sumithra Vattigunta, MD (Palm Beach Cancer Institute, West Palm Beach, FL), Pramvir Verma, MD (Fort Belvoir Community Hospital, Fort Belvoir, VA), Jeanine L Werner, MD (Anne Arundel Medical Center, Annapolis, MD), Gail S. Wright, MD, FACP, FCCP (Florida Cancer Specialists & Research Institute, New Port Richey, FL), Denise A. Yardley, MD (Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, TN), Robyn Young, MD (The Center for Cancer and Blood Disorders, Fort Worth, TX), Andrew Zahalsky, MD (Monongahela Valley Hospital, Monongahela, PA).

FIG A1.

SOPHIA study design. CBA, central blinded analysis; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

FIG A2.

CONSORT diagram. All randomly assigned patients were included in the intention-to-treat population; randomly assigned patients who received at least one dose of study treatment were included in the safety population. Reasons for withdrawals are shown. ^aA patient may have more than one reason for screening failure. AE, adverse event; PD, progressive disease; tx, treatment.

FIG A3.

PFS assessed by the investigator in the intention-to-treat population (cutoff, June 14, 2021; n = 536). HR, hazard ratio; PFS, progression-free survival.

TABLE A1.

Investigator-Assessed ORR by CD16A

TABLE A2.

Summary of AEs in the Safety Population (cutoff, June 14, 2021)

TABLE A3.

AEs in the Safety Population, Regardless of Causality (cutoff, June 14, 2021)

APPENDIX 2. SUPPLEMENTAL MATERIAL

Supplemental Efficacy Results

The median progression-free survival assessed by the investigator in the intention-to-treat population was nominally statistically different between the two treatment groups: 5.7 months with margetuximab versus 4.4 months with trastuzumab (hazard ratio, 0.73; 95% CI, 0.60 to 0.88; P = .001; Appendix Fig A3). These findings were similar at the cutoff of September 2019 when the median progression-free survival assessed by the investigator was 5.7 months with margetuximab versus 4.4 months with trastuzumab (hazard ratio, 0.71; 95% CI, 0.58 to 0.86; P < .001).⁵

All 536 patients were evaluable for response. Margetuximab recipients had higher investigator-assessed objective response rate (ORR) than trastuzumab recipients (26% v 14%; Appendix Table A1). These rates were similar at the cutoff of September 2019 when the investigator-assessed ORR was 25% versus 14%.⁵ Subgroup analysis of ORR by CD16A genotype showed that margetuximab improved ORR over trastuzumab across all CD16A-158 genotypes, except in the CD16A-158V homozygous patients, who experienced improved ORR from trastuzumab treatment instead (Appendix Table A1).

Supplemental Safety Results

Adverse events (AEs) of special interest included infusion-related reactions (IRRs) and left ventricular (LV) dysfunction. All-grade IRRs were more common with margetuximab than with trastuzumab (36 [14%] v 9 [3%], respectively; Appendix Tables A2 and A3). Among margetuximab recipients, grade ≥ 3 IRRs were reported in five (2%) patients and IRRs leading to discontinuation in three (1.1%) patients. No trastuzumab recipients had grade ≥ 3 IRRs or IRRs leading to discontinuation. AEs of LV dysfunction occurred in eight patients (3%) in both treatment groups (Appendix Table A2). Grade ≥ 3 LV dysfunction AEs were observed in three margetuximab recipients (1%) and one trastuzumab recipient (0.4%). AEs of LV dysfunction requiring dose delay or discontinuation were experienced in four margetuximab-treated (2%) versus seven trastuzumab-treated patients (3%).

DATA SHARING STATEMENT

Overall data will be available but not individual patient data.

AUTHOR CONTRIBUTIONS

Conception and design: Hope S. Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Cristina Saura, Shengyan Hong, William J. Gradishar

Administrative support: Hope S. Rugo, Giuseppe Curigliano, Peter A. Kaufman, Emily J. Ashley

Provision of study materials or patients: Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy J. Pluard, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Peter A. Kaufman, William J. Gradishar

Collection and assembly of data: Hope S. Rugo, Seock-Ah Im, Giuseppe Curigliano, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy J. Pluard, Francesco Ricci, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Rinat Yerushalmi, Peter A. Fasching, Peter A. Kaufman, Emily J. Ashley, Minori Koshiji Rosales, William J. Gradishar

Data analysis and interpretation: Hope S. Rugo, Seock-Ah Im, Fatima Cardoso, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Gail S. Wright, Cristina Saura, Michelino De Laurentiis, Timothy J. Pluard, Francesco Ricci, Christelle Levy, Ursa Brown-Glaberman, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Peter A. Kaufman, Emily J. Ashley, Raul Perez-Olle, Shengyan Hong, Minori Koshiji Rosales, William J. Gradishar

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial

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