IMPORTANCE: ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. OBJECTIVE: To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. DESIGN, SETTING, AND PARTICIPANTS: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. INTERVENTIONS: Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. MAIN OUTCOMES AND MEASURES: Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. RESULTS: A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02492711.

Centre Antoine Lacassagne Department of Medical Oncology University Côte d'Azur Nice France

Centre François Baclesse Institut Normand du Sein Caen France

Chaim Sheba Medical Center Breast Oncology Institute Ramat Gan Israel

Champalimaud Clinical Center Champalimaud Foundation Breast Unit Lisbon Portugal

Davidoff Cancer Center Rabin Medical Center Beilinson Hospital Petah Tikva Israel

Department of Breast and Thoracic Oncology Istituto Nazionale Tumori Fondazione Pascale Naples Italy

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Medicine and Surgery University of Parma Medical Oncology and Breast Unit University Hospital of Parma Parma Italy

Department of Oncology Asan Medical Center Seoul Korea

Department of Oncology Vejle Hospital Vejle Denmark

Division of Hematology Oncology Northwestern University Chicago Illinois

Division of Hematology Oncology University of New Mexico Comprehensive Cancer Center Albuquerque

Erlangen University Hospital Department of Gynecology and Obstetrics Comprehensive Cancer Center Erlangen EMN Department of Gynecology and Obstetrics Friedrich Alexander University of Erlangen Nuremberg Erlangen Germany

European Institute of Oncology IRCCS Division of Early Drug Development University of Milano Milan Italy

Florida Cancer Specialists and Research Institute New Port Richey

IOB Institute of Oncology Quironsalud Group Madrid and Barcelona Spain

Maastricht University Medical Center Division of Medical Oncology Department of Internal Medicine GROW School of Oncology and Developmental Biology Maastricht the Netherlands

MacroGenics Inc Rockville Maryland

RS McLaughlin Durham Regional Cancer Centre Lakeridge Health Oshawa Ontario Canada

Sarah Cannon Research Institute Tennessee Oncology PLLC Nashville

Seoul National University Hospital Cancer Research Institute Seoul National University College of Medicine Seoul Korea

Stanford Comprehensive Cancer Institute Stanford University School of Medicine Stanford California

University of California San Francisco Helen Diller Family Comprehensive Cancer Center

Vall d'Hebron Institute of Oncology Barcelona Spain

Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology Medical Oncology Service Barcelona Spain

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