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Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA oncology Rugo, H. S., Im, S. A., Cardoso, F. n., Cortés, J. n., Curigliano, G. n., Musolino, A. n., Pegram, M. D., Wright, G. S., Saura, C. n., Escrivá-de-Romaní, S. n., De Laurentiis, M. n., Levy, C. n., Brown-Glaberman, U. n., Ferrero, J. M., de Boer, M. n., Kim, S. B., Petráková, K. n., Yardley, D. A., Freedman, O. n., Jakobsen, E. H., Kaufman, B. n., Yerushalmi, R. n., Fasching, P. A., Nordstrom, J. L., Bonvini, E. n., Koenig, S. n., Edlich, S. n., Hong, S. n., Rock, E. P., Gradishar, W. J. 2021

Abstract

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.To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC.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.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.Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All a was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis.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?

View details for DOI 10.1001/jamaoncol.2020.7932

View details for PubMedID 33480963