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Clinical Trial
. 2021 Apr 1;7(4):573-584.
doi: 10.1001/jamaoncol.2020.7932.

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial

Hope S Rugo  1 , Seock-Ah Im  2 , Fatima Cardoso  3 , Javier Cortés  4   5 , Giuseppe Curigliano  6 , Antonino Musolino  7 , Mark D Pegram  8 , Gail S Wright  9 , Cristina Saura  10 , Santiago Escrivá-de-Romaní  10 , Michelino De Laurentiis  11 , Christelle Levy  12 , Ursa Brown-Glaberman  13 , Jean-Marc Ferrero  14 , Maaike de Boer  15 , Sung-Bae Kim  16 , Katarína Petráková  17 , Denise A Yardley  18 , Orit Freedman  19 , Erik H Jakobsen  20 , Bella Kaufman  21 , Rinat Yerushalmi  22 , Peter A Fasching  23 , Jeffrey L Nordstrom  24 , Ezio Bonvini  24 , Scott Koenig  24 , Sutton Edlich  24 , Shengyan Hong  24 , Edwin P Rock  24 , William J Gradishar  25 ; SOPHIA Study Group
Affiliations
Clinical Trial

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial

Hope S Rugo et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rugo reported receiving grants from MacroGenics during the conduct of the study; and grants from Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, and Daiichi Sankyo and personal fees from Puma and Samsung outside the submitted work. Dr Im reported receiving grants from Daewoong Pharmaceutical; grants and personal fees from AstraZeneca, Pfizer, and Roche; and personal fees from Amgen, Eisai, Hanmi Pharmaceutical, Novartis, Lilly, and Merck Sharp & Dohme outside the submitted work. Dr Cardoso reported receiving personal fees from MacroGenics during the conduct of the study; and personal fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, MacroGenics, Medscape, Merck Sharp & Dohme, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seattle Genetics, and Teva outside the submitted work. Dr Cortés reported receiving personal fees from Roche, Celgene, AstraZeneca, Cellestia, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech Pharma, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Bioasis Technologies, Clovis Oncology, Boehringer Ingelheim, Novartis, Eisai, Pfizer, and Samsung Bioepis; honoraria from Samsung Bioepis, Pfizer, Eisai, Novartis, Roche, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme; serving on advisory boards for Boehringer Ingelheim, Clovis Oncology, Bioasis, Leuko, GlaxoSmithKline, Merck Sharp & Dohme, Servier, Lilly, Polyphor, Athenex, Erytech, Daiichi Sankyo, Seattle Genetics, Merus, Biothera, Cellestia, AstraZeneca, Celgene, and Roche; and owning stock from MedSIR outside the submitted work; and travel, accommodation, and expenses from Roche, Novartis, Eisai, Pfizer, and Daiichi Sankyo. Dr Curigliano reported receiving travel grants from Roche; serving on advisory boards for Pfizer, Seattle Genetics, Novartis, AstraZeneca, Lilly, Merck Sharp & Dohme, Daichi Sankyo, Genomic Health, and Ellipsis; and serving as a steering committee member for Bristol Myers Squibb outside the submitted work. Dr Musolino reported receiving personal fees from MacroGenics during the conduct of the study; and grants and personal fees from Roche and Eisai and personal fees from Novartis and Lilly outside the submitted work. Dr Pegram reported receiving personal fees from MacroGenics and Roche during the conduct of the study. Dr Wright reported receiving payment to Sarah Cannon Research Institute for conduct of clinical trial from MacroGenics during the conduct of the study; and payment to Sarah Cannon Research Institute for conduct of clinical trial from AbbVie, Incyte, Genentech, Novartis, Lilly, Janssen, Astellas, Celgene, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, G1 Therapeutics, Medivation, Merrimack, Pfizer, Tesaro, and Odonate Therapeutics outside the submitted work. Dr Saura reported receiving personal fees from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, F. Hoffmann-La Roche Ltd, Genomic Health, Merck, Sharp and Dohme España SA, Novartis, Odonate Therapeutics, Pfizer, Philips HealthWork, Pierre Fabre, prIME Oncology, Puma, Synthon, and Sanofi Aventis outside the submitted work. Dr Escrivá-de-Romaní reported receiving grants from MacroGenics during the conduct of the study; and grants from Synthon and Zymeworks; grants, personal fees, and nonfinancial support from Roche; personal fees and nonfinancial support from Pierre Fabre; personal fees from Eisai, Kyowa Kirin, and Esteve; and nonfinancial support from Daiichi Sankyo outside the submitted work. Dr De Laurentiis reported receiving grants from MacroGenics during the conduct of the study; and grants from Daiichi Sankyo; grants and personal fees from Roche, Novartis, Pfizer, Eli Lilly, Pierre Fabre, and AstraZeneca; personal fees from Celgene, Eisai, Genomic Health, and Amgen outside the submitted work. Dr Brown-Glaberman reported receiving personal fees from Novartis, Eisai, Biotheranostics, and Seattle Genetics outside the submitted work. Dr de Boer reported receiving grants from Parexel during the conduct of the study; and grants from Novartis, Pfizer, and Eli Lilly and grants and personal fees from Roche outside the submitted work. Dr Kim reported participation as a consultant in advisory boards for Novartis, AstraZeneca, Lilly, Enzychem Lifesciences, Dae Hwa Pharmaceutical Co Ltd, ISU Abxis, and Daiichi Sankyo and receiving research funding (paid to institution) from Novartis, Sanofi-Aventis, and DongKook Pharmaceutical Co Ltd outside the submitted work. Dr Petráková reported receiving personal fees from Novartis, Roche, Merck Sharp & Dohme, and Pfizer outside the submitted work. Dr Yardley reported a consultant/advisory role (paid to institution) for Bristol Myers Squibb, Genentech/Roche, Eisai, Biotheranostics, Daiichi Sankyo/Lilly, Celgene, Novartis, NanoString Technology, and MacroGenics; research funding (paid to institution) from Daiichi Sankyo, Clovis Oncology, AstraZeneca, Genentech/Roche, InventisBio, Syndax, Lilly, MedImmune, Pfizer, Eisai, Novartis, Medivation, Tesaro, Immunomedics, AbbVie, Merck, and Oncothyreon; and participation in speakers bureaus and travel/accommodations/expenses for Novartis and Genentech/Roche outside the submitted work. Dr Jakobsen reported receiving financial support from Cascadian Therapeutics during the conduct of the study; and grants from Cascadian Therapeutics and grants and personal fees from Roche, Novartis, Lilly, and Pfizer outside the submitted work. Dr Kaufman reported receiving personal fees from Pfizer and AstraZeneca outside the submitted work. Dr Fasching reported receiving personal fees from MacroGenics during the conduct of the study; and grants from Cepheid and personal fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, and Seattle Genetics outside the submitted work. Dr Bonvini reported receiving salary, stocks, and stock options from MacroGenics as compensation as a condition of employment. Dr Koenig is an employee of MacroGenics and reported holding a patent to US20180298100 pending and a patent to US20160257761 pending. Drs Nordstrom, Hong, and Rock and Mr Edlich are or were employees of MacroGenics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flow/Patient Disposition
All randomized patients were included in the intention-to-treat population; randomized patients who received at least 1 dose of study treatment were included in the safety population; randomized patients with baseline measurable disease were included in the RE population. AE indicates adverse event; PD, progressive disease; RE, response evaluable; tx, treatment. aA patient may have more than 1 reason for screening failure. bAs of the October 10, 2018, cutoff. cAs of the April 10, 2019, cutoff, 37 patients remained on margetuximab therapy vs 20 on trastuzumab therapy. dAs of the October 10, 2018, cutoff and the September 10, 2019, cutoff. eAs of the April 10, 2019, cutoff. fAs of the September 10, 2019, cutoff, there were 266 margetuximab-treated patients and 270 trastuzumab-treated patients in the RE population.
Figure 2.
Figure 2.. Progression-Free Survival (PFS) in the Intention-to-Treat Population
A, Kaplan-Meier estimates of PFS in the intention-to-treat population by central blinded analysis (CBA), based on the October 2018 cutoff. B, Kaplan-Meier estimates of PFS in the intention-to-treat population by investigator assessment, based on the October 2018 cutoff. C, Kaplan-Meier estimates of PFS in the intention-to-treat population by investigator assessment, based on the September 2019 cutoff. The dashed line indicates 50% (median PFS); plus signs, censored data. HR indicates hazard ratio. aPFS analysis was triggered by last randomization on October 10, 2018, after 265 PFS events occurred. bPFS analysis performed as of September 10, 2019, after 430 PFS events occurred.
Figure 3.
Figure 3.. Overall Survival (OS) in the Intention-to-Treat Population (September 2019 Cutoff)a
Kaplan-Meier estimates of OS in the intention-to-treat population, based on the September 2019 cutoff. The dashed line indicates 50% (median OS); plus signs, censored data. HR indicates hazard ratio. aOS analysis performed as of September 10, 2019, data cutoff, after 270 of 385 (70%) events needed for final OS analysis had occurred.
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