As reported in JAMA Oncology by Hope S. Rugo, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues, the phase III SOPHIA trial has shown significantly prolonged progression-free survival with margetuximab-cmkb plus chemotherapy vs trastuzumab plus chemotherapy in patients with HER2-positive breast cancer whose disease had progressed on two or more prior anti-HER2 therapies and one to three lines of therapy for metastatic disease.¹

The trial supported the December 2020 approval of margetuximab for use in combination with chemotherapy for adults with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Hope S. Rugo, MD

As noted by the investigators, margetuximab is a chimeric antibody that shares HER2 specificity with trastuzumab but also incorporates an engineered Fc region designed to increase immune activation.

Study Details

In the open-label trial, 536 patients from sites in 17 countries were randomly assigned between August 2015 and October 2018 to receive margetuximab at 15 mg/kg once every 3 weeks plus chemotherapy (n = 266) or trastuzumab at 6 mg/kg (after an 8-mg/kg loading dose) once every 3 weeks plus chemotherapy (n = 270); investigators selected chemotherapy prior to randomization. Randomization was stratified by metastatic sites (two or fewer, more than two), lines of therapy for metastatic disease (two or fewer, more than two), and chemotherapy choice. 

Among all patients, chemotherapy choices were 3-week cycles of vinorelbine in 35.6%, capecitabine in 26.7%, eribulin in 25.4%, and gemcitabine in 12.3%. Capecitabine was given at 1,000 mg/m² twice daily for 14 days followed by 7 days off, and eribulin at 1.4 mg/m², gemcitabine at 1,000 mg/m², or vinorelbine at 25 to 30 mg/m² were given before antibody infusion on days 1 and 8 of each cycle. Sequential primary endpoints were progression-free survival on central blinded analysis and overall survival.

For the margetuximab vs trastuzumab groups: 100% vs 98.9% were women; median age was 55 years (range = 29–83 years) vs 56 years (range = 27–86 years); 77.1% vs 82.2% were white, 7.5% vs 5.2% Asian, and 6.0% vs 4.4% were Black/African American; region was Europe for 57.1% vs 51.1% and North America for 32.0% vs 37.8%; Eastern Cooperative Oncology Group performance status was 0 or 1 (44.0% vs 40.4%) in all patients; 97.7% vs 97.8% had metastatic disease (most common sites = bone in 57.5% vs 57.44% and lymph nodes in 52.6% vs 55.9%) and 98.5% vs 97.0 had measureable disease.

Progression-Free and Overall Survival

The primary progression-free analysis was triggered by the last trial randomization in October 2018, with a median follow-up of 2.8 months. Median progression-free survival at that time was 5.8 months (95% confidence interval [CI] = 5.5–7.0 months) in the margetuximab group vs 4.9 months (95% CI = 4.2–5.6 months) in the trastuzumab group (hazard ratio [HR] = 0.76, 95% CI = 0.59–0.98, P = .03). Rates at 3, 6, and 9 months were 73% vs 65%, 45% vs 37%, and 27% vs 19%. Median investigator-assessed progression-free survival was 5.6 vs 4.2 months (HR = 0.70, 95% CI = 0.56–0.87, P = .001).

In stratification subgroups, hazard ratios for the margetuximab vs trastuzumab groups were 0.94 (95% CI = 0.67–1.31) for two or fewer and 0.63 (95% CI = 0.44–0.89) for more than two metastatic sites; 0.81 (95% CI = 0.60-1.10) for two or fewer and 0.72 (95% CI = 0.48-1.08) for more than two prior lines of therapy in the metastatic setting; and 0.77 (95% CI = 0.47–1.29) for capecitabine, 0.66 (95% CI = 0.42–1.05) for eribulin, 0.58 (95% CI = 0.29–1.18) for gemcitabine, and 0.90 (95% CI = 0.60–1.35) for vinorelbine as chemotherapy choice.

At the second planned interim analysis of overall survival in September 2019, the median follow-up for overall survival was 15.6 months. Median overall survival was 21.6 months (95% CI = 18.9–24.1 months) in the margetuximab group vs 19.8 months (95% CI = 17.5–22.3 months) in the trastuzumab group (HR = 0.89, 95% CI = 0.69–1.13, P = .33). Rates at 3, 6, and 9 months were 75% vs 75%, 60% vs 56%, and 44% vs 40%.

Among 524 response-evaluable patients, objective response on blinded analysis was observed in 22% vs 16% of patients (P = .06); the clinical benefit rate was 37% vs 25% (P = .003); and the median duration of response was 6.1 vs 6.0 months.

Adverse Events

Safety analysis as of April 2019, representing an additional 6 months of follow-up after the primary progression-free survival analysis, included 264 patients treated with margetuximab and 266 treated with trastuzumab. The most common nonhematologic adverse events of any grade in the margetuximab group were fatigue (42.0% vs 35.3% in trastuzumab group), nausea (32.6% vs 32.3%), and diarrhea (25.0% vs 25.2%). The most common grade ≥ 3 nonhematologic adverse events were fatigue (4.9% vs 3.0%), diarrhea (2.3% vs 2.3%), and asthenia (2.3% vs 2.0%). The most common grade 3 or 4 hematologic abnormalities were neutropenia (19.7% vs 12.4%), decreased neutrophil count (8.7% vs 10.5%), and anemia (4.9% vs 6.4%). Any-grade infusion-related reactions, observed primarily in cycle 1, occurred in 13.3% vs 3.4% of patients. 

Adverse events led to discontinuation of therapy in 3.0% vs 2.6%. Fatal adverse events, none considered to be related to treatment, occurred in three patients in the margetuximab group (1.1%) vs two in the trastuzumab group (0.8%).

The investigators concluded: “In this phase III randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in [progression-free survival] compared with trastuzumab plus chemotherapy in [HER2]-positive [advanced breast cancer] after progression on two or more prior anti-[HER2] therapies. Final [overall survival] analysis is expected in 2021.”  

DISCLOSURE: The study was supported by MacroGenics. Dr. Rugo has served as a consultant or advisor to Celltrion, Puma Biotechnology, and Samsung; has received institutional research funding from Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca Spain, Daiichi Sankyo, MacroGenics, Mylan, Novartis, and Pfizer.

REFERENCE

1. Rugo HS, Im SA, Cardoso F, et al: Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: A phase 3 randomized clinical trial. JAMA Oncol 7:573-584, 2021.