As reported in JAMA Oncology by Hope S. Rugo, MD, 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 who experienced disease progression after two or more prior anti-HER2 therapies.

The trial supported the December 2020 approval of margetuximab for use in combination with chemotherapy for treatment of adult patients 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.

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.

“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.”

— Hope S. Rugo, MD, and colleagues

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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 random assignment; among all patients, chemotherapy choices were vinorelbine in 35.6%, capecitabine in 26.7%, eribulin in 25.4%, and gemcitabine in 12.3%.

All but one patient had received prior treatment with pertuzumab, and 91.2% had received prior treatment with ado-trastuzumab emtansine. Overall, 34.6% of the margetuximab group and 32.2% of the trastuzumab group had received three or more prior therapies for metastatic disease.  

Sequential primary endpoints were progression-free survival on central blinded analysis and overall survival.  

Progression-Free and Overall Survival

The primary progression-free analysis was triggered by the last trial random assignment in October 2018, with 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).

At the second planned interim analysis of overall survival in September 2019, median follow-up for overall survival was 15.6 months. Median overall survival was 21.6 months (95% CI = 18.86–24.05 months) in the margetuximab group vs 19.8 months (95% CI = 17.54–22.28 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 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 the first cycle—were observed 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 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.”

Dr. Rugo, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by MacroGenics, Inc. For full disclosures of the study authors, visit jamanetwork.com.