Hope Rugo, MD
Margetuximab in combination with chemotherapy improved progression-free survival (PFS) compared with trastuzumab (Herceptin) and chemotherapy in heavily pretreated patients with metastatic HER2-positive breast cancer, according to findings from the phase III SOPHIA trial (NCT02492711).1
Results showed that patients in the margetuximab arm experienced a 24% reduction in the risk of disease progression or death versus patients in the trastuzumab arm (HR, 0.76; P
= .033). Regarding safety, MacroGenics, the developer of the investigational immune-enhancing monoclonal antibody, noted that the margetuximab combination demonstrated acceptable safety and tolerability versus the trastuzumab regimen.
Also, in the trial, approximately 85% of patients in the study were CD16A (FcγRIIIa) 158F allele carriers, which was previously linked with diminished clinical response to trastuzumab and other antibodies. In this subgroup, there was a 32% reduction in the risk of disease progression or death for patients the margetuximab arm versus the trastuzumab arm (HR, 0.68; P
"There are currently no approved agents for the treatment of patients with metastatic HER2-positive breast cancer who have previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine,” Hope S. Rugo, MD, director, Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center, said in a press release. “If margetuximab is approved, based on SOPHIA data, I believe that this agent could become a valuable treatment option for these patients."
Additional SOPHIA findings will be presented at an upcoming medical meeting and are being prepared for publication. In a press release, MacroGenics stated that it plans to submit a biologics license application in the second half of 2019. Follow-up for overall survival (OS) is ongoing, which was recommended by an independent data safety monitoring committee.
In the international, open-label randomized SOPHIA study, 536 patients across 200 sites were treated with either margetuximab or trastuzumab in combination with either capecitabine, eribulin, gemcitabine, or vinorelbine. All patients previously received treatment with trastuzumab and pertuzumab (Perjeta), and approximately 90% received prior treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla).
Margetuximab was administered at 15 mg/kg every 3 weeks plus chemotherapy at their standard doses: capecitabine at 1000 mg/m2 twice daily for 2 weeks in a 21-day cycle, eribulin at 1.4 mg/m2
on day 1 and 8 of a 21-day cycle, gemcitabine at 1000 mg/m2
on days 1 and 8 of a 21-day cycle, or vinorelbine at 25 to 30 mg/m2
on days 1 and 8 of a 21-day cycle. Trastuzumab was given at an 8-mg/kg loading dose followed by 6 mg/kg every 3 weeks plus chemotherapy with one of the above-mentioned regimens.
The primary endpoints were PFS by independent radiological review, OS, and incidence of grade ≥3 infusion-related reactions; secondary endpoints include investigator-assessed PFS, objective response rate, and incidence of all-grade infusion-related reactions.
The trial also includes a nonrandomized substudy cohort of an estimated 78 patients to evaluate the safety of a reduced margetuximab infusion rate in those receiving the agent as a single agent or in combination with chemotherapy.
To be eligible for enrollment, patients must have had metastatic or locally advanced relapsed/refractory HER2-positive breast cancer, previously received ≥2 prior lines of HER2-directed therapy, prior treatment with 1 to 3 lines of therapy in the metastatic setting, life expectancy of ≥12 weeks, and acceptable laboratory parameters.
To enroll in the substudy cohort, patients must have received ≥4 or more prior lines of therapy in the metastatic setting, and have received trastuzumab, pertuzumab, and T-DM1.
Those with untreated brain metastasis, a history of uncontrolled seizures within 6 months of randomization, history of prior transplant, history of clinically significant cardiovascular disease, clinically significant pulmonary compromise, and any condition that would be a contraindication to receiving trastuzumab, were excluded from enrollment.
Early phase I findings with margetuximab demonstrated activity in HER2-positive breast cancer, gastric cancers, or other malignancies that overexpress HER2. Sixty-six patients received margetuximab intravenously at doses from 0.1 to 6.0 mg/kg for 3 of every 4 weeks—determined as Regimen A (n = 34)—or once every 3 weeks at a 10- to 18-mg/kg dose, known as Regimen B (n = 32).
Results showed that the maximum-tolerated dose was not reached for either regimen. Among 60 response-evaluable patients, there were 7 (12%) confirmed partial responses and 30 (50%) cases of stable disease—26 of whom had previously received HER2-targeted therapy.2 Additionally, the treatment was well tolerated; there were mostly grade 1/2 toxicities consisting of pyrexia, nausea, anemia, diarrhea, and fatigue.
"We are pleased with the SOPHIA clinical results and are especially grateful to the patients, their caregivers, trial investigators, and site personnel who participated in the study," Scott Koenig, MD, PhD, president and CEO of MacroGenics, said in a statement. “Our Fc-engineered, immune-enhanced molecule has demonstrated a superior outcome in a head-to-head study against Herceptin. We look forward to additional opportunities to develop margetuximab in other HER2-positive breast and gastric cancer populations."
- MacroGenics Announces Positive Results from Pivotal Phase 3 SOPHIA Study of Margetuximab. MacroGenics. Published February 6, 2019. https://bit.ly/2SaTHh7. Accessed February 6, 2019.
- Bang Y, Giaccone G, Im SA, et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;1(4):855-861. doi: 10.1093/annonc/mdx002.