The results of the second interim analysis show that with an overall survival (OS) of 21.6 months, margetuximab plus chemotherapy improved OS by 1.8 months compared with trastuzumab plus chemotherapy (19.8 months) (HR, 0.885; 95% CI, 0.693-1.130; P = .326), in the intent-to-treat (ITT) population.
Based on the results of the analysis, MacroGenics plans to submit a Biologics License Application to the FDA before the close of 2019.1
The open-label phase III randomized study is evaluating efficacy with primary endpoints of independent radiological review of progression-free survival (PFS) and OS versus the combination of trastuzumab (Herceptin) plus chemotherapy. The incidence of grade 3 or higher infusion-related reactions was another primary endpoint. Secondarily, PFS assessed by study investigators, overall response rate, and infusion reactions of all grades were additional objectives of the study. The pre-specified exploratory objective was an evaluation of the effect of CD16A allelic variation on margetuximab activity.
Eligible patients were required to have received a least 2 prior lines of anti-HER2-directed therapy in the metastatic setting. Patients who received prior pertuzumab in the neoadjuvant setting, however, could enter the trial with only 1 prior line of anti-HER2-directed therapy. The overall pretreatment limit was 3 prior lines of treatment in the metastatic setting. All patients in the study had received previous treatment with trastuzumab and pertuzumab (Perjeta) and about 90% had prior T-DM1 (ado-trastuzumab emtansine; Kadcyla). Patients with untreated brain metastases, clinically significant pulmonary compromise, and any condition that would compromise treatment with trastuzumab where excluded. The trial also excluded patients with a history of uncontrolled seizures, clinically significant cardiovascular disease, or prior, stem cell, bone marrow, or solid organ transplantation.
In the study, subjects were randomized 1:1 to intravenous (IV) margetuximab 15 mg/kg every 3 weeks plus chemotherapy or IV trastuzumab 6 (8 for loading dose) mg/kg every 3 weeks plus chemotherapy of either standard-dose capecitabine, eribulin, gemcitabine, or vinorelbine. The study design required 257 PFS events to prove PFS superiority.2
According to previously reported findings, the median PFS by central blinded analysis was 5.8 months in the margetuximab arm versus 4.9 months in the trastuzumab arm (HR, 0.76; P = .033), and by investigator assessment, the HR for PFS was 0.70 (P = .001).
In the subgroup of patients carrying the CD16A-158F allele, accounting for about 85% of the ITT population, the median OS was 23.7 months with margetuximab compared with 19.4 months with trastuzumab (HR, 0.793; 95% CI, 0.607-1.035; P = .087). Of the 15% of patients who were homozygous for the CD16A-158V allele, treatment with margetuximab was inferior to trastuzumab. The final pre-specified analysis will reportedly occur after 385 events have occurred.1
Both combinations regimens showed similar safety profiles and were consistent with previous study data. There were more occurrences of grade 3 or greater AEs in patients being treated with margetuximab (55%) than trastuzumab (53%). Trastuzumab caused more serious AEs (n = 45) compared with margetuximab (n = 50). A greater number of grade 1/2 infusion-related reactions were seen with margetuximab compared with trastuzumab.1
The phase III SOPHIA study is ongoing and no longer recruiting patients. The expected completion date is March 2021. The intricate data from the trial will be presented during an oral presentation at the San Antonio Breast Cancer Symposium in December of 2019.
- MacroGenics Announces Second Interim Overall Survival Data from Phase 3 SOPHIA Study of Margetuximab in Patients with HER2-Positive Metastatic Breast Cancer [press release]. Rockville, MD; October 22, 2019; https://bit.ly/32GPSl. Accessed October 23, 2019.
- Rugo HS, Im SA, Wright GL, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(suppl; abstr 1000).