Additional data from SOPHIA study of margetuximab for HER2-positive metastatic breast cancer

MacroGenics, Inc.,has announced additional details of the results from the Phase III SOPHIA study of margetuximab in patients with HER2-positive metastatic breast cancer who have previously been treated with anti-HER2-targeted therapies.

Margetuximab is an investigational, immune-enhancing monoclonal antibody derived from the Company’s proprietary Fc Optimization technology platform. The study met its first sequential primary endpoint of progression-free survival (PFS).The median PFS of patients treated with margetuximab and chemotherapy was 5.8 months compared to 4.9 months in patients treated with trastuzumab and chemotherapy (hazard ratio [HR]=0.76; 95% CI: 0.59-0.98; P=0.033). Among the approximately 85% of patients carrying the CD16A 158F allele, a pre-specified exploratory subpopulation in the study, PFS was prolonged by 1.8 months in the margetuximab arm compared to the trastuzumab arm (6.9 months versus 5.1 months; HR=0.68; 95% CI: 0.52-0.90; P=0.005). The objective response rate (ORR), a secondary outcome measure in the SOPHIA study, was 22% in the margetuximab arm (95% CI: 17.3-27.7%) compared to 16% in the trastuzumab arm (95% CI: 11.8-21.0%). The data cut-off date for the primary PFS analysis of the study was October 10, 2018. At the time of the primary PFS analysis, overall survival (OS) data based on 158 events were immature. The median OS at that time was prolonged by 1.7 months in patients treated with margetuximab and chemotherapy compared to patients treated with trastuzumab and chemotherapy. For the exploratory sub-population of patients carrying the CD16A 158F allele, the median OS was prolonged by 6.8 months in the margetuximab arm compared to the trastuzumab arm. The Company anticipates conducting a second pre-specified interim OS analysis based on 270 events in the second half of this year. The final pre-specified OS analysis is planned after 385 events have accrued, and is projected to be completed in 2020.

The activity observed to date in SOPHIA is promising. This is the first randomized Phase III study that was designed to examine the potential benefit of Fc modification and the role of Fc-gamma receptor genotypes on anti-HER2 antibody efficacy. Margetuximab with chemotherapy had an acceptable safety profile, generally comparable overall to that of trastuzumab and chemotherapy. Grade 3 or greater adverse events occurred in 138 (52%) patients on the margetuximab arm compared to 128 (48%) patients on the trastuzumab arm. Serious adverse events occurred in 39 (15%) patients on the margetuximab arm compared to 46 (17%) patients on the trastuzumab arm. Infusion-related reactions were more common with margetuximab treatment than with trastuzumab (13% versus 4%) and were mostly Grade 1 or 2 and associated with the first dose. MacroGenics recently held a pre-BLA meeting regarding margetuximab with the FDA). The company plans to submit a Biologics License Application (BLA) to the FDA in the second half of 2019.

About the SOPHIA Study : The SOPHIA study (NCT02492711) is a randomized, open-label Phase III clinical trial evaluating margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer. To be eligible for the study, patients must have received at least two prior lines of anti-HER2-directed therapy in the metastatic setting, or in the case of having received (neo)adjuvant pertuzumab, at least one prior line of anti-HER2-directed therapy in the metastatic setting; and who have received at least one and no more than three prior lines of therapy overall in the metastatic setting. All study patients had previously received trastuzumab (Herceptin) and pertuzumab (Perjeta ), and approximately 90% had previously received ado-trastuzumab emtansine (Kadcyla). The study enrolled 536 patients who were randomized 1:1 to receive either margetuximab (n=266) given intravenously at 15 mg/kg every three weeks or trastuzumab (n=270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every three weeks in combination with one of four chemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine) given at the standard dose. Patients were stratified by the number of metastatic sites (?2 or >2), number of lines of prior therapy for metastatic disease (?2 or >2) and choice of chemotherapy. Intent-to-treat analysis occurred after 265 PFS events. Primary endpoints are sequentially-assessed PFS, determined by centrally-blinded radiological review, and OS. Key secondary endpoints are PFS by investigator assessment and ORR. PFS and ORR were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)