FDA Approves Margetuximab-cmkb, Chemo Combo for Pretreated Metastatic HER2+ Breast Cancer

The FDA has approved margetuximab-cmkb (Margenza) in combination with chemotherapy for the treatment of adult patients with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2 regimens, at least 1 of which was for metastatic disease, according to MacroGenics, the developer of the agent.

The approval was based on safety and efficacy results observed in the pivotal, randomized, open-label, phase 3 SOPHIA trial (NCT02492711). The trial compared margetuximab-cmkb plus chemotherapy to trastuzumab (Herceptin) plus chemotherapy in patients with HER2-positive metastatic breast cancer who had previously been treated with anti-HER2-targeted therapies.

Overall, the study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with margetuximab-cmkb plus chemotherapy compared with trastuzumab plus chemotherapy (HR, 0.76; 95% CI, 0.59-0.98; P = .033; median progression-free survival [PFS], 5.8 vs 4.9 months). The objective response rate (ORR) for margetuximab-cmkb plus chemotherapy was 22% and 16% for trastuzumab plus chemotherapy.

The final overall survival (OS) analysis is expected to be reported in the second half of 2021.

“Early detection and treatment have had a positive impact on the survival of patients with breast cancer, but the prognosis for people diagnosed with metastatic breast cancer remains poor, and additional treatments are needed,” Hope S. Rugo, MD, professor of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said in a press release. “As the only HER2-targeted agent to have shown a PFS improvement versus trastuzumab in a head-to-head Phase 3 clinical trial, MARGENZA with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.”

A total of 536 patients were randomized 1:1 to receive either margetuximab-cmkb (n = 266) given intravenously at a dose of 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at a dose of 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with 1 of 4 chemotherapy agents (capecitabine, eribulin, gemcitabine, or vinorelbine) given at the standard doses. All of the study participants had previously received trastuzumab, all but 1 had previously received pertuzumab, and 91% had previously received ado-trastuzumab emtansine (T-DM1).

Of note, an intent-to-treat PFS analysis was planned following 265 PFS events.

The dual primary end points of the study are sequentially assessed PFS, determined by blinded, centrally reviewed radiological review, followed by overall survival (OS). Additional key secondary end points are PFS by investigator assessment, ORR, and duration of response. Moreover, tertiary end points include ORR by investigator assessment and safety. PFS and ORR were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

Regarding safety, adverse events (AEs) occurring in greater than 20% of patients with margetuximab-cmkb in combination with chemotherapy were fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%).

Importantly, the margetuximab-cmkb US prescribing information includes a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

Additionally, margetuximab-cmkb may cause infusion related reactions (IRRs); IRRs occurred in 13% of patients treated with margetuximab-cmkb, though most IRRs were reported as grade 2 or less. Grade 3 IRRs occurred in 1.5% of patients.

In addition to the phase 3 SOPHIA trial, margetuximab-cmkb is also being evaluated in combination with checkpoint blockade in the phase 2/3 MAHOGANY trial for the treatment of patients with HER2-positive gastroesophageal cancer (NCT04082364), and in combination with tebotelimab (PD-1 × LAG-3 bispecific DART molecule) in various HER2-positive tumors (NCT03219268).

Reference:

MacroGenics Announces FDA Approval of MARGENZA™ for Patients with Pretreated Metastatic HER2-Positive Breast Cancer [news release]. Rockville, MD. Published December 16, 2020. Accessed December 16, 2020. http://ir.macrogenics.com/news-releases/news-release-details/macrogenics-announces-fda-approval-margenzatm-patients