A NOVEL ANTI-HER2 TREATMENT APPROVED BY FDA

 A new monoclonal antibody that targets HER2+ in breast cancer, margetuximab-cmkb (Margenza), has been approved by the Food and Drug Administration (FDA).

The new drug is indicated for use in combination with chemotherapy for the treatment of patients with metastatic HER2-positive breast cancer who have already received two or more prior anti-HER2 regimens, with at least one for metastatic disease.

Margetuximab-cmkb is also the first HER2-targeted therapy shown to improve progression-free survival (PFS) as compared with the first ever HER2-targeted agent, trastuzumab (Herceptin) in a head-to-head phase 3 clinical trial (known as SOPHIA).

"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," said Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education, University of California San Francisco Diller Family Comprehensive Cancer Center, San Francisco, California, in a company press release.

"As the only HER2-targeted agent to have shown a PFS improvement vs trastuzumab in a head-to-head phase 3 clinical trial, margetuximab with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies," said Rugo, who is an investigator in the SOPHIA trial.

Like trastuzumab, margetuximab-cmkb binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc gamma receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells, according to the manufacturer.

Details of the Pivotal Trail

The SOPHIA trial was a randomized, open-label phase 3 clinical trial that compared margetuximab-cmkb plus chemotherapy to trastuzumab plus chemotherapy in both arms, in patients with HER2-positive metastatic breast cancer, who had previously been treated with anti-HER2-targeted therapies. All patients in the cohort had previously received trastuzumab, all but one patient had previously also received pertuzumab, and most of the patients (91%) had also been treated with ado-trastuzumab emtansine, or T-DM1.

The trial randomly assigned 536 patients to receive either margetuximab-cmkb A (n = 266) given intravenously at 15 mg/kg every 3 weeks or trastuzumab (n = 270) given intravenously at 6 mg/kg (or 8 mg/kg for loading dose) every 3 weeks in combination with either capecitabine, eribulin (Halaven), gemcitabine, or vinorelbine, given at the standard doses.

As compared with trastuzumab, margetuximab plus chemotherapy led to a significant 24% reduction in the risk for progression or death compared (HR = 0.76).

The median PFS also favored margetuximab (5.8 months vs 4.9 months), as did the overall response rate (22% vs 16%).

The final overall survival analysis is expected in the second half of 2021.

Common adverse events associated with the margetuximab regimen included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%). Infusion-related reactions occurred in 13% of patients receiving margetuximab, and almost all were grade 1 or 2, with only 1.5% at grade 3.

The product also carries a boxed warning for left ventricular dysfunction and embryo-fetal toxicity.

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