FDA Approves MARGENZA® for HER2 Positive Metastatic Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2 oncoprotein is also expressed by tumor cells in gastroesophageal and other solid tumors.

HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (Ado-Trastuzumab Emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.MOA-of-MARGENZA

MARGENZA® (Margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that binds to the HER2 oncoprotein with high specificity and affinity and inhibits tumor cell proliferation, and survival by mediating Antibody-Dependent Cellular Cytotoxicity (ADCC). It is postulated that the Fab portion of MARGENZA® has the same specificity and affinity to HER2 oncoprotein as Trastuzumab, with similar ability to disrupt signaling. However, the modified Fc region of MARGENZA® which binds Fc receptor expressing cells such as immune cells, has increased affinity for activating Fc receptor FCGR3A (CD16A) and decreases affinity for inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater ADCC and Natural Killer cell activation.

The SOPHIA study is a randomized, multicenter, open-label Phase III clinical trial, in which MARGENZA® plus chemotherapy was compared to Trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. This study enrolled 536 patients who were randomized 1:1 to receive either MARGENZA® 15 mg/kg IV every three weeks (N=266) or Trastuzumab 6 mg/kg (or 8 mg/kg for loading dose) IV every three weeks (N=270), in combination with either Capecitabine, Eribulin, Gemcitabine or Vinorelbine, given at the standard doses. All study patients had previously received Trastuzumab, all but one patient had previously received PERJETA® (Pertuzumab), and 91% of patients had previously received KADCYLA®. Patients were stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting and number of metastatic sites. The dual Primary endpoints of the study were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Additional efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR) assessed by BICR.

This study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with MARGENZA® plus chemotherapy compared with Trastuzumab plus chemotherapy (HR= 0.76; P=0.033), with a median PFS of 5.8 months versus 4.9 months respectively. Treatment benefit was more pronounced in patients with CD16A genotypes containing a 158F allele (median PFS 6.9 versus 5.1 months, HR=0.68; P=0.005). The ORR for MARGENZA® plus chemotherapy was 22%, with a median Duration of Response of 6.1 months, compared to an ORR of 16% and median Duration of Response of 6.0 months for Trastuzumab plus chemotherapy. The final Overall Survival (OS) analysis is expected in the second half of 2021. The most common adverse drug reactions occurring in more than 10% of patients receiving MARGENZA® plus chemotherapy included fatigue/asthenia, nausea, diarrhea, vomiting, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

It was concluded that MARGENZA® in combination with chemotherapy significantly improved PFS, compared to Trastuzumab plus chemotherapy, in pretreated patients with HER2 positive metastatic breast cancer. MARGENZA® along with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.

SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy (C) versus trastuzumab + C in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. Rugo HS, Im SA, Shaw Wright GL, et al. J Clin Oncol 37, 2019 (suppl; abstr 1000)