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Analysis of Condition
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Breast cancer is the most common cancer in women, with more than 260,000 new cases and 40,000 deaths annually. HER2-positive breast cancer comprises approximately 20 to 25% of the entire breast cancer population. HER2 gene amplification or HER2 protein overexpression in breast cancer tumors are associated with more aggressive clinical disease and historically poorer prognosis. Advanced or metastatic HER2-positive breast cancer is incurable.
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Advanced or metastatic HER2-positive
breast cancer is a serious and life-threatening
condition with an ongoing
unmet medical need. |
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Current Treatment Options
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Treatment goals for metastatic HER2-positive breast cancer are palliative in nature to delay disease progression, prolong survival, and reduce cancer-related symptoms. The combination of trastuzumab, pertuzumab, and taxane is an FDA approved treatment for patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. T-DM1 is FDA approved for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane. Other standard options can include fam-trastuzumab deruxtecan-nxki, neratinib or lapatinib plus capecitabine, tucatinib plus capecitabine and trastuzumab, or trastuzumab combined with another chemotherapeutic agent.
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There is an unmet medical need to improve the outcomes of patients
with HER2-positive advanced or
metastatic breast cancer whose disease has progressed on available HER2-directed therapies. |
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Benefit
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The efficacy of margetuximab plus chemotherapy was evaluated in SOPHIA, a multicenter, randomized, open-label, active controlled trial of margetuximab plus chemotherapy versus trastuzumab plus chemotherapy in patients with advanced or metastatic HER2-positive who have received prior anti-HER2 based regimens in the metastatic setting. Median PFS in the margetuximab plus chemotherapy arm was 5.8 months (95% CI: 5.5, 7.0) compared to 4.9 months (95% CI: 4.2, 5.6) in the trastuzumab plus chemotherapy arm (HR = 0.76; 95% CI: 0.59, 0.98; p = 0.033). OS was immature (70% of targeted OS events). Median OS was 21.6 months (95%CI: 17.7, 23.8) in the margetuximab plus chemotherapy arm compared to 19.8 months (95% CI: 15.5, 21.2) in the trastuzumab plus chemotherapy arm (HR 0.89; 95% CI: 0.69, 1.13; p=0.3264). The ORR was 22% (95% CI: 17%, 27%) in the margetuximab plus chemotherapy arm vs 16% (95% CI: 12%, 20%) in the trastuzumab arm. Median duration of response was 6.1 months (95%CI: 4.1, 9.1) vs 6.0 months (95%CI: 4.0, 6.9), respectively.
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SOPHIA resulted in a statistically significant difference in PFS when margetuximab plus chemotherapy was compared to trastuzumab plus chemotherapy. Although the PFS improvement is only 0.9 months, margetuximab plus chemotherapy represents a replacement therapy for trastuzumab plus chemotherapy and patients may benefit from having an alternative therapy.
Overall survival was immature; however no apparent detriment was observed in patients who received margetuximab plus chemotherapy compared to those that received trastuzumab plus chemotherapy. |
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Risk and Risk Management
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Common adverse reactions observed >10% of patients treated with margetuximab plus chemotherapy on SOPHIA were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain. Three percent of patients discontinued margetuximab plus chemotherapy due to an adverse reaction and 2.6% of patients discontinued trastuzumab plus chemotherapy due to an adverse reaction Fatal adverse reactions occurred in 1.1% of patients who received margetuximab plus chemotherapy and in 0.8% of patients who received trastuzumab plus chemotherapy. Serious adverse reactions occurred in 16% of patients who received margetuximab plus chemotherapy and in 18% of patients who received trastuzumab plus chemotherapy, respectively. Dose interruptions due to an adverse reaction occurred in 11% of patients who received margetuximab plus chemotherapy and 3.0% of patients who received trastuzumab plus chemotherapy, respectively.
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Margetuximab demonstrated acceptable tolerability for the indicated population with a serious and life-threatening disease.
The safe use of margetuximab plus chemotherapy can be managed through appropriate labeling, including boxed warning for left ventricular dysfunction and embryofetal toxicity as well as a warning and precaution for infusion related reactions. No REMS is indicated. |
