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Old 12-17-2020, 09:22 PM   #1
Nguyen
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Join Date: Nov 2005
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The FDA has approved margetuximab-cmkb

FDA Approves Margetuximab-cmkb Plus Chemo in Pretreated Metastatic HER2+ Breast Cancer

December 16, 2020 - The FDA has approved margetuximab-cmkb plus chemotherapy for use in adult patients with metastatic HER2-positive breast cancer who have previously received 2 or more anti-HER2 regimens, at least one of which was for metastatic disease.
FDA

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 previously received 2 or more anti-HER2 regimens, at least one of which for metastatic disease.1

The regulatory decision was based on findings from the phase 3 SOPHIA trial (NCT02492711), in which the Fc-engineered monoclonal antibody plus chemotherapy demonstrated a statistically significant reduction in the risk of disease progression or death of 24% vs trastuzumab (Herceptin) in combination with chemotherapy (HR, 0.76; 95% CI, 0.59-0.98; P =.033). The median PFS with the margetuximab-cmkb regimen was 5.8 months vs 4.9 months with the trastuzumab regimen.

Moreover, the objective response rate reported with the margetuximab-cmkb/chemotherapy combination was 22% vs 16% with trastuzumab plus chemotherapy.

Data from the final overall survival (OS) analysis of the trial are anticipated to be released in the second half of 2021, according to MacroGenics, Inc.

“The approval of [margetuximab-cmkb] is an exciting milestone for MacroGenics and, more importantly, it brings a new treatment option to metastatic breast cancer patients. We are grateful for the patients who participated in this study, as well as their families, and everyone who played a role in helping MacroGenics reach this milestone,” Scott Koenig, MD, PhD, president and CEO of MacroGenics, stated in a press release. “As we prepare for our first commercial launch and look forward to being able to deliver [margetuximab-cmkb] to patients, we continue to focus on developing and commercializing innovative antibody-based therapeutics for the treatment of cancer with 8 product candidates currently in clinical development.”

In the open-label phase 3 trial, investigators set out to examine the combination of margetuximab-cmkb and chemotherapy vs trastuzumab and chemotherapy in patients with HER2-positive metastatic breast cancer who had received prior treatment with HER2-targeted therapies. All participants had received prior trastuzumab, and all but 1 participant had previously received pertuzumab (Perjeta). Moreover, 91% of patients had received prior treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla).

A total of 536 patients were enrolled to SOPHIA and they were randomized 1:1 to receive either intravenous (IV) margetuximab-cmkb at a dose of 15 mg/kg every 3 weeks (n = 266) or IV trastuzumab at a dose of 6 mg/kg, or a loading dose of 8 mg/kg, every 3 weeks (n = 270) in combination with 1 of the following 4 chemotherapy agents: capecitabine, eribulin, vinorelbine, or gemcitabine.

The co-primary end points of the trial included sequentially-assessed PFS, which was assessed by blinded, centrally-reviewed radiological review, followed by OS. Important secondary end point comprised PFS per investigator evaluation, ORR, and duration of response. Tertiary end points of the trial included ORR per investigator evaluation and safety. PFS and ORR were examined in accordance with RECIST v1.1 criteria.

Earlier data from a prespecified interim OS analysis of the trial that were presented during the 2019 San Antonio Breast Cancer Symposium demonstrated that at a median follow-up of 15.6 months, the median OS in the intent-to-treat population was 21.6 months with margetuximab-cmkb/chemotherapy vs 19.8 months with trastuzumab/chemotherapy (HR, 0.89; 95% CI, 0.69-1.13; P = .326).2,3

Moreover, the ORR per investigator assessment was also found to be significantly improved with the margetuximab-cmkb regimen compared with the trastuzumab regimen, at 25.2% vs 13.7%, respectively (P = .0006). The clinical benefit rate in the investigational arm was 48.1% vs 35.6% in the control arm (P = .0025).

The ORR in the margetuximab-cmkb/chemotherapy arm included a 1.9% complete response (CR) rate, a 23.3% partial response (PR) rate, and a 53.8% stable disease rate; 15.0% of patients experienced progressive disease. In the trastuzumab/chemotherapy arm, the ORR was comprised of a CR rate of 1.5%, a PR rate of 12.2%, and stable disease rate of 58.5%, and a progressive disease rate of 21.1%. The median DOR in the investigative and control arms was 6.9 months vs 7.0 months, respectively.

Regarding safety, toxicities reported in more than 20% of patients who received margetuximab-cmkb plus chemotherapy included fatigue/asthenia (57%), nausea (33%), diarrhea (25%), and vomiting (21%).

Notably, the US Prescribing information has a Boxed Warning for left ventricular dysfunction and embryo-fetal toxicity. Moreover, margetuximab-cmkb is known to cause infusion-related reactions (IRRs); these reactions were reported by 13% of patients who were treated with the regimen. However, most of the cases reported were grade 2 or less in severity. Grade 3 IRRs were experienced by 1.5% of patients.

"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," lead study investigator Hope S. Rugo, MD, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of San Francisco Helen Diller Family Comprehensive Cancer Center, added in the 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-cmkb] with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies."

Margetuximab-cmkb is anticipated to become available in March 2021, according to the pharmaceutical company.
References

MacroGenics announces FDA approval of Margenza for patients with pretreated metastatic HER2-positive breast cancer. News release. MacroGenics, Inc. December 16, 2020. Accessed December 16, 2020. http://bit.ly/3gTMuLq.
Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-02.
Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(suppl 15):1000. doi:10.1200/JCO.2019.37.15_suppl.1000
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