FDA Cancels ODAC Meeting for BLA of Margetuximab in HER2+ Breast Cancer

The FDA has announced that they will no longer hold an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the Biologics License Application (BLA) for margetuximab (MGAH22) in combination with chemotherapy as a potential treatment of patients with HER2-positive breast cancer. However, the FDA still plans to meet the Prescription Drug User Fee Act (PDUFA) date of December 18, 2020, for the application review.1

"Since submitting the BLA for margetuximab, we have worked collaboratively with the FDA to answer the Agency’s questions as they arise," said Scott Koenig, MD, president, and chief executive officer of MacroGenics, in a statement. "We will continue to work closely with the Agency to potentially bring margetuximab as a treatment option to patients with HER2-positive metastatic breast cancer."

The BLA was submitted to the FDA in December 2019 based on data from the phase III SOPHIA clinical trial. In this study, margetuximab plus chemotherapy was compared with trastuzumab (Herceptin) with chemotherapy to determine the efficacy of the study drug in this patient population.

According to the data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), the median overall survival (OS) was 26.1 months with margetuximab in the intention-to-treat (ITT) group (95% CI, 18.86-24.05) versus 19.8 months (95% CI, 17.54-22.28) in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P=.326).2

Investigators also noted a significant improvement in the overall response rate (ORR) with the margetuximab combination compared with trastuzumab plus chemotherapy. The median ORR was 25.2% with margetuximab versus 13.7% with trastuzumab (P =.0006). There was also an improvement in the clinical benefit rate, which was 48.1% with margetuximab versus 35.6% in the trastuzumab group (P =.0025).

In the margetuximab arm, the complete response (CR) rate was 1.9%, and the partial response (PR) rate was 23.3%. Additionally, there was a 53.8% incidences of stable disease (SD), and 15% of patients had progressive disease (PD). In the trastuzumab arm, the CR rate was 1.5%, the PR rate was 12.2%, the SD rate of 58.5%, and a PD rate of 21.1%. Overall, the median duration of response in the margetuximab was 6.9 months versus 7.0 months with trastuzumab.

The median progression-free survival (PFS) in the margetuximab arm was 5.7 months (95% CI, 5.22-6.97) compared with 4.4 months in the trastuzumab arm (95% CI, 4.14-5.45), as assessed by the study investigators (HR, 0.71; 95% CI, 0.58-0.86; P =.0006). The risk of disease progression or death overall was 29%.

Grade ≥3 adverse events (AEs) occurred in 142 patients on the margetuximab arm (53.8%) compared with 140 patients on the trastuzumab arm (52.6%). Serious AEs occurred in 43 patients on the margetuximab arm (16.3%) compared with 49 patients on the trastuzumab arm (18.4%). Infusion-related reactions were more common with margetuximab than with trastuzumab (13% vs 3%), which were mostly grade 1/2 and associated with the first cycle. There were 4 grade 4 infusion-related reactions in the margetuximab arm versus none in the trastuzumab arm.

The co-primary end points of the study included PFS, OS, and incidence of grade 3 or greater infusion-related reactions. Secondary end points included investigator-assessed PFS, ORR, and the incidence of all-grade infusion-related reactions.

Margetuximab is a monoclonal antibody targeting HER2, which is expressed by tumor cells in the breast, gastroesophageal, and other solid tumors. The agent was designed to block HER2 and has demonstrated similar HER2 binding and antiproliferative effects as trastuzumab. HER2 expression is present in about 15% to 20% of breast cancer cases, and targeted therapies, such as margetuximab, appear to improve outcomes in this patient population.

_References

1. _{MacroGenics provides update on FDA review of margetuximab for HER2-positive metastatic breast bancer. News release. MacroGenics, Inc. May 28, 2020. Accessed May 28, 2020 https://bit.ly/2U2XQ5N.}
2. _{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.}