Magrenza (margetuximab) is an Fc-engineered, monoclonal antibody that targets the HER2 oncoprotein, provides HER2 blockade, and has similar HER2 binding and antiproliferative effects as trastuzumab. Its Fc optimization technology enhances the engagement of the immune system. Macrogenics is developing this drug for HER2-positive cancers and has already bagged the FDA approval in December 2020 as a 3L+ treatment option for metastatic HER2-positive breast cancer, along with Orphan drug designation from FDA for Gastric cancers.
Margenza comes with two boxed warnings for left ventricular dysfunction and embryo-fetal toxicity. The drug has had a decent commercial hit with the launch in mid-March and was ranked USD 3.2 million in sales in Q2 of 2021. Even the company has “modest expectations” for Margenza sales, given the competitive landscape in the HER2-positive breast cancer market.
While in the case of HER2 positive gastric cancer (GC) or gastroesophageal junction (GEJ) cancer, a Phase II/III MAHOGANY is currently evaluating the drug in combination with checkpoint inhibition, with or without chemotherapy, as a potential first-line treatment. The MAHOGANY study is based on results from a completed Phase II study of margetuximab plus pembrolizumab, an anti-PD-1 monoclonal antibody. In this Phase II study, the drug was evaluated in a 2L treatment setting for patients who have previously been treated with chemotherapy and trastuzumab in the metastatic setting. The data from Phase II, which was presented at ESMO in September 2019, indicated a better median OS and decreased grade ≥3 TRAEs than Trastezumab plus chemotherapy, but the ORR and median PFS was not improved. The company decided to advance margetuximab from 2L treatment to 1L treatment in the Phase II/III MAHOGANY trial based on the data.
The MAHOGANY trial has two modules A and B. Module A is a single-arm cohort (Cohort A) and will evaluate the safety and efficacy of margetuximab plus retifanlimab with ORR as a primary endpoint in an attempt to achieve a chemo-free treatment paradigm. Module B is a 4-arm cohort, where patients will be randomized to margetuximab plus chemotherapy plus retifanlimab, margetuximab plus chemotherapy plus MGD013 (Tebotelimab), margetuximab plus chemotherapy, or Herceptin (trastuzumab) plus chemotherapy. A checkpoint inhibitor (CPI) (retifanlimab or MGD013) will be selected from Cohort B Part 1 and will be evaluated in a randomized 2-arm cohort (Cohort B Part 2, 250 patients per arm) of margetuximab plus chemotherapy plus retifanlimab or MGD013, or trastuzumab plus chemotherapy.
The results from Cohort A will be presented as poster 1379P at the ESMO 2021. The company anticipates that Module A will receive the US Accelerated Approval for chemo-free regimen. Therefore, it is evident that the company might replace Herceptin plus chemotherapy as a 1L treatment, the current SOC.
Nonetheless, Daichi Sankyo’s drug Enhertu (Fam-trastuzumab deruxtecan) recently got approval in the US, Europe, and Japan for adult patients with locally advanced or metastatic HER2 positive GC or GEJ adenocarcinoma who have received a prior Herceptin-based regimen. Now the drug is also being evaluated in previously untreated patients. We expect that margetuximab and enhertu will compete with Herceptin in 1L setting in the future, which depends on the much awaited data set to present during the upcoming ESMO 2021 conference that will showcase the potential margetuximab holds as a 1L therapy.
