Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

The classical mouse mutant postaxial hemimelia results from a mutation in the Wnt 7a gene.

The study of spontaneous mutations has aided the understanding of developmental processes. A large collection of spontaneous or "classical" mouse mutations has been accumulated over many decades. One of the mutations causes the postaxial hemimelia (px) phenotype, which consists of limb patterning defects accompanied by Müllerian duct-associated sterility in both sexes. We were intrigued that both the limb and the Müllerian duct px phenotypes are similar to those caused by mutations in the gene encoding the Wnt 7a signaling molecule. In this paper, we investigate the nature of the px mutation. Morphological analysis and breeding experiments demonstrate that the px phenotype indeed results from a mutation in the Wnt 7a gene. Molecular analysis demonstrates that px results from a 515-bp deletion in the Wnt 7a gene. This generates an abnormal splicing event, which ultimately produces a truncated Wnt 7a protein of half the normal size. Thus, the px mutation is predicted to be a likely null allele of the Wnt 7a gene. Our results provide another interesting example of a classical mutation that disrupts an important patterning gene in development.