(EAY 131-B MATCH): Phase II Study of Afatinib in Patients with Tumors with HER2 Activating Mutations
The human epidermal growth factor receptor (HER) family pathway plays a critical role in multiple cellular functions. There are four members in this family: HER1 (epidermal growth factor receptor [EGFR] or ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Activation of the pathway via homo- or heterodimerization of these receptors can lead to cell proliferation, differentiation and survival. Agents targeting EGFR and HER2 have demonstrated activity in selected malignancies with HER2 overexpression/amplification or EGFR mutations. The human epidermal growth factor receptor-2 (ErbB2, HER2) is a transmembrane tyrosine kinase receptor which regulates cell growth and survival, as well as adhesion, migration, differentiation, and other cellular responses. The human epidermal growth factor receptor-2 (ErbB2, HER2) drives tumor proliferation with downstream signaling through the PI3K-AKT and MEK-ERK pathways. HER2 overexpression and amplification has been identified as a poor prognostic marker in a subset of patients diagnosed with breast, gastric or gastroesophageal junction cancer. However; agents targeting this pathway have significantly improved the survival of patients with HER2+ breast and gastric cancer. Recently, mutations of the HER2 receptor tyrosine kinase have been identified in several different cancers. These mutations can reside in the kinase domain (D769Y, D769H, L755S, V777L, V842I, or in-frame exon 20 insertions) or the extracellular domain (G309A, G309E, S310F, S310Y or E321G) of HER2. These mutations have been found in breast, lung, ovarian, and bladder cancers. Evidence supports that at least in some tumors, these mutations (both kinase and extracellular domains) function as driver mutations. It is known that 2-4% of NSCLC harbor activating mutations and that such mutations are also found in ovarian cancers as well as several other cancer subtypes. Recently, in a small study of 15 micropapillary urothelial carcinoma (MPUC), 40% harbored a HER2 mutations compared to the 9.4% seen in 64 cases of non-MPUC cases.16 HER2 activating mutations lead to constitutive activation of the receptor and downstream AKT and MEK pathways.Afatinib dimaleate (hereafter, referred to as afatinib) is a potent and selective, oral irreversible inhibitor of ErbB family members. It is one of several dual EGFR/HER2 targeted agents in clinical development. Afatinib was more effective than erlotinib against EGFR mutant cancers in preclinical models. Afatinib has been reported to have efficacy against HER2 activating mutations.
NCG 275215 B