First-generation, reversible @entity470 ( @entity470 ) @entity4149 kinase inhibitors (TKIs), @entity3866 and @entity4562 , represented an important addition to the treatment armamentarium for @entity1149 ( @entity1149 ) @entity1 with activating @entity470 mutations. However, all @entity1 inevitably develop acquired resistance to these agents, primarily due to secondary @entity470 mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of @entity12379 , an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the @entity470 , @entity1 @entity1722 , @entity7514 , and @entity12251 receptors. In two phase III trials in @entity1 with @entity470 mutation-positive @entity1149 , first-line @entity12379 significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, @entity12379 significantly improved overall survival in @entity1 harboring @entity470 Del19 mutations. @entity12379 has also demonstrated clinical activity in @entity1149 @entity1 who had progressed on @entity3866 / @entity4562 , particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with @entity1311 versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with @entity12379 versus @entity3866 for the second-line treatment of @entity1 with @entity957 . The activity of @entity12379 in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. @entity12379 has a well-defined safety profile with characteristic gastrointestinal ( @entity294 , @entity3136 ) and cutaneous (rash/acne) adverse events.

Next-Generation Covalent Irreversible Kinase Inhibitors in XXXX : Focus on @entity12379 .

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity3136 :: ('MESH:D013280', 'Disease') :: ['stomatitis'] @entity4562 :: ('MESH:C419708', 'Chemical') :: ['gefitinib'] @entity7514 :: ('2065', 'Gene') :: ['HER3'] @entity1722 :: ('2064', 'Gene') :: ['epidermal growth factor receptor (HER)-2'] @entity470 :: ('1956', 'Gene') :: ['EGFR', 'epidermal growth factor receptor'] @entity12379 :: ('MESH:C522924', 'Chemical') :: ['Afatinib', 'afatinib'] @entity12251 :: ('2066', 'Gene') :: ['HER4'] @entity1149 :: ('MESH:D002289', 'Disease') :: ['NSCLC', 'non-small-cell lung cancer'] @entity1311 :: ('MESH:D017239', 'Chemical') :: ['paclitaxel'] @entity957 :: ('MESH:D002294', 'Disease') :: ['squamous cell carcinoma of the lung'] @entity294 :: ('MESH:D003967', 'Disease') :: ['diarrhea'] @entity4149 :: ('D014443', 'Chemical') :: ['tyrosine'] @entity3866 :: ('MESH:C400278', 'Chemical') :: ['erlotinib']
@entity1149 :: (MESH:D002289,Disease) :: ['NSCLC']
