and Amplifications Determine Response to HER2 Inhibition in -Amplified Esophagogastric Cancer.

Sanchez-Vega, Francisco; Hechtman, Jaclyn F; Castel, Pau; Ku, Geoffrey Y; Tuvy, Yaelle; Won, Helen; Fong, Christopher J; Bouvier, Nancy; Nanjangud, Gouri J; Soong, Joanne; Vakiani, Efsevia; Schattner, Mark; Kelsen, David P; Lefkowitz, Robert A; Brown, Karen; Lacouture, Mario E; Capanu, Marinela; Mattar, Marissa; Qeriqi, Besnik; Cecchi, Fabiola; Tian, Yuan; Hembrough, Todd; Nagy, Rebecca J; Lanman, Richard B; Larson, Steven M; Pandit-Taskar, Neeta; Schöder, Heiko; Iacobuzio-Donahue, Christine A; Ilson, David H; Weber, Wolfgang A; Berger, Michael F; de Stanchina, Elisa; Taylor, Barry S; Lewis, Jason S; Solit, David B; Carrasquillo, Jorge A; Scaltriti, Maurizio; Schultz, Nikolaus; Janjigian, Yelena Y     «

Sanchez-Vega, Francisco; Hechtman, Jaclyn F; Castel, Pau; Ku, Geoffrey Y; Tuvy, Yaelle; Won, Helen; Fong, Christopher J; Bouvier, Nancy; Nanjangud, Gouri J; Soong, Joanne; Vakiani, Efsevia; Schattner, Mark; Kelsen, David P; Lefkowitz, Robert A; Brown, Karen; Lacouture, Mario E; Capanu, Marinela; Mattar, Marissa; Qeriqi, Besnik; Cecchi, Fabiola; Tian, Yuan; Hembrough, Todd; Nagy, Rebecca J; Lanman, Richard B; Larson, Steven M; Pandit-Taskar, Neeta; Schöder, Heiko; Iacobuzio-Donahue, Christine A;...     »

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of and . Heterogeneous Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking amplification or with acquisition of amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in and coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in -amplified EG cancer. SIGNIFICANCE: Analysis of patients with -amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with / coamplification and amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones...     «

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib r...     »