Background: HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical data suggested efficacy of trastuzumab (Herceptin) in patients with HER2 immunochemistry 3+ (IHC3+) status or positive fluorescence in situ hybridization (FISH). The heat shock protein HSP90 is a molecular chaperone modulating stability and/or transport of intracellular client proteins including HER2. In breast cancer HSP90 inhibition showed anticancer activity in HER2-positive patients after trastuzumab failure. Here we are investigating the efficacy of the combination of trastuzumab and the HSP90 inhibitor AUY922 in lung cancer patients with aberrant HER2. Methods: This phase II study recruits metastatic NSCLC patients with HER2 overexpression (IHC DAKO-score 3+) or amplification (FISH positive) or activating mutation after failure of at least one previous standard treatment. In the first part of the study, patients are treated with trastuzumab only (initially 4mg/kg, followed by 2 mg/kg weekly). CT scan is scheduled every 6 weeks during treatment. In case of disease progression, AUY922 (70 mg/m2) is given additionally. Patients are recruited in two German centers: in Cologne and Essen. Results: Within the Network of Genomic Medicine in Cologne, 3,863 NSCLC patients of all stages were screened. Patients with overexpression were tested for amplification and mutation. HER2 amplification was seen in 4% and HER2 mutations in 1.6% of all adenocarcinomas. Patients in Essen are screened separately. The study is ongoing. Five patients with HER2 amplifications were treated in the study. Two patients progressed after 6 and 12 weeks on the combination. One patient showed clinical progression within first 6 weeks on trastuzumab. Two patients are still ongoing on trastuzumab monotherapy. The best CT response was -29.3% in patient on trastuzumab and AUY922 at week 6. Conclusions: HER2 overexpression, amplification or mutation is a rare genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented Clinical trial information: DRKS00003301.