Despite high response rates to osimertinib in patients with EGFR mutation positive (EGFRm+) NSCLC, resistance inevitably develops. HER2 overexpression and amplification is detected in 13% of NSCLC-patients with acquired TKI-resistance. Previously, we showed that trastuzumab and paclitaxel in this setting is associated with a 41% ORR. Here, we evaluated the efficacy and toxicity of trastuzumab-emtansine (T-DM1) and osimertinib in patients with HER2 overexpression and/or amplification after progression on osimertinib as last line of treatment. We report a pre-planned interim analysis. In this multicenter single arm phase II study with a safety run-in (NCT03784599), eligible patients (≥18 years, WHO PS ≤2) with EGFRm+ NSCLC, progressing on EGFR TKI treatment and with HER2 overexpression (IHC ≥2+ in ≥10% of the cells) and/or HER2 amplification (ISH and/or NGS) were included. Patients were treated with T-DM1 3.6 mg/kg (IV infusion) every 3 weeks and osimertinib 80 mg QD. For patients with progression on 1st or 2nd generation EGFR TKIs, osimertinib monotherapy was initiated and T-DM1 was added at time of progression on osimertinib. Primary endpoints were to assess the ORR after 12 weeks and to evaluate safety of the combination treatment. In the safety run in, assessed in a classical 3+3 design, the first 3 patients received T-DM1 3.0 mg/kg. If none of these 3 patients developed a dose limiting toxicity (DLT), the T-DM1 dose was escalated to the standard dose of 3.6 mg/kg. Responses were assessed every 6 weeks according to RECIST 1.1. Treatment was continued until progression or unacceptable toxicity. Sample size was calculated using Simon’s two stage minimax design (H0=41%, H1>55%, 80% power, one-sided type I error rate of 10%, sample size: 58 patients, cohort A ORR 16/36 in order to proceed to cohort B). From January 15 2019 until April 6 2021, 27 patients were included and started with T-DM1. In the safety run in, none of the patients developed a DLT. Therefore, the study continued with osimertinib 80 mg QD and T-DM1 3.6 mg/kg IV infusion q 3 weeks. ORR and DCR after 6 weeks of treatment, evaluable in 24 patients, was 0% and 63% (16/24) respectively. One patient is not yet evaluable for the primary endpoint. ORR and DCR after 12 weeks of treatment were 13% (3/23) and 43% (10/23). DCR in HER2 IHC2+ and 3+ cohort was 36% (5/14) and 55% (5/9). Median PFS was 2.8 months (95% CI, 2.3-3.3 months), median duration of disease control was 20 weeks (range 4-47 weeks). Grade 2/3 adverse events occurred in 29%/21% of patients, including pneumonitis, LVEF decrease, fatigue, erythema and CK elevation. There were no grade 4 and 5 therapy-related adverse events. TRAEMOS is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC and progression on osimertinib to target HER2 bypass track resistance. Safety profile is favorable compared to cytotoxic chemotherapy, however this treatment strategy showed very limited efficacy. Further clinical evaluation of this regimen is not warranted.