Brief Report|Articles in Press, 100481

Trastuzumab-emtansine and osimertinib (TRAEMOS) combination therapy to target HER2 bypass track resistance in EGFR mutation positive NSCLC

Open AccessPublished:February 23, 2023DOI:
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      EGFR TKI improved the survival of metastatic EGFRm+ NSCLC patients. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found upon progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with T-DM1 could re-induce tumor responses.


      In this multicenter single arm phase I/II study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (IV) every 3 weeks and osimertinib 80 mg QD. Primary endpoints were ORR at 12 weeks and safety.Responses were assessed every 6 weeks (RECIST 1.1). Sample size was calculated using Simon’s two stage minimax design (H0=41%, H1>55%, 80% power, one-sided type I error 10%: A ORR 16/36 was needed in order to proceed to 58 patients).


      From 01-2019 until 04-2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1/27). Median PFS was 2.8 months (95% CI, 1.4-4.6 months). Most frequent treatment-related adverse events (TRAEs) of any grade were fatigue, diarrhea and nausea, among these, grade 3 in 4 patients. There were no grade 4 or 5 therapy-related AEs.


      TRAEMOS is the first trial combining T-DM1 and osimertinib in EGFRm+ NSCLC patients to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared to cytotoxic chemotherapy; but treatment showed limited efficacy. Further clinical evaluation of this regimen is not warranted.

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