Background: HER2 expression as well as amplification has been well recognized in tumor biopsies of pts with an EGFR mutation who developed EGFR TKI resistance. It is unknown whether HER2 targeting in this setting can result in tumor responses. Methods: Single arm open label phase II study to study the safety and efficacy of paclitaxel-trastuzumab treatment in pts with a sensitizing EGFR mutation who show tumor membrane HER2 expression in a tumor biopsy (immunohistochemistry (IHC) ≥1) after progression on EGFR TKI treatment. Paclitaxel (60 mg/m2) and trastuzumab (first dose 4 mg/kg, thereafter 2 mg/kg) were dosed weekly until disease progression or unacceptable toxicity. Primary end-point was tumor response according to RECIST. Sample size of 20 pts was calculated to evaluate the primary objective of ≥30% objective response rate. The study was deemed positive when ≥7 pts would show a partial or complete response. Results: 21 pts were enrolled from 08-2012 to 02-2017. 7 pts were exon 21 L858R positive and 14 exon 19 del. Last TKI was erlotinib (n = 6), gefitinib (n = 4), rociletinib (n = 3) or osimertinib (n = 8). Median HER2 IHC was 2+ (range 1-3). 17 pts were evaluable for response assessment, while 4 pts are awaiting their first response scan. The primary end-point was met with 7/17 pts (41%) showing a partial response. 2 pts showed stable disease, 7 progressive disease and 1 pt had clinical progression before CT response evaluation. Median duration of response was 9 (range 6-18) months with one ongoing responder. 3 pts experienced grade ≥3 toxicity, including fatigue, neuropathy and neutropenia. Upon progression on study treatment, all responding pts were rebiopsied. 4/6 samples were negative for HER2 (IHC), suggesting that the combination effectively targeted HER2 positive tumor cells. Conclusions: The study met its primary end-point. Paclitaxel-trastuzumab induces durable objective tumor responses in EGFR TKI pretreated pts with an activating EGFR mutation and HER2 bypass track activation. The treatment was well tolerated. Post-progression tumor biopsies showed absence of HER2 staining in the majority of pts, suggesting effective HER2 targeting. Clinical trial information: NCT02226757