Background: The NCI-MATCH is the largest national signal-finding trial incorporating centralized genomic testing to direct pts to molecularly targeted phase 2 treatment arms. HER2 gene amp is observed in many different tumor types. Methods: HER2 amp was defined as copy number (CN) ≥7 based on tumor sequencing on an adapted Oncomine AmpliSeq™ panel under FDA investigational device exemption. Pts with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Pts received T-DM1 at 3.6 mg/kg IV Q3 weeks until toxicity or disease progression. Tumor assessments occurred Q3 cycles for 33 cycles and Q4 cycles thereafter. Primary endpoint was objective response. Correlative studies included correlating HER2 CN, HER2 protein levels by IHC, HER2:CEP17 ratio (by FISH), PTEN loss, MYC amplification and PIK3CA mutation status with response. Results: 37 eligible pts were treated between 11/15-3/17. Median age was 65 (range 39-80). 33% had received > 3 lines of prior therapy. Median HER2 CN was 17 (7-139). Various histologies were treated: colon carcinoma (ca) (n = 7), ovarian ca (n = 6), rare tumors such as cholangioca (n = 1), carcinosarcoma of the uterus (n = 1), salivary gland ca (n = 3), among others. 3/37 (8.1%, 90% CI 2.2%-19.6%) had a confirmed partial response including 1 patient each with salivary duct ca of parotid gland, squamous cell ca of parotid gland and extramammary Paget’s disease of the scrotum. Additionally, 43% had stable disease (SD) including 3/3 evaluable ovarian and uterine ca respectively. Median duration of SD was 4.6 months. The 6-month PFS rate was 24.8% (90% CI 15.0%-41.1%). Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. Median treatment duration was 4 cycles (range 1- 23). Data from correlative analysis will be presented at the meeting. Conclusions: T-DM1 was well tolerated. Clinical activity was observed in HER2 amp non breast and gastric/GEJ adenoca pts warranting further study either alone or in combinations particularly in some histologies such as salivary gland tumors. Clinical trial information: NCT02465060