Ado-trastuzumab emtansine (T-DM1) in patients with HER2 amplified tumors excluding breast and gastric/gastro-esophageal junction (GEJ) adenocarcinomas: Results from the NCI-MATCH Trial (EAY131) Sub-protocol Q.

BACKGROUND The NCI-MATCH is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2 amplified histologies other than breast and gastro-esophageal tumors. METHODS Eligible patients had HER2 amplification at a copy number (CN) > 7 based on targeted NGS with a custom Oncomine AmpliSeq™ panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg intravenously every 3 weeks until toxicity or disease progression. Tumor assessments occurred every 3 cycles. The primary endpoint was centrally-assessed objective response rate (ORR). Exploratory endpoints included correlating response with HER2 copy number (CN) by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in 1 patient). Median HER2 CN was 17 (range: 7-139). Partial responses were observed in 2 (5.6%) patients: 1 mucoepidermoid carcinoma of parotid gland and 1 parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease (SD) including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression free survival rate was 23.6% (90% CI 14.2%-39.2%). Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene copy number as determined by the NGS assay. CONCLUSION T-DM1 was well tolerated. While this subprotocol did not meet the primary endpoint for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.