@article{aedf3776dbb743b7ac671933b352f4fd,
title = "Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q",
abstract = "Background: The National Cancer Institute—Molecular Analysis for Therapy Choice (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 gastroesophageal tumors. Methods: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq{\texttrademark} (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 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 one patient). Median HER2 CN was 17 (range 7–139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease 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% confidence interval 14.2% to 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 CN as determined by the NGS assay. Conclusion: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point 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.",
keywords = "HER2-amplified, NCI-MATCH, NGS, T-DM1",
author = "Jhaveri, {K. L.} and Wang, {X. V.} and V. Makker and Luoh, {S. W.} and Mitchell, {E. P.} and Zwiebel, {J. A.} and E. Sharon and Gray, {R. J.} and S. Li and McShane, {L. M.} and Rubinstein, {L. V.} and D. Patton and Williams, {P. M.} and Hamilton, {S. R.} and Conley, {B. A.} and Arteaga, {C. L.} and Harris, {L. N.} and O'Dwyer, {P. J.} and Chen, {A. P.} and Flaherty, {K. T.}",
note = "Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748) and the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233290, UG1CA233341, UG1CA233329, UG1CA233180, NCI P30 CA142543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. None declared. KJ: consultant or advisory board: Novartis, Spectrum Pharmaceuticals, ADC Therapeutics, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Synthon and Lily Pharmaceuticals; research funding (to the institution): Novartis, Clovis Oncology, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, Pfizer and Zymeworks. VM: consultant/advisory board: Eisai, Merck, Karyopharm, IBM Watson; research funding (to the institution): Astra Zeneca, Eisai, Merck, Lilly Pharmaceuticals, Karyopharm, Takeda, Genentech. S-WL: consultant or advisory board: PDX Pharmaceuticals. EPM: honoraria from Sanofi; consultant or advisory board: Genentech; research funding (to the institution): Genentech and Sanofi. RJG: research funding: Abbott Molecular, Agios, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Millennium, Novartis, Onyx, Pfizer, Sanofi, Sequenta, Syndax. PMW: patents, royalties, other intellectual property—co-inventor of the DLBCL cell of origin patent recently filed by the NIH. SH: grant support: National Cancer Institute; consultant or advisory board: Bristol-Myers Squibb, Guardant, HalioDx, Loxo-Oncology, Merck, Thermo Fisher Scientific, Centers for Medicare and Medicaid Services, and Fred Hutchinson Cancer Research Center. CLA: grant support: Pfizer, Lilly, Radius, PUMA Biotechnology, Bayer, Takeda, Symphogen; advisory board/steering committee: Daiichi Sankyo, ABBVIE, Novartis, Lilly, Sanofi, Radius, Taiho Oncology, PUMA Biotechnology, Merck, H3Biomedicine, Symphogen, OrigiMed, Immunomedics, Petra Pharma, G1 Therapeutics, Athenex; stock options: Provista, Y-TRAP. LNH: patents, royalties, other intellectual property—Philips Healthcare. POD: consultant or advisory role: Bristol-Myers Squibb, Five Prime Therapeutics, Forty Seven, Genentech; research funding: Amgen, Bayer, BBI Healthcare, Bristol-Myers Squib, Celgene, Five Prime Therapeutics, Forty Seven, Genentech, GlaxoSmithKlin, Merck, Mirati Therapeutics, Novartis, Pfizer, Pharmacyclics. KTH: stock and other ownership interests: Clovis Oncology, Loxo, Strata Oncology, X4 Pharma; consultant or advisory board: Adaptimmune, Aeglea Biotherapeutics, Amgen, Asana Biosciences, Bristol-Myers Squibb, Genentech, Incyte, Lilly, Loxo, Merck, Novartis, Oncoceutics, Roche, Sanofi, Shattuck Labs, Tolero Pharmaceuticals; research funding: Novartis and Sanofi. All remaining authors have declared no conflicts of interest. ECOG-ACRIN Cancer Research Group, Memorial Sloan Kettering Cancer Center SupportP30 CA008748, National Cancer Institute of the National Institutes of HealthU10CA180820U10CA180794UG1CA233302UG1CA233290UG1CA233341UG1CA233329UG1CA233180NCI P30 CA142543, National Institutes of Health Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O{\textquoteright}Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748) and the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233290, UG1CA233341, UG1CA233329, UG1CA233180, NCI P30 CA142543. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = nov,
doi = "10.1093/annonc/mdz291",
language = "English (US)",
volume = "30",
pages = "1821--1830",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "11",
}