PMID- 25923549 OWN - NLM STAT- MEDLINE DCOM- 20150518 LR - 20220603 IS - 1533-4406 (Electronic) IS - 0028-4793 (Linking) VI - 372 IP - 18 DP - 2015 Apr 30 TI - AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. PG - 1689-99 LID - 10.1056/NEJMoa1411817 [doi] AB - BACKGROUND: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. METHODS: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. RESULTS: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. CONCLUSIONS: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.). FAU - Janne, Pasi A AU - Janne PA AD - From the Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston (P.A.J.); National Taiwan University and National Taiwan University Hospital (J.C.-H.Y.) and Cheng Kung University Hospital (W.-C.S.) - both in Taipei, Taiwan; Seoul National University Hospital (D.-W.K.), Samsung Medical Center (M.-J.A.), Asan Medical Center (S.-W.K.), and Yonsei Cancer Center, Yonsei University Health System (J.-H.K.) - all in Seoul, South Korea; Institut Gustave Roussy, Villejuif, France (D.P.); National Cancer Center Hospital, Tokyo (Y.O.); Winship Cancer Institute of Emory University, Atlanta (S.S.R.); Vanderbilt Ingram Cancer Center, Nashville (L.H.); Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC (D.H.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (E.F.); and AstraZeneca, Macclesfield (P.F., M.C., K.H.B., P.A.D., S.G.), and University of Manchester, Christie Hospital, Manchester (M.R.) - both in the United Kingdom. FAU - Yang, James Chih-Hsin AU - Yang JC FAU - Kim, Dong-Wan AU - Kim DW FAU - Planchard, David AU - Planchard D FAU - Ohe, Yuichiro AU - Ohe Y FAU - Ramalingam, Suresh S AU - Ramalingam SS FAU - Ahn, Myung-Ju AU - Ahn MJ FAU - Kim, Sang-We AU - Kim SW FAU - Su, Wu-Chou AU - Su WC FAU - Horn, Leora AU - Horn L FAU - Haggstrom, Daniel AU - Haggstrom D FAU - Felip, Enriqueta AU - Felip E FAU - Kim, Joo-Hang AU - Kim JH FAU - Frewer, Paul AU - Frewer P FAU - Cantarini, Mireille AU - Cantarini M FAU - Brown, Kathryn H AU - Brown KH FAU - Dickinson, Paul A AU - Dickinson PA FAU - Ghiorghiu, Serban AU - Ghiorghiu S FAU - Ranson, Malcolm AU - Ranson M LA - eng SI - ClinicalTrials.gov/NCT01802632 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (Acrylamides) RN - 0 (Aniline Compounds) RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 3C06JJ0Z2O (osimertinib) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM CIN - N Engl J Med. 2015 Apr 30;372(18):1760-1. doi: 10.1056/NEJMe1500181. PMID: 25923556 CIN - Nat Rev Clin Oncol. 2015 Jul;12(7):373. doi: 10.1038/nrclinonc.2015.93. PMID: 25963089 MH - Acrylamides/*administration & dosage/adverse effects/pharmacokinetics MH - Adult MH - Aged MH - Aged, 80 and over MH - Aniline Compounds/*administration & dosage/adverse effects/pharmacokinetics MH - Antineoplastic Agents/*administration & dosage/adverse effects MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - Drug Resistance, Neoplasm/*genetics MH - ErbB Receptors/antagonists & inhibitors/*genetics MH - Female MH - Humans MH - Lung Neoplasms/*drug therapy/genetics MH - Male MH - Middle Aged MH - Mutation MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/pharmacokinetics EDAT- 2015/04/30 06:00 MHDA- 2015/05/20 06:00 CRDT- 2015/04/30 06:00 PHST- 2015/04/30 06:00 [entrez] PHST- 2015/04/30 06:00 [pubmed] PHST- 2015/05/20 06:00 [medline] AID - 10.1056/NEJMoa1411817 [doi] PST - ppublish SO - N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.