AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
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.).
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.
Pasi A
PA
Jänne
James Chih-Hsin
JC
Yang
Dong-Wan
DW
Kim
David
D
Planchard
Yuichiro
Y
Ohe
Suresh S
SS
Ramalingam
Myung-Ju
MJ
Ahn
Sang-We
SW
Kim
Wu-Chou
WC
Su
Leora
L
Horn
Daniel
D
Haggstrom
Enriqueta
E
Felip
Joo-Hang
JH
Kim
Paul
P
Frewer
Mireille
M
Cantarini
Kathryn H
KH
Brown
Paul A
PA
Dickinson
Serban
S
Ghiorghiu
Malcolm
M
Ranson
D000178:Acrylamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles; D011743:Pyrimidines
D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines