Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).

Lung Cancer - Non-Small Cell Metastatic
Session Type and Session Title: 
Clinical Science Symposium, Targeting EGFR: The Next 10 Years
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 8009^)
Pasi A. Janne, Suresh S. Ramalingam, James Chih-Hsin Yang, Myung-Ju Ahn, Dong-Wan Kim, Sang-We Kim, David Planchard, Yuichiro Ohe, Enriqueta Felip, Claire Watkins, Mireille Cantarini, Serban Ghiorghiu, Malcolm Ranson; Dana-Farber Cancer Institute, Boston, MA; The Winship Cancer Institute of Emory University, Atlanta, GA; National Taiwan University, Graduate Institute of Oncology, Taipei, Taiwan; Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Seoul National University Hospital, Seoul, South Korea; Asan Medical Center, Seoul, South Korea; Gustave Roussy, Villejuif, France; National Cancer Center Hospital East, Kashiwa, Japan; Vall d'Hebron University Hospital, Barcelona, Spain; AstraZeneca, Macclesfield, United Kingdom; University of Manchester, Christie Hospital, Manchester, United Kingdom

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Abstract Disclosures


Background: AZD9291 is a selective, third generation EGFR-TKI, effective against both EGFR-TKI sensitizing and resistance T790M mutations in preclinical models. We are conducting a phase I study of AZD9291 in EGFR mutant (EGFRm+) NSCLC pts. Methods: EGFRm+ NSCLC pts, with acquired resistance to EGFR-TKIs, were enrolled in a multicenter trial (NCT01802632) into dose escalation and expansion cohorts. AZD9291 was administered orally, at doses of 20–240 mg once daily. Stable brain metastases were allowed. All pts were assessed for pharmacokinetics (PK), response to therapy, and adverse events (AEs). Prospective mandatory central T790M testing was required in the expansion cohorts and was optional for dose escalation cohorts. Results: As of 16 January 2014, 199 pts (62% female, median age 60, Asian/Caucasian 65%/32%, immediate prior EGFR-TKI therapy: 57%) were enrolled including 31 across 5 dose levels in the dose escalation and 168 in 8 dose expansion cohorts. Median number of prior EGFR therapies: 1 (range, 1-5). PK was dose proportional, median t1/2 ~50 h. Plasma exposures achieved at all doses are predicted to be efficacious in preclinical models. Among all evaluable pts to date, the confirmed+unconfirmed overall response rate (c+uORR) was 51% (91/177). RECIST responses were observed at all dose levels and in brain metastases. In 132 pts with centrally confirmed T790M, the c+uORR in 89 EGFR T790M+ pts was 64% (95% CI; 53%, 74%) and in 43 EGFR T790M- pts was 23% (95% CI; 12%, 39%).The overall disease control rate (CR+PR+SD) in T790M+ pts was 96% (85/89). Among the 60 pts with a confirmed response, 97% (58/60) were ongoing at data cut-off; longest duration of response to date >8 months. No dose limiting toxicities were observed. Most common AEs (≥15%), mostly CTCAE Grade 1, were: diarrhea (30%), rash (24%), and nausea (17%). Grade 3/4 AEs occurred in 16% of pts. Six pts (3%) had dose reductions. Five reports of ILD-like events are under investigation. Conclusions: AZD9291 has robust efficacy and is well tolerated in EGFRm+ NSCLC pts with acquired resistance to EGFR-TKIs. Pts with EGFR T790M+ tumors have higher ORR with AZD9291 compared with those with EGFR T790M- tumors. Clinical trial information: NCT01802632.