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Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
Abstracts by Pasi A. Janne:
A phase II trial of erlotinib for EGFR mutant NSCLC to prospectively assess biopsy feasibility and acquired resistance at disease progression.Meeting: 2015 ASCO Annual Meeting | Abstract No: 8076
A prospective evaluation of cell free DNA (cfDNA) genotyping and circulating tumor cells (CTC) in EGFR mutant NSCLC patients (pts) treated with erlotinib.Meeting: 2015 ASCO Annual Meeting | Abstract No: 11068
A prospective validation of plasma ddPCR for rapid EGFR and KRAS genotyping of advanced NSCLC patients (pts).Meeting: 2015 ASCO Annual Meeting | Abstract No: 11089
Presentations by Pasi A. Janne:
Meeting: 2012 ASCO Annual Meeting
Session: Tumor Biology (Oral Abstract Session)
Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC).Meeting: 2012 ASCO Annual Meeting Abstract No: 7503Session: Lung Cancer - Non-small Cell Metastatic (Oral Abstract Session)
Meeting: 2012 ASCO Annual Meeting
Session: Personalized Medicine in Lung Cancer in 2012 (Education Session)