TY - JOUR
T1 - Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer
AU - Pietanza, M. Catherine
AU - Gadgeel, Shirish M.
AU - Dowlati, Afshin
AU - Lynch, Thomas J.
AU - Salgia, Ravi
AU - Rowland, Kendrith M.
AU - Wertheim, Michael S.
AU - Price, Katharine A.
AU - Riely, Gregory J.
AU - Azzoli, Christopher G.
AU - Miller, Vincent A.
AU - Krug, Lee M.
AU - Kris, Mark G.
AU - Beumer, Jan H.
AU - Tonda, Margaret
AU - Mitchell, Ben
AU - Rizvi, Naiyer A.
N1 - Funding Information:
Disclosure: Supported by Exelixis, Inc. Thomas J. Lynch has served as a consultant for Merck, BI, and Supergen; has served on the Board of Directors for Infinity; and holds a patent with Partners Healthcare for EGFR mutations. Gregory J. Riely has received a grant for research or other work related to the topic of this manuscript. Vincent A. Miller has served as a consultant for Boehringer Ingelheim, and has received honoraria from OSI-Astellus, Genentech, and Clovis. Ben Mitchell and Margaret Tonda are employees of the organization and held stock in the organization.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. Methods: Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, XL647 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. Results: Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7-6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation-positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5-11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. Conclusions: XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules.
AB - XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. Methods: Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, XL647 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. Results: Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7-6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR-sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation-positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5-11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. Conclusions: XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules.
KW - Acquired resistance
KW - EGFR-resistance mutation
KW - EGFR-sensitizing mutation
KW - Molecular analysis
KW - Tyrosine kinase inhibitor
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U2 - 10.1097/JTO.0b013e31824c943f
DO - 10.1097/JTO.0b013e31824c943f
M3 - Article
C2 - 22722787
AN - SCOPUS:84862115744
SN - 1556-0864
VL - 7
SP - 856
EP - 865
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 5
ER -