Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer.
OBJECTIVE
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.
Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY, USA. pietanzm@mskcc.org
M Catherine
MC
Pietanza
Shirish M
SM
Gadgeel
Afshin
A
Dowlati
Thomas J
TJ
Lynch
Ravi
R
Salgia
Kendrith M
KM
Rowland
Michael S
MS
Wertheim
Katharine A
KA
Price
Gregory J
GJ
Riely
Christopher G
CG
Azzoli
Vincent A
VA
Miller
Lee M
LM
Krug
Mark G
MG
Kris
Jan H
JH
Beumer
Margaret
M
Tonda
Ben
B
Mitchell
Naiyer A
NA
Rizvi
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D015331:Cohort Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D014018:Tissue Distribution; D018631:ras Proteins / Q000235:genetics
D053961:Azabicyclo Compounds; D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C512478:EGFR protein, human; C571826:XL647