Phase I trial of sorafenib in combination with gefitinib in patients with refractory or recurrent non-small cell lung cancer.
OBJECTIVE
To evaluate the combination of sorafenib and gefitinib in patients with advanced non-small cell lung cancer.


METHODS
In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.


RESULTS
Thirty-one patients were treated (n=12, part A; n=19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C(max) (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n=8, part A; n=12, part B) had stable disease >or=4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.


CONCLUSIONS
Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non-small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
Adjei
Alex A
AA
Roswell Park Cancer Institute, Buffalo, New York 14263, USA. alex.adjei@roswellpark.org
Molina
Julian R
JR
Mandrekar
Sumithra J
SJ
Marks
Randolph
R
Reid
Joel R
JR
Croghan
Gary
G
Hanson
Lorelei J
LJ
Jett
James R
JR
Xia
Chenghua
C
Lathia
Chetan
C
Simantov
Ronit
R
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D000077157:Sorafenib
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D000077156:Gefitinib