Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma.
OBJECTIVE
Sorafenib tosylate (sorafenib, BAY 43-9006, Nexavar) is a multi-kinase inhibitor that targets tumor cell proliferation and angiogenesis. These studies evaluated the efficacy and tolerability of combinations of sorafenib plus agents used to treat non-small cell lung cancer (NSCLC) using preclinical models of that disease.


METHODS
Intravenous (iv) vinorelbine and interperitoneal (ip) cisplatin were administered intermittently (q4d x 3) in combination with sorafenib administered orally (po) once daily for 9 days starting on the same day as the standard agent. In studies with sorafenib and gefitinib, both agents were administered po daily for 10 days starting on the same day. Treatment in all studies was initiated against established sc tumors, and each study was conducted in duplicate. Efficacy was assessed as the delay in tumor growth to a specified size (TGD).


RESULTS
Vinorelbine (6.7 mg/kg) and sorafenib (40 mg/kg) produced TGDs of 2.4 and 7.8 days, respectively, in the NCI-H460 NSCLC model. Combination therapy produced a 10.0-day TGD with no increase in toxicity. Combination therapy in the NCI-H23 NSCLC model with the highest evaluated dose levels of sorafenib plus cisplatin was well tolerated and produced TGDs equivalent to those produced by cisplatin alone. Lower dose levels of each agent produced approximately additive TGD's. Combination therapy in the A549 NSCLC model with sorafenib and gefitinib produced TGDs equivalent to that produced by sorafenib alone with no toxicity. Tumor growth in the MDA-MB-231 mammary tumor model, that contains mutations in signal transduction proteins downstream of the EGF receptor (the target of gefitinib) was also inhibited by sorafenib, but not by gefitinib.


CONCLUSIONS
Concurrent administration of sorafenib and vinorelbine, cisplatin or gefitinib was at least as efficacious as the individual agents alone and was well tolerated. These results support the inclusion of sorafenib in clinical trials in NSCLC employing combinations of both cytotoxic and cytostatic agents.
Carter
Christopher A
CA
Bayer Pharmaceuticals Corporation, West Haven, CT 06516, USA. christopher.carter.b@bayer.com
Chen
Charles
C
Brink
Cheryl
C
Vincent
Patrick
P
Maxuitenko
Yulia Y
YY
Gilbert
Karen S
KS
Waud
William R
WR
Zhang
Xiaomei
X
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003603:Cytotoxins / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D011799:Quinazolines / Q000494:pharmacology; D000077157:Sorafenib; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000077235:Vinorelbine; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D003603:Cytotoxins; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; D014747:Vinblastine; D000077157:Sorafenib; D002945:Cisplatin; D000077235:Vinorelbine; D000077156:Gefitinib