Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma.
OBJECTIVE
Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors with proven clinical benefit in patients with metastatic renal cell carcinoma (RCC). This phase I/II study investigated sunitinib in combination with an epidermal growth factor receptor inhibitor, gefitinib, in patients with metastatic RCC.


METHODS
In phase I, patients received sunitinib 37.5 or 50 mg in 6-week cycles (4 weeks on treatment, 2 off) plus gefitinib 250 mg, both once daily, to determine the sunitinib maximum tolerated dose (MTD). Pharmacokinetics was assessed for both drugs. In phase II, patients received sunitinib MTD plus gefitinib to evaluate the safety and antitumor activity of this combination.


RESULTS
Forty-two patients were enrolled: 11 in phase I, and 31 in phase II. In phase I, 2 dose-limiting toxicities were observed with sunitinib 50 mg (grade 2 left ventricular ejection fraction decline and grade 3 fatigue), and 37.5 mg was declared the MTD. Thirteen patients treated at the MTD achieved a partial response (objective response rate: 37%; 95% confidence interval, 22-55) and 12 (34%) had stable disease. Median progression-free survival was 11 months (95% confidence interval, 6-17). The most commonly reported grade 3/4 treatment-related adverse event was diarrhea (14%), the only grade 3/4 adverse event to occur in >2 patients. Pharmacokinetic analyses did not indicate any drug-drug interactions.


CONCLUSIONS
In metastatic RCC, sunitinib plus gefitinib demonstrated comparable efficacy to sunitinib monotherapy with an acceptable safety profile. Dosing, pharmacokinetic profile, and safety support study of sunitinib plus an epidermal growth factor receptor inhibitor in other tumor types.
Motzer
Robert J
RJ
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. motzerr@mskcc.org
Hudes
Gary R
GR
Ginsberg
Michelle S
MS
Baum
Michael S
MS
Harmon
Charles S
CS
Kim
Sindy T
ST
Chen
Isan
I
Redman
Bruce G
BG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D000077210:Sunitinib; D016019:Survival Analysis; D016896:Treatment Outcome
D007211:Indoles; D011758:Pyrroles; D011799:Quinazolines; D000077156:Gefitinib; D000077210:Sunitinib