Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.
BACKGROUND
Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We aimed to assess the activity and safety of axitinib in patients with metastatic renal-cell cancer who had failed on previous cytokine-based treatment.


METHODS
Between Oct 3, 2003, and April 7, 2004, 52 patients were enrolled. All patients who had at least one measurable target lesion received axitinib orally (starting dose 5 mg twice daily). The primary endpoint was objective response (ie, percentage of patients with confirmed complete response or partial response by use of Response Evaluation Criteria In Solid Tumors [RECIST] criteria. Secondary endpoints were duration of response, time to progression, overall survival, safety, pharmacokinetics, and patient-reported health-related quality of life. This trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00076011.


RESULTS
In an intention-to-treat analysis, two complete and 21 partial responses were noted, for an objective response rate of 44.2% (95% CI 30.5-58.7). Median response duration was 23.0 months (20.9-not estimable; range 4.2-29.8). However, 12 of 23 initial responders progressed with response duration ranging from 4.2 months to 26.5 months. Additionally, 22 patients showed stable disease for longer than 8 weeks, including 13 patients with stable disease for 24 weeks or longer. Four patients had early disease progression. Three patients had missing response data. Median time to progression was 15.7 months (8.4-23.4, range 0.03-31.5) and median overall survival was 29.9 months (20.3-not estimable; range 2.4-35.8). Treatment-related adverse events included diarrhoea, hypertension, fatigue, nausea, and hoarseness. Treatment-related hypertension occurred in 30 patients and resolved with antihypertensive treatment in all but eight patients, of whom seven patients had a history of hypertension at baseline.


CONCLUSIONS
Axitinib shows clinical activity in patients with cytokine-refractory metastatic renal-cell cancer. Although 28 patients had grade 3 or grade 4 treatment-related adverse events, these adverse events were generally manageable and controlled by dose modification or supportive care, or both. Further studies are needed to confirm these findings.
Rixe
Olivier
O
Pitié-Salpêtrière Hospital, University of Paris, Paris, France. olivier.rixe@psl.ap-hop-paris.fr
Bukowski
Ronald M
RM
Michaelson
M Dror
MD
Wilding
George
G
Hudes
Gary R
GR
Bolte
Oliver
O
Motzer
Robert J
RJ
Bycott
Paul
P
Liau
Katherine F
KF
Freddo
James
J
Trask
Peter C
PC
Kim
Sinil
S
Rini
Brian I
BI
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000077784:Axitinib; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007191:Indazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007191:Indazoles; D016898:Interferon-alpha; D007376:Interleukin-2; D000077784:Axitinib