Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer.
OBJECTIVE
Pazopanib and lapatinib are tyrosine kinase inhibitors that target vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit or epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu), respectively. In cervical cancer, EGFR and HER2/neu overexpression and high microvascular density correlate with survival.


METHODS
Patients with measurable stage IVB persistent/recurrent cervical carcinoma not amenable to curative therapy and at least one prior regimen in the metastatic setting were randomly assigned in a ratio of 1:1:1 to pazopanib at 800 mg once daily, lapatinib at 1,500 mg once daily, or lapatinib plus pazopanib combination therapy (lapatinib at 1,000 mg plus pazopanib at 400 mg once daily or lapatinib at 1,500 mg plus pazopanib at 800 mg once daily). Therapy continued until progression or withdrawal because of adverse events (AEs). Primary end point was progression-free survival (PFS), and secondary end points were overall survival (OS), response rate (RR), and safety. The futility boundary was crossed at the planned interim analysis for combination therapy compared with lapatinib therapy, and the combination was discontinued.


RESULTS
Of 230 patients enrolled, 152 were randomly assigned to the monotherapy arms: pazopanib (n = 74) or lapatinib (n = 78). Most patients (62%) had recurrent cancer. Pazopanib improved PFS (hazard ratio [HR], 0.66; 90% CI, 0.48 to 0.91; P = .013) and OS (HR, 0.67; 90% CI, 0.46 to 0.99; P = .045). Median OS was 50.7 weeks and 39.1 weeks and RRs were 9% and 5% for pazopanib and lapatinib, respectively. The only grade 3 AE > 10% was diarrhea (11% pazopanib and 13% lapatinib). Grade 4 AEs were 9% (lapatinib) and 12% (pazopanib).


CONCLUSIONS
This study confirms the activity of antiangiogenesis agents in advanced and recurrent cervical cancer and demonstrates the benefit of pazopanib based on the prolonged PFS and favorable toxicity profile.
Monk
Bradley J
BJ
University of California Irvine Medical Center, Orange, CA 92868, USA. bjmonk@uci.edu
Mas Lopez
Luis
L
Zarba
Juan J
JJ
Oaknin
Ana
A
Tarpin
Carole
C
Termrungruanglert
Wichai
W
Alber
Jacquelyn A
JA
Ding
Jie
J
Stutts
Melissa W
MW
Pandite
Lini N
LN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007191:Indazoles; D000077341:Lapatinib; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D019233:Retreatment; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000401:mortality
D020533:Angiogenesis Inhibitors; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; D000077341:Lapatinib; C516667:pazopanib