Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial
Cediranib is a potent oral inhibitor of VEGFR-1,-2,-3 and inhibits VEGF signalling. A phase III trial in first relapse of ‘platinum-sensitive' ovarian cancer was performed following evidence of cediranib activity in ovarian cancer and manageable toxicity.
ICON6 is an international three-arm, double-blind placebo-controlled randomised trial. Patients received up to 6 cycles of platinum-based chemotherapy, randomised 2:3:3 to placebo (reference), cediranib 20mg/d during chemotherapy followed by placebo for up to 18 months (concurrent), or cediranib followed by maintenance cediranib (concurrent+maintenance). The primary endpoint was progression-free survival (PFS) in the reference vs. concurrent+maintenance arms. Secondary endpoints were overall survival (OS), toxicity and quality of life.
456 patients from 63 centres were enrolled; median age 62 years, ECOG performance status 0/1. Baseline characteristics, e.g. previous treatment interval >12 months (67%) were balanced between arms. PFS comparing reference and concurrent+maintenance using a log-rank test gave a p-value of 0.00001 with an associated Hazard Ratio (HR) of 0.57 (95% CI 0.45-0.74). However, because of non-proportional hazards (p=0.0237 for PFS and p=0.0042 for OS) the HR can be difficult to interpret, and instead survival time was estimated using restricted means (RM) and HRs are given for completeness. The RM estimates an increased time to progression of 3.2 months from 9.4 to 12.6, during 2 years. Similarly using RM, OS increased by 2.7 months from 17.6 to 20.3 (HR 0.70; log-rank test p=0.0419). PFS using RM for the reference vs. concurrent arms saw an increase of 2.0 months from 9.4 to 11.4 months (HR 0.68; log-rank test p=0.0022). Adverse events significantly more common in the cediranib-maintenance arm were hypertension, diarrhoea, hypothyroidism, hoarseness, haemorrhage, proteinuria and fatigue.
Cediranib given concurrently with platinum-based chemotherapy improves PFS and when continued as maintenance significantly improves both progression-free and overall survival in women with recurrent ovarian cancer.