Addition of panitumumab to irinotecan: Results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC).
Seymour MT., Brown SR., Richman S., Middleton GW., Maughan T., Olivier C., Gwyther SJ., Wadsley J., Chau I., Hickish T., Dawson LK., Falk S., O'Callaghan A., Benstead K., Wadd N., Oliver A., Chambers P., Marshall H., Napp V., Quirke P., UK NCRI Colorectal Clinical Studies Group None.
3523 Background: Phase III trials show inconsistent effects when anti-EGFR drugs are added to cytotoxic therapy in aCRC. Benefits, when present, are confined to patients (pts) determined retrospectively to have KRAS wild-type (wt) tumours. PICCOLO is a multicentre randomized controlled trial, amended in June 2008 to include prospective KRAS testing, to evaluate the addition of panitumumab (Pan) to single-agent irinotecan (Ir) as second- or subsequent-line therapy for KRAS-wt aCRC. METHODS: Eligible pts had: measurable aCRC progressing during/after ≥1 prior regimen with fluoropyrimidines ± other drugs; no prior Ir; WHO PS 0-2. Until June '08, pts were allocated 1:1:1 to Ir, IrPan or Ir/ciclosporin, with retrospective KRAS analysis. Thereafter, KRAS was tested prospectively (by pyrosequencing of c.12-13 and 61) and pts with KRAS-wt were allocated 1:1 to Ir (Ir 350 mg/m(2) [300 mg/m(2) if ≥70 yrs or PS2], q3w) or IrPan (same Ir plus Pan 9 mg/kg, q3w). Primary analysis is ITT overall survival (OS) in KRAS-wt pts not pretreated with anti-EGFR therapy (80% power, HR 0.70, α=0.05, 2-sided). Secondary endpoints include % progression-free at 12 wks, PFS, RR, toxicity and QL. Planned molecular subgroups include BRAF, NRAS, KRAS c.146 and PIK3CA. RESULTS: 460 KRAS-wt pts were recruited to the primary analysis (324 after June '08, KRAS-tested prospectively); median age 63 yrs; 94% PS0-1; 95% had received prior oxaliplatin. With 312 events and median follow-up of survivors 10.2 mo, OS was not improved: median IrPan = 10.4 mo, Ir = 10.5 mo, HR 0.91 (95%CI [0.73, 1.14], p=0.44), but trended towards improved survival after 12 mo. Planned subgroup analysis shows worse survival, and disbenefit with Pan in BRAF-mut pts (n=63, HR=1.87, [95%CI 1.07, 3.27]); conversely, KRAS/BRAF-wt pts show a stronger but still non-significant trend towards benefit (n=348, HR=0.86 [0.66, 1.11]). CONCLUSIONS: PICCOLO did not meet its primary endpoint of improved OS with panitumumab in KRAS-wt aCRC, but a trend was seen towards survival benefit after 12 months, especially in KRAS/BRAF-wt pts. Conversely, pts with BRAF-mut tumours had significant disbenefit with Pan. Full results, including PFS and planned molecular subgroups, will be presented.