Dose-escalation study using up to twice the standard dose of cetuximab in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST study): Preliminary data

摘要: 3554 Background: Response to the epidermal growth factor receptor (EGFR) inhibitor, cetuximab appears to correlate with the intensity of the associated skin reaction. This randomized multicenter study investigated the effect of cetuximab dose escalation on EGFR activation and downstream signaling in skin and tumor biopsies, on activity and skin reactions in patients (pts) with EGFR-expressing mCRC, failing prior irinotecan (I). Methods: Pts with ≥1 measurable lesion suitable for biopsy were eligible and were randomized 22 days after starting treatment with cetuximab (initial dose 400mg/m2 then 250mg/m2/week(w)) plus I (2-weekly regimen 180 mg/m2) if they had not experienced >grade 1 skin reaction, any other >grade 2 cetuximab-related toxicity and were not intolerant to I. Pts were randomized to standard cetuximab dose (arm A; 250 mg/m2/w) or dose-escalation (arm B; cetuximab dose increased by 50 mg/m2 q 2 w up to 500 mg/m2, until >grade 2 toxicity or tumor response). Pts not randomized (arm C) continued with the standard regimen after day 22. Skin and tumor biopsies were taken pre- and during treatment. Results: Of 273 screenedpts, 221 were EGFR-expressing and 166 were recruited. 45 pts were randomized to arm A, 44 to arm B and 76 were in arm C. By August 2005, 18 pts had reached the highest dose (500mg/m2/w), with no concerns over safety. All baseline and second biopsies are available. Safety results are presented for the first 36 pts in arm B. M/F 23/13, median age 60 y (34–79), median Karnofsky performance score 90 (80–100). All pts reported here had received cetuximab for at least 6 weeks. Maximum dose reached at w 6: 350mg/m2/w (300mg/m2 in 36 pts at w 4; 350mg/m2 in 31 pts at w 6). Relevant grade 3/4 toxicities were diarrhea (2.8%) and fatigue (5.6%). No grade 3/4 skin reactions occurred. Conclusions: Cetuximab at a dose of 350 mg/m2 is well tolerated in pts who have had no or mild skin reactions in response to standard dose treatment. Further dose escalation is possible. No early increase of skin toxicity is observed. Analysis of efficacy and pharmacokinetics/dynamics is ongoing. [Table: see text]