Cetuximab reversal of resistance to chronomodulated chemotherapy in heavily-pretreated patients with metastatic colorectal cancer (MCC) without amplification of epidermal growth factor receptor (EGFR) gene

Abstract

13104 Background Skin toxicity and EGFR amplification reportedly predicted for Cetux-reversal of MCC resistance to standard chemotherapy. We explored these relations for Cetux reversal of resistance to chronomodulated chemotherapy (Chrono) with irinotecan (CPT11, peak at 5 am), 5-fluorouracil-leucovorin (FU-LV, peak at 4 am) and oxaliplatin (l-OHP, peak at 4 pm). Methods: 40 pts with progressive MCC on 3 prior chemotherapy lines received weekly Cetux (250 mg/m2) and q2–3 wks CPT11-based (30 pts) or oxaliplatin-based (10 pts) Chrono. Toxicities and response were assessed q2–3 wks and q2 months (mo) respectively. Tumor EGFR expression was determined by immunohistochemistry for all pts and gene copies by fluorescent in situ hybridization (FISH) for 25 pts. Results: All pts had prior progression on CPT11, FU-LV and l-OHP. Median age: 61 yo; M/F: 24/16; WHO PS 0/1/2: 27/9/4; colon/rectum: 21/19; M sites 1/2/≥ 3: 12/15/13; liver/lung: 32/29; pre-existing peripheral sensory neuropathy grade ≥ 2: 11 pts. A median of 8 courses of Cetux-Chrono was given (1 to 22). Three pts withdrew for grade 4 allergy. 37 pts were assessable for other toxicities and 36 for response (1 too early). Gr 2–3 acneiform skin rash occurred in 27 pts (73%), with gr3 in 11 pts (29.7%). Other main gr 3–4 toxicities were diarrhea (27% of the pts), neutropenia (24.3%) and neuropathy (21.6%). Disease progressed in 12 pts (33.3%) and was controlled in 24 pts (66.7%) including 13 stable disease (36.1%) and 10 objective responses (8 PR and 2 CR) - 27.8% [95% C.L. 12.9 to 42.7]. EGFR was expressed in 32 pts (80%), with >10% + tumor cells for 14 pts (35%). 3/6 EGFR- pts (50%) and 7/32 EGFR+ pts (21.9%) responded. No gene amplification was documented in the 25 tumors (7 responders). A positive correlation between skin rash and disease control was suggested (p from χ2 = 0.08). Median progression free and overall survival (mo) are 5.3 [2.9–8.4] and 11.1 [8.6–13.6] respectively. Conclusions: Cetux partly alleviated MCC resistance to Chrono, independently of tumor EGFR protein expression or gene amplification, possibly through interfering with TGFα. This EGFR ligand carries poor prognosis for MCC and alters circadian clock function. [Table: see text]