Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial

Abstract

4000 Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone. [Table: see text]

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

“…Several randomized clinical trials have demonstrated superior response rates and progression-free survival times with doublet therapy compared with single-agent fluoropyrimidine therapy [10 -12]. The monoclonal antibodies bevacizumab and cetuximab have contributed further improvements in the response rate and overall survival when combined with chemotherapy [13,14]. A meta-analysis conducted by Grothey et al [15] indicated that patients with advanced CRC received the greatest survival benefit when treated with all of the active therapeutic classes of medications during the course of treatment.…”

KRAS mutational status assessment in patients with metastatic colorectal cancer: are the clinical implications so clear?

“…This phase III study compared conventional FOLFIRI chemotherapy with the FOLFIRI chemotherapy combined with cetuximab. Preliminary efficacy results were presented at ASCO 2007(Van Cutsem et al 2007. In 1198 patients of the Intent-To-Treat population, the objective response rate was significantly higher with addition of cetuximab (47% vs. 39%, P = 0.038), and the progression-free survival was also longer (8.9 vs. 8 months, P = 0.048).…”

A phase 2 study of cetuximab in combination with docetaxel in chemotherapy‐refractory/resistant patients with advanced nonsmall cell lung cancer

“…This observation has also been described in studies with EGFR inhibitors in colorectal, lung, pancreatic, and head and neck cancer. 33,[38][39][40] Preliminary studies examining whether patients should be treated with higher drug levels until experiencing a clinically significant rash have been reported in the context of colorectal cancer, and suggest improved efficacy with the use of the ''dose-to-rash'' strategy. 41 However, this remains to be established in larger Phase 3 studies and in other tumor types.…”