Cetuximab With FOLFIRI Cuts Metastatic Colorectal Cancer Risk

Allison Gandey

June 19, 2007

June 19, 2007 (Chicago) –- A new trial has shown that adding cetuximab (Erbitux, Bristol-Myers Squibb) to folinic acid, fluorouracil, and irinotecan (FOLFIRI) treatment reduces the risk for metastatic colorectal cancer growth or spread by 15%. The Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer(CRYSTAL) trial is the first phase 3 study to assess the combination therapy as a first-line therapy. "These findings suggest we have a new option for the initial treatment of metastatic colorectal cancer," lead investigator Eric Van Cutsem, MD, from the University Hospital Gasthuisberg, in Leuven, Belgium, told reporters here at the American Society of Clinical Oncology 43rd Annual Meeting.


Discussing the findings, Hans-Joachim Schmoll, MD, from Martin Luther University, in Halle, Germany, agreed that cetuximab added to FOLFIRI represents a new first-line option. He applauded the investigators on a straightforward trial design with a well-balanced treatment group studied in a standard patient population. "The trial is clearly positive, demonstrating a significant improvement," he said at the meeting. But he noted that skin toxicity in 85% of patients (18.7% grade 3/4) and low efficacy in patients with a poor prognosis would limit the combination's use for all patients first line.


At a press briefing, moderator William Blackstock, MD, from the Wake Forest University School of Medicine, in Winston-Salem, North Carolina, called the findings "modest." He said the new cetuximab combination simply adds to a number of existing regimens. During an interview with Medscape, Dr. Blackstock said that while the combination will provide an important new option for some patients, he does not anticipate it will change clinical practice. "It's not that impressive," he said.


Speaking to reporters, Dr. Van Cutsem pointed out that his team clearly met the study end point (progression-free survival time). "Based on these results, we will be looking for ways to further improve on activity, and our goal is to enable more and more patients to undergo resection." The secondary end points of the trial included overall response rate, disease control rate, overall survival time, quality of life, and safety.


Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor. It is currently approved by the US Food and Drug Administration as a second- or third-line metastatic colorectal cancer therapy. In the CRYSTAL trial, investigators studied patients with histologically confirmed unresectable metastatic colorectal cancers. They randomized 599 patients to receive FOLFIRI with cetuximab and another 599 patients to receive FOLFIRI alone.


Patients received cetuximab 400 mg/m2 as an initial dose, then 250 mg/m2 per week. The FOLFIRI was administered every 2 weeks and comprised irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil bolus 400 mg/m2, and 5-fluorouracil infusion 2400 mg/m2 over 46 hours.


CRYSTAL Trial: Independent Assessment of Response
Outcome
FOLFIRI (n=599), %
FOLFIRI With Cetuximab (n=599), %
Complete response
0.3
0.5
Partial response
38.4
46.4
Stable disease
46.7
37.4
Progressive disease
9.0
8.8
Overall response rate
(95% CI)

38.7 (34.8 – 42.8)
46.9 (42.9 – 51.0)
Disease Control Rate
85.5
84.3

Grade 3 and 4 Adverse Events
Events
FOLFIRI (n=602), %
FOLFIRI With Cetuximab (n=600), %
Any
59.5
78.0
Neutropenia
23.3
26.7
Febrile neutropenia
2.2
2.7
Diarrhea
10.5
15.2
Vomiting
5.0
4.5
Fatigue
4.5
5.0
Skin reactions
0.2
18.7
Infusion-related reactions
0
2.3

During his presentation, Dr. Van Cutsem reported the addition of cetuximab to FOLFIRI was associated with higher response rates (P = .0038) and threefold higher resection rates for initially unresectable disease (P = .0034). He also showed that patients with liver metastases as the only disease site achieved a longer progression-free survival than the rest of the population.


The researchers observed no excess mortality or deaths related to cetuximab. And they reported that skin reactions showed a strong correlation with efficacy. Responding to the presentation, Dr. Schmoll suggested that combination cetuximab and FOLFIRI could be given without dose reductions throughout treatment.


The study is ongoing, and survival follow-up, quality of life, and molecular marker evaluation results will be reported next.


American Society of Clinical Oncology 43rd Annual Meeting: Abstract 4000. Presented June 5, 2007.


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