Cetuximab in First-line Treatment With FOLFOX or FOLFIRI Yields Low Rate of Progressive Disease

NEW ORLEANS-Cetuximab (Erbitux) added to first-line treatment with FOLFIRI or FOLFOX-4 has an acceptable safety profile, is active, and has yielded a low rate of progressive disease in patients with metastatic colorectal cancer, two phase II studies show. While results are still early, the response rates reported to date by investigators suggest cetuximab(Drug information on cetuximab) has promise when incorporated into standard first-line therapy for this patient population. Logical Progression
First-line cetuximab with FOLFIRI is a logical progression from earlier studies assessing use of the monoclonal antibody in patients who had already failed first-line therapy. Previous researchers confirmed the efficacy of cetuximab plus irinotecan(Drug information on irinotecan) in metastatic colorectal cancer, showing a greater response rate and lower rate of progressive disease vs cetuximab alone (ASCO 2003, abstract 1012). Philippe Rougier, MD, of Hôpital Ambroise Pare, Boulogne, France, re- ported safety and some efficacy data from a phase II study in 42 patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (abstract 3513). They received cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m² IV weekly. The FOLFIRI regimen was administered every 2 weeks, with either a low or high dose of fluorouracil(Drug information on fluorouracil) (5-FU). Those in the low-dose group received irinotecan (CPT-11, Camptosar) 180 mg/m², folinic acid 400 mg/m², and 5-FU 300 mg/m² bolus plus infusion of 2,000 mg/m² over 46 hours. In the high-dose group, 5-FU was given as a 400 mg/m² bolus plus infusion of 2,400 mg/m² over 46 hours. Acceptable Safety Profile
No dose-limiting toxicities were seen with the low-dose regimen. Among an initial 13 patients treated at the higher dose level, dose-limiting toxicities were seen in 2 patients (15%). Based on this acceptable safety profile, investigators enrolled an additional 29 patients at the higher dose level. At that dose level, partial responses were seen in 17 patients (43%), while 18 (45%) had stable disease, for a total tumor growth control in 35 patients (88%). The 43% response rate excludes some unconfirmed responses, which the researchers reclassified as stable disease. Regardless of that, the low rate of progressive disease is notable, according to Dr. Rougier. In addition, five partial responders with initially unresectable liver metastases went on to surgery after treatment. Of those, four had a documented complete resection. There were few dose-limiting toxicities, even at the higher dose level. The most common grade 3/4 toxici- ties were leukopenia (17%), diarrhea (14%), and skin toxicity (7%). Only two of these toxicities (4%) were classified as grade 4, including one leukopenia and one asthenia. "The important thing is that only 12% of patients progressed, which is in the lower range of what has been reported with more recent [studies]," Dr. Rougier said. "[The combination] is really worth a phase III trial that just started, which is a European multicenter comparison of FOLFIRI alone vs FOLFIRI and cetuximab." Combination With FOLFOX-4
Researchers from Vall d'Hebron University Hospital in Barcelona, Spain, reported on a phase II trial using cetuximab plus FOLFOX-4 in patients with EGFR-expressing metastatic colorectal cancer (abstract 3512). Almost all had at least stable disease, and a few had complete responses. "The data from our study are consistent with earlier study results, and indicate the potential for earlier use of cetuximab in combination with standard first-line therapies," said lead investigator Josep Tabernero, MD, PhD, of Vall d'Hebron University Hospital. Dr. Tabernero reported on 43 patients who received cetuximab/FOLFOX- 4. Responses were seen in 34, including 2 complete responses (5%) and 32 partial responses (76%). Another 7 (17%) had stable disease. Serious adverse events included neutropenia, diarrhea, and skin rash. Researchers said those findings were encouraging enough to merit further investigation. "With 5-year survival reported at only 3% in patients with metastatic colorectal cancer, there is a real need to improve treatment options for these patients," Dr. Tabernero said. A monoclonal antibody with activity against epidermal growth factor receptor (EGFR), cetuximab was approved by the US Food and Drug Administration in February 2004 for patients with metastatic colorectal cancer in combination with irinotecan, or alone if patients cannot tolerate irinotecan. FOLFIRI is a combination of 5-FU/folinic acid/ irinotecan, and FOLFOX-4 is a combination of 5-FU/folinic acid/oxaliplatin (Eloxatin).