In colorectal cancer patients progressing after second- and third-line therapies, cetuximab (Erbitux) is an option that may prolong progression-free and overall survival, according to phase III studies presented at the American Association for Cancer Research 2007 centennial annual meeting.
LOS ANGELESIn colorectal cancer patients progressing after second- and third-line therapies, cetuximab (Erbitux) is an option that may prolong progression-free and overall survival, according to phase III studies presented at the American Association for Cancer Research 2007 centennial annual meeting.
When administered in the third-line setting, cetuximab improved survival by 23%, compared with best supportive care (BSC), in the NCIC CO.17 trial (abstract LB-1), reported Derek Jonker, MD, assistant professor, University of Ottawa, and the Canadian co-chair of the study. The trial was conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), in collaboration with the Australasian Gastro-Intestinal Trials Group (AGITG). "This is the first time a single biologic targeted agent has demonstrated a survival advantage in patients with colorectal cancer, and the first time an EGFR-targeting drug has achieved this goal," Dr. Jonker said.
NCIC CO.17 enrolled 572 colorectal cancer patients with EGFR detectable by immunohistochemistry. Patients had received an anti-thymidylate synthase inhibitor5-fluorouracil or capecitabine (Xeloda)and had failed both irinotecan (Camptosar) and oxaliplatin (Eloxatin) (unless these drugs were contraindicated). Patients were randomized to BSC alone (n = 285) or BSC plus cetuximab 400 mg/m2 loading dose followed by a weekly infusion of 250 mg/m2 (n = 287). The primary endpoint was overall survival. The final analysis was performed when 456 deaths were observed.
Patients receiving cetuximab had a 23% reduction in mortality and a 32% reduction in the risk of disease progression. Median survival was 6.1 months in the cetuximab arm and 4.6 months in the BSC arm, producing a hazard ratio (HR) of 0.77 (P = .0046). All subgroups (age, performance status, sex) experienced a survival benefit. Median progression-free survival was 1.9 vs 1.8 months (HR 0.68. P < .0001). The benefits in terms of overall survival and time to progression were robust even after adjustments were made for multiple baseline variables, Dr. Jonker added.
Objective responses were observed in 19 patients (6.6%) receiving cetuximab but in no patients (0%) assigned to BSC (P < .0001). Stable disease was observed in 84 patients (29.3%) and 29 patients (10.2%), respectively, for a disease control rate of 35.9% vs 10.2%.
In an exploratory analysis, skin toxicity was strongly correlated with response and survival. Median survival was 2.6 months in patients with no rash, 4.8 months in those with grade 1 rash, and 8.4 months in those with grade 2+ rash.
The safety profile was consistent with other cetuximab studies. Grade 3+ toxicities were significantly more frequent in the cetuximab arm, including rash/desquamation (12% vs 0%), infection without neutropenia (13% vs 5%), confusion (6% vs 0%), other pain (15% vs 7%), and hypomagnesemia (6% vs 0%). Grade 3 anemia, however, was more common with BSC alone (4% vs 11%).
"These are clear and unambiguous results," Dr. Jonker noted at a press conference. "Cetuximab delayed tumor growth, which resulted in patients living longer."
There was little crossover in the study, since at the time it was performed, BSC was the standard of care in the participating sites (Canada, Australia, New Zealand, Singapore) and cetuximab was not officially available, Dr. Jonker said.
In the second-line setting (abstract LB-2), there was substantial crossover to cetuximab, and this may explain why overall survival was not improved in the EPIC (Erbitux Plus Irinotecan in Colorectal Cancer) trial, said principal investigator Alberto F. Sobrero, MD, of the San Martino Hospital, Genoa, Italy. While overall survival was not affected, there was a 31% reduction in disease progression in patients receiving cetuximab in combination with irinotecan, compared with irinotecan alone, he reported.
The multinational phase III trial included 1,298 colorectal cancer patients who had demonstrated resistance to oxaliplatin (primarily FOLFOX) with or without bevacizumab (Avastin). Patients were randomized to irinotecan 250 mg/m2 every 3 weeks or irinotecan plus cetuximab 400 mg/m2 followed by 250 mg/m2 weekly.
Irinotecan was used as the control because when the study was designed, FOLFIRI was not yet being used, Dr. Sobrero explained. Irinotecan and cetuximab have been shown to substantially inhibit tumor growth, possibly synergistically, in vivo, and to produce high response rates in multiple clinical trials, he added.
Median overall survival was similar: 10.7 months with the combination vs 9.9 months with irinotecan alone. Progression-free survival, however, was significantly improved: 2.6 months vs 4 months (P < .0001). Response rates were also significantly improved, doubling from 4.1% to 16.4% (P < .0001), Dr. Sobrero reported.
"We have very positive efficacy databut it did not affect overall survival, unlike what was seen in the third-line setting," he said at the late-breaking session. "We believe a good explanation is that nearly 50% of the control arm received cetuximab post-trial. Excluding these crossovers in a post hoc analysis, median survival was 6.2 months for controls vs 10.2 months for the cetuximab arm.
Dr. Sobrero said the findings mean "we are not changing practice [by adding cetuximab] but we are impacting on clinical practice. Cetuximab is a key agent for the optimal treatment of advanced colorectal cancer."
Patients on cetuximab received significantly more treatmenta median of five vs three cycles and 35% more chemotherapy. While this may have positively impacted the outcome, it produced more toxicity, especially diarrhea. Diarrhea grade 3-4 was seen in 16% of controls and 28% of cetuximab patients. More vomiting and fatigue was also seen with the combination. As expected, acneiform rash (any grade) was observed in 5% vs 76% (only 8% severe).
Rash was correlated with survival. Cetuximab-treated patients who did not develop a rash had a median survival of 5.8 months, compared with 15.6 months for patients with grade 3-4 rash.
"Patients in the experimental arm lived 55% longer without tumor progression. While going from 2.6 to 4 months without progression may not sound terrific, we are used to making incremental progress in clinical oncology. The tumor control rate increased from 46% to 61%. So two major determinants of efficacy were impacted upon by the combination," he stated.
The message of the trial, Dr. Sobrero said, is that "if you use cetuximab earlier on, in the second line, patients are much more likely to respond, and they live longer without tumor progression."
Both studies included only patients with EGFR-expressing tumors. However, at a press conference the investigators and discussants noted that EGFR expression by immunohistochemistry has not been related to response to cetuximab in colorectal cancer (see article on page 4 for a report of a possible new predictive marker for cetuximab).