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The addition of cetuximab to a standard three-drug regimen known as FOLFIRI reduced the risk of progression by about 15% for metastatic colorectal cancer patients receiving first-line treatment in the randomized phase III CRYSTAL trial.
Cetuximab (Erbitux), a monoclonal antibody, also was associated with significantly higher response rates and a threefold higher resection rate for initially unresectable metastases, compared with FOLFIRI chemotherapy alone, Dr. Eric Van Cutsem reported.
Cetuximab is approved in the United States for metastatic colorectal cancer patients in combination with irinotecan or as a single agent in those who can't tolerate irinotecan, and is approved in Europe as a third-line treatment in combination with irinotecan-based chemotherapy.
The investigators randomized 1,217 patients to a FOLFIRI regimen of irinotecan 180 mg/m², folinic acid 400 mg/m², and a 5-fluorouracil 400 mg/m² bolus plus 2,400 mg/m² as a 46-hour continuous infusion every 2 weeks or to a FOLFIRI regimen plus intravenous cetuximab 400 mg/m² on day 1, then 250 mg/m² weekly.
Participants had histologically confirmed, unresectable, metastasized colorectal cancer; epidermal growth factor receptor (EGFR) expression in the primary tumor or metastasis; and at least one bidimensionally measurable lesion. Their median age was 61 years.
The study met its primary end point of significantly increased progression-free survival (PFS) with the addition of cetuximab, as assessed by blinded independent review, said Dr. Van Cutsem of University Hospital Gasthuisberg Leuven (Belgium).
In an intent-to-treat analysis of 599 patients in each arm, median PFS was 8.9 months in the cetuximab group and 8 months in the control group. The 1-year PFS rates were 34% and 23%, respectively. This translates into a 15% risk reduction of progression.
The overall response rate was significantly higher in the cetuximab group than in the control group (46.9% vs. 38.7%).
Significantly more patients with initially unresectable tumors treated with cetuximab could undergo an R0 resection, compared with those treated with FOLFIRI alone (4.3% vs. 1.5%). "These are patients in whom there was no residual tumor after resection of metastatic disease," Dr. Van Cutsem said.
Among the 20% of patients in the study whose metastases were confined to the liver, adding cetuximab more than doubled the resection rate (9.8% vs. 4.5%).
Patients with metastases only in the liver experienced a greater treatment benefit than did the overall population, with a median PFS of 11.4 months after treatment with cetuximab plus FOLFIRI and 9.2 months after treatment with FOLFIRI alone.
In a safety analysis, grade 3/4 adverse events were less frequent among 602 patients treated with FOLFIRI, compared with 600 patients treated with FOLFIRI plus cetuximab (59.5% vs. 78%). Skin reactions, which have been reported as severe in other clinical trials of cetuximab, occurred more frequently in the cetuximab group than in the control group (18.7% vs. 0.2%), but none were grade 4, Dr. Van Cutsem said.
There was no correlation between EGFR expression and efficacy, whereas skin reactions showed a strong correlation with efficacy, he said. The median PFS for patients with grade 3 skin rashes was 11.3 months, compared with 9.4 months for grade 2 and 5.4 months for grade 0 or 1.
All-cause 60-day mortality after treatment started and 30-day mortality after treatment stopped were similar in both groups. No cetuximab-related deaths occurred. Data on overall survival, quality of life, and biomarkers will be forthcoming, Dr. Van Cutsem said.
ASCO discussant for the trial Dr. Hans-Joachim Schmoll of Martin Luther University, Halle, Germany, said, "The beneficial effect of cetuximab known from salvage treatment is now definitely arrived in the first-line treatment."
The eagerly awaited CRYSTAL results also confirm the findings of the smaller phase II trial CALGB 80203, presented at last year's ASCO meeting, which showed a significant difference in response rates favoring first-line treatment with cetuximab in combination with either FOLFIRI or FOLFOX chemotherapy over chemotherapy alone (52% vs. 38%), Dr. Schmoll said.
"A proper selection of patients for the different treatment options we have available based on molecular markers is crucial to define the best candidates for cetuximab or bevacizumab in first-line treatment," Dr. Schmoll said. "K-RAS [gene] mutation is promising, but not standard today out of clinical trials."
Van Cutsem E. et al. 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.
Commentary |
This was a randomized phase III trial of 1,217 patients receiving FOLFIRI with or without cetuximab. Median progression-free survival was significantly longer for the cetuximab group compared to the FOLFIRI-only group (8.9 months vs. 8 months, P =.036). Response rate was also significantly increased by cetuximab (46.9% vs. 38.7%, P = .005). Treatment was generally well tolerated. A small subgroup of patients with liver-only metastases had more complete surgical resections in the cetuximab group. The study demonstrates the beneficial biologic effect of front-line cetuximab, but the difference in progression-free survival is less than 1 month. As a clinician this result is less than one would have hoped when cetuximab is used in the first-line setting. It gives one pause when considering the drug for second- or third-line use. — Stuart M. Lichtman, M.D.
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