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Background We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab.
Methods We randomly assigned patients with epidermal growth factor receptor–positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival.
Results A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab–FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type–KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab–FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P=0.008).
Conclusions First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102
[ClinicalTrials.gov]
.)
The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab (Erbitux), is effective in combination with irinotecan in patients with metastatic colorectal cancer or as a single agent in patients with metastatic colorectal cancer that progresses even when irinotecan is used.6,7 Phase 1 and 2 studies have shown cetuximab to have activity when added to irinotecan-based therapy8,9 or oxaliplatin-based therapy10,11,12 as first-line treatment.
There are no biomarkers that reliably predict responses to cetuximab, but the examination of outcomes based on the presence of mutations of the KRAS gene shows promise. KRAS encodes a small G protein that links ligand-dependent receptor activation to intracellular pathways of the EGFR signaling cascade. Mutation at key sites within the gene, commonly at codons 12 and 13, causes constitutive activation of KRAS-associated signaling. Growing evidence indicates that tumor KRAS mutation is associated with the inefficacy of cetuximab13,14,15,16,17 and the monoclonal anti-EGFR immunoglobulin G2 antibody panitumumab.18,19
In our multicenter phase 3 trial, Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL), we investigated the efficacy and safety of irinotecan in combination with a simplified regimen of fluorouracil and leucovorin (FOLFIRI) plus cetuximab20 in the initial treatment of metastatic colorectal cancer. We also conducted a retrospective subgroup analysis to investigate the influence of the tumor KRAS mutation status on outcome.
Methods
Patients
Inclusion criteria were an age of 18 years or older, histologically confirmed adenocarcinoma of the colon or rectum, first occurrence of metastatic disease that could not be resected for curative purposes, immunohistochemical evidence of tumor EGFR expression, Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less, and adequate hematologic, hepatic, and renal function. Exclusion criteria were previous exposure to an anti-EGFR therapy or irinotecan-based chemotherapy, previous chemotherapy for metastatic colorectal cancer, adjuvant treatment that was terminated 6 months or less before the start of treatment in our trial, and the use of radiotherapy, surgery (excluding previous diagnostic biopsy), or any investigational drug in the 30-day period before the start of treatment in our trial.
The protocol was approved by independent ethics committees and the governmental authorities in each country, as required. The trial was carried out in accordance with the Declaration of Helsinki (October 1996). All patients provided written and oral informed consent.
Study Design
This trial was a randomized, open-label, multicenter study comparing 14-day cycles of cetuximab plus FOLFIRI and FOLFIRI alone. We randomly assigned patients (in a 1:1 ratio) to one of the two treatment groups using a stratified permuted-block procedure, with ECOG performance status (0 or 1 vs. 2) and region (sites in Western Europe vs. Eastern Europe vs. outside Europe) as stratification factors.
The primary end point was progression-free survival time, defined as the time from randomization to disease progression or death from any cause within 60 days after the last tumor assessment or after randomization. Secondary end points included the overall survival time, the rate of best overall response (the proportion of patients with a confirmed complete response or partial response, defined as a response persisting for at least 28 days), and safety end points (including the incidence and type of adverse events, laboratory variables, and vital signs).
The number of patients undergoing surgery with a curative intent (any resection of metastasis with a goal of cure or complete resection of all lesions to R0) was prospectively analyzed. A retrospective subgroup analysis was used to investigate associations between the progression-free survival time, overall survival time, or response rate and the KRAS mutation status of tumors. An independent review committee (consisting of radiologists and oncologists) performed a preplanned, blinded, retrospective review (based on modified World Health Organization criteria) of radiologic assessments and clinical data to determine the day of progression and the best overall response.
The study was designed by Merck (Darmstadt) together with the primary academic investigator. Data were collected by principal investigators at each center, and statistical analyses were conducted by a contract research organization (Quintiles), supervised by Merck (Darmstadt). The primary academic investigator had access to all the data and vouches for the completeness and accuracy of the reported data and the analyses.
Treatment
On day 1 of each 14-day period during the study, patients in the FOLFIRI group received a 30- to 90-minute infusion of irinotecan at a dose of 180 mg per square meter of body-surface area; an infusion, for 120 minutes, of racemic leucovorin or L-leucovorin at a dose of 400 or 200 mg, respectively, per square meter of body-surface area; fluorouracil in a bolus of 400 mg per square meter of body-surface area and then continuous infusion for 46 hours of 2400 mg per square meter of body-surface area.
During the study, patients in the cetuximab–FOLFIRI group received cetuximab in an initial 120-minute infusion on day 1 of 400 mg per square meter of body-surface area, followed by 60-minute infusions of cetuximab at a dose of 250 mg per square meter of body-surface area, once weekly (Fig. 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). FOLFIRI was given after the cetuximab infusion on day 1 of each period.
Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal of consent occurred. In the event of predefined toxic effects related to chemotherapy or cetuximab, protocol-specified treatment modifications were permitted.
Assessments
Computed tomography or magnetic resonance imaging was performed every 8 weeks until disease progression was observed to have occurred. Follow-up evaluations were performed every 3 months. Adverse events (the severity of which were assessed according to the National Cancer Institute Common Toxicity Criteria, version 2.0) and concomitant medication use were recorded continuously.
KRAS Mutation Status
DNA was extracted from formaldehyde-fixed, paraffin-embedded tumor-biopsy specimens and screened for KRAS mutations in codons 12 and 13 with the use of a polymerase-chain-reaction (PCR) clamping and melting curve method21 (implemented by means of a LightMix k-ras Gly12 assay, TIB MOLBIOL). PCR amplification of the wild-type KRAS sequence was suppressed in this process by the incorporation in the reaction mix of a locked nucleic-acid oligomer22 spanning codons 12 and 13 of the KRAS gene (see the Methods section in the Supplementary Appendix).
Statistical Analysis
We aimed to enroll enough patients to yield the occurrence of 633 progression events, which would give a statistical power of 80% to reject the null hypothesis of no significant difference in the progression-free survival time between the two treatment groups, assuming a hazard ratio of 0.8 and a significance level of a two-sided log-rank test fixed at 5%. All statistical-analysis methods were prespecified. All reported P values are two-sided and were not adjusted for multiple testing.
Analysis of the progression-free survival time was based on Kaplan–Meier curves (product-limit estimates)23 and performed on all patients who received at least one dose of a study drug. Results between the two treatment groups were compared with the use of a log-rank test24 after stratification according to the ECOG performance status and region. Secondary efficacy analyses were supportive, exploratory, and nonconfirmatory. The rates of best overall response and surgery with curative intent were compared between the two treatment groups with the use of a Cochran–Mantel–Haenszel test,25 stratified according to the randomization strata. The efficacy-analysis methods were repeated for the subgroup with samples that could be evaluated for KRAS mutation status (the KRAS population). The heterogeneity of treatment effects between the subgroups with wild-type and mutant KRAS was explored retrospectively with the use of a statistical test for interaction applied through a Cox model for progression-free survival time and overall survival time and a logistic-regression model for overall response rate. Hazard and odds ratios are expressed for cetuximab plus FOLFIRI as compared with FOLFIRI alone.
Safety analyses were carried out with the use of data from all patients receiving at least one dose of any study drug. Adverse events were categorized according to the Medical Dictionary for Regulatory Activities (version 10.0) system organ classes and preferred terms, as well as predefined special adverse event categories in which the preferred terms are pooled.
Results
Patients
From July 2004 through November 2005, 2020 patients were screened at 189 of the 201 centers, and 1217 underwent randomization, of which 1198 were subsequently treated (599 in each of the two groups) at 184 centers (Fig. 2 in the Supplementary Appendix). Four patients were treated but did not undergo randomization; therefore, the safety population comprised 1202 patients (600 receiving cetuximab plus FOLFIRI and 602 receiving FOLFIRI alone).
In the safety population, the cetuximab–FOLFIRI group had a median duration of 25.0 weeks (interquartile range, 12.9 to 40.4) of cetuximab treatment, 26.0 weeks (interquartile range, 14.0 to 40.3) of irinotecan treatment, and 26.0 weeks (interquartile range, 13.8 to 40.4) of fluorouracil treatment. The FOLFIRI group had a median duration of 25.7 weeks (interquartile range, 15.1 to 35.9) of irinotecan treatment and 25.7 weeks (interquartile range, 14.9 to 36.0) of fluorouracil treatment. The median duration of follow-up was 29.9 months (95% confidence interval [CI], 29.1 to 30.5) with cetuximab plus FOLFIRI and 29.4 months (95% CI, 28.8 to 30.4) with FOLFIRI alone. Seven patients were lost to follow-up — two in the cetuximab–FOLFIRI group and five in the FOLFIRI group. In the primary analysis population, post-study chemotherapy with or without EGFR antibody therapy was administered to 63.9% and 6.2% of patients, respectively, receiving cetuximab plus FOLFIRI and 68.8% and 25.4%, respectively, of those receiving FOLFIRI. The findings were similar for the KRAS population.
The study groups were well balanced in terms of baseline characteristics with regard to the patients, disease, and treatment (Table 1). Altogether, 60.5% of the study population was male, 96.5% had an ECOG performance status of 0 or 1, and the colon was the primary tumor site in 60.2%.
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Progression events occurred in 298 patients receiving cetuximab plus FOLFIRI and 322 receiving FOLFIRI alone; cetuximab–FOLFIRI treatment reduced the risk of progression by 15% as compared with FOLFIRI alone (adjusted hazard ratio for cetuximab–FOLFIRI, 0.85; 95% CI, 0.72 to 0.99; P=0.048) (Figure 1A and Table 2). The median progression-free survival times were 8.9 months with cetuximab plus FOLFIRI and 8.0 months with FOLFIRI alone. As of the cutoff date for collection of survival data of December 31, 2007, there were 412 deaths in the cetuximab–FOLFIRI group and 416 in the FOLFIRI group. The adjusted hazard ratio for death with cetuximab plus FOLFIRI was 0.93 (95% CI, 0.81 to 1.07; P=0.31) (Figure 1B). Median overall survival times were 19.9 months in the cetuximab–FOLFIRI group and 18.6 months in the FOLFIRI group (Table 2). Confirmed complete or partial tumor responses occurred in 281 patients (46.9%) receiving cetuximab plus FOLFIRI and in 232 patients (38.7%) receiving FOLFIRI alone. The adjusted odds ratio for a tumor response with cetuximab–FOLFIRI treatment, as compared with FOLFIRI alone, was 1.40 (95% CI, 1.12 to 1.77; P=0.004) (Table 2). The rate of surgery for metastases was higher in the cetuximab–FOLFIRI group than in the FOLFIRI group (7.0% vs. 3.7%), as was the rate of R0 resection with curative intent before disease progression (4.8% vs. 1.7%; odds ratio for cetuximab–FOLFIRI, 3.02; 95% CI, 1.45 to 6.27; P=0.002).
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Tumor samples obtained at baseline from 540 patients were suitable for the analysis of KRAS mutation status; samples from the remaining patients were either of insufficient size or not available. Tumors of 348 patients (64.4%) had wild-type KRAS and those of 192 patients (35.6%) had mutated KRAS. More patients in the FOLFIRI group than in the cetuximab–FOLFIRI group had wild-type–KRAS tumors (66.9% vs. 62.1%). The hazard ratios for progression were similar in the primary analysis population (0.85) and the KRAS population (0.82).
The association between KRAS mutation status and treatment, with regard to progression-free survival, was not significant (P=0.07), nor was there a significant treatment interaction for overall survival (P=0.44). There was, however, a significant interaction of mutation status with tumor response (P=0.03).
Hazard ratios for progression-free survival among patients receiving cetuximab plus FOLFIRI, as compared with FOLFIRI alone, who had tumors with wild-type KRAS and who had tumors with mutant KRAS were 0.68 (P=0.02) and 1.07 (P=0.75), respectively (Figure 1C and Figure 2A). Median progression-free surviv). Median progression-free survival times with cetuximab–FOLFIRI and FOLFIRI were 9.9 months and 8.7 months, respectively, in the wild-type–KRAS population and 7.6 and 8.1 months, respectively, in the mutant-KRAS population. Hazard ratios for overall survival in the wild-type–KRAS and mutant-KRAS populations were 0.84 and 1.03, respectively (Figure 1D and Figure 2A). Median overall survival times in the cetuximab–FOLFIRI group and the FOLFIRI group were 24.9 months and 21.0 months, respectively, in the wild-type–KRAS population and 17.5 and 17.7 months, respectively, in the mutant-KRAS population. Among patients with wild-type–KRAS tumors, the response rate in the cetuximab–FOLFIRI group was 59.3% and in the FOLFIRI group 43.2% (odds ratio, 1.91; 95% CI, 1.24 to 2.93) (Figure 2B). Among those with mutated-KRAS tumors, the response rate was 36.2% in the cetuximab–FOLFIRI group and 40.2% in the FOLFIRI group (odds ratio, 0.80; 95% CI, 0.44 to 1.45).
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The overall incidence of grade 3 or 4 adverse events was 79.3% in the cetuximab–FOLFIRI group and 61.0% in the FOLFIRI group (P<0.001) (Table 3); the incidence of any such events, excluding skin reactions, was 74.0% in the cetuximab–FOLFIRI group. The administration of cetuximab plus FOLFIRI, as compared with FOLFIRI alone, was associated with significantly more skin reactions (all) (19.7% vs. 0.2%, P<0.001) and acne-like rash (16.2% vs. 0.0%, P<0.001). None of the skin reactions or acne-like rashes reported were grade 4. Median progression-free survival times among patients in the cetuximab–FOLFIRI group were found to increase with an increasing grade of rash. With cetuximab plus FOLFIRI, there was a higher incidence of grade 3 or 4 diarrhea (15.7%, vs. 10.5% with FOLFIRI alone; P=0.008) and infusion-related reactions (2.5% vs. 0.0%, P<0.001), but these effects were able to be managed with protocol-defined treatment modifications. The incidence of treatment-related serious adverse events was 26.0% with cetuximab plus FOLFIRI and 19.3% with FOLFIRI alone. There were no cetuximab-related deaths.
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We found that the initial treatment of metastatic colorectal cancer with a combination of cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of disease progression by 15% (hazard ratio, 0.85; P=0.048). The addition of cetuximab to FOLFIRI also increased the response rate by nearly 10%. There was no significant difference between the treatment groups in overall survival, however. Treatment added after the conclusion of a study can confound the analysis of overall survival,26,27 and in this study, approximately two thirds of patients in each group received subsequent chemotherapy after completion of the study, and 25.4% of patients in the FOLFIRI group and 6.2% in the cetuximab–FOLFIRI group received EGFR antibody therapy after the study. Adding cetuximab to FOLFIRI increased the rate of resection of metastases, but whether this increase improves the potential for cure or long-term survival is unknown.
Tumor tissue for the analysis of KRAS mutation status was available from approximately half the patients. The incidence of KRAS mutations (36%) was in keeping with previous reports.28,29 There was an interaction between treatment group and KRAS status for the response to cetuximab–FOLFIRI (P=0.03) but not for progression-free survival (P=0.07) or overall survival (P=0.44). The hazard ratio for progression-free survival among patients with wild-type–KRAS tumors in the cetuximab–FOLFIRI group, as compared with the FOLFIRI group, was 0.68 (95% CI, 0.50 to 0.94), which suggests that the cetuximab–FOLFIRI combination reduces the risk of progression in such patients. The hazard ratio of 0.68 for progression-free survival in this group is consistent with the hazard ratio of 0.57 reported in the randomized, phase 2 OPUS trial (Oxaliplatin and Cetuximab in First-Line Treatment of mCRC trial; ClinicalTrials.gov number, NCT00125034 [ClinicalTrials.gov] ), with cetuximab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX-4) among patients with wild-type–KRAS disease.30 It is also within the range of the hazard ratios for progression-free survival of 0.54 and 0.83 reported in association with combinations of two cytotoxic drugs plus bevacizumab.31,32 The predictive power of the KRAS mutation status of tumors with regard to their responsiveness to cetuximab has been shown previously in studies of cetuximab, alone or in combination with irinotecan, administered to patients with metastatic colorectal cancer that had progressed after previous treatment.13,14,15,33,34 A similar effect has also been reported in a study of previously treated patients receiving panitumumab in combination with the best supportive care.18,19
The safety profile of the cetuximab–FOLFIRI treatment was in line with that expected. The incidence rates of grade 3 or 4 diarrhea, skin reactions, and infusion-related reactions were significantly higher with cetuximab plus FOLFIRI than with FOLFIRI alone, and the overall incidence of grade 3 or 4 adverse events was higher with cetuximab (79.3%, vs. 61.0%; P<0.001). However, these adverse events were generally manageable.
This trial provides confirmation that, as compared with FOLFIRI alone, cetuximab plus FOLFIRI reduces the risk of progression of metastatic colorectal cancer when used as the first-line treatment and that this benefit is seen mainly in patients with wild-type–KRAS tumors.
Supported by Merck (Darmstadt).
Dr. Van Cutsem reports receiving consulting or advisory fees from Amgen, Merck (Darmstadt), Pfizer, Roche, and Sanofi-Aventis; lecture fees from Amgen, Merck (Darmstadt), Roche, and Sanofi-Aventis; and grant support from Merck (Darmstadt) and Roche; Dr. Köhne, consulting or advisory fees and lecture fees from Amgen, Merck (Darmstadt), Pfizer, Roche, and Sanofi-Aventis; Dr. Lim, lecture fees from Roche; Dr. Folprecht, advisory fees from Roche, lecture fees from Merck (Darmstadt), Pfizer, and Sanofi-Aventis, and grant support from Merck (Darmstadt) and Sanofi-Aventis; Dr. Tejpar, grant support from Merck (Darmstadt); and Dr. Rougier, consulting or advisory fees from Merck (Darmstadt), Pfizer, Roche, and Sanofi-Aventis and lecture fees from Merck (Darmstadt), Pfizer, and Sanofi-Aventis. Drs. Stroh, Schlichting, and Nippgen report being employees of Merck (Darmstadt). No other potential conflict of interest relevant to this article was reported.
We thank our patients and nursing staff, contributors from other centers, and Merck (Darmstadt) personnel.
Source Information
From the University Hospital Gasthuisberg, Leuven (E.V.C., S.T.); and Imelda Ziekenhuis, Bonheiden (G.D.) — both in Belgium; Klinikum Oldenburg, Oldenburg (C.-H.K.); Universitätsklinikum Carl Gustav Carus, Dresden (G.F.); and Merck, Darmstadt (C.S., M.S., J.N.) — all in Germany; Országos Onkológiai Intézet, Budapest (E.H.); Petz Aladár County Teaching Hospital, Gy
r (T.P.); and St. László Hospital, Budapest (G.B.) — all in Hungary; Wielkopolskie Centrum Onkologii, Poznan, Poland (J.Z.); Chang Gung Memorial Hospital, Taoyuan, Taiwan (C.-R.C.C.); Moscow City Oncology Clinical Hospital 62, Moscow (A.M.); National University Hospital, Singapore, Singapore (R.L.); Yonsei University College of Medicine, Seoul, South Korea (J.K.R.); University of Witwatersrand, Johannesburg, South Africa (P. Ruff); and Hôpital Ambroise Paré, Boulogne, France (P. Rougier).
Address reprint requests to Dr. Van Cutsem at the University Hospital Gasthuisberg, Digestive Oncology Unit, Herestraat 49, 3000 Leuven, Belgium, or at eric.vancutsem{at}uz.kuleuven.ac.be.
References
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Related Letters:
Cetuximab for Metastatic Colorectal Cancer
Spiro H., Roila F., Garassino M. C., Ballatori E., Bria E., Cuppone F., Di Maio M., Garattini S., Torri V., Floriani I., Van Cutsem E., Rougier P., Köhne C.-H.
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N Engl J Med 2009;
361:95-97, Jul 2, 2009.
Correspondence
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