“The CALGB/SWOG 80405 trial was designed and formulated in 2005, and the rationale was simple: we had new drugs --bevacizumab and cetuximab-- and the study was designed to determine if one was better than the other in first-line for patients with colon cancer,” said lead study author Alan P. Venook, distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco, USA.
The CALGB/SWOG 80405 trial studied patients whose tumours were KRAS wild-type at codons 12 and 13. Patients received mFOLFOX6 or FOLFIRI at the discretion of their doctor and were randomised to cetuximab (578 patients) or bevacizumab (559 patients).
“There was no meaningful difference in outcome between treatment arms,” said Venook. “In both arms patients lived close to 30 months. About 10% of patients lived more than 5 years. Overall patients did much better than anticipated and it was indifferent to the type of treatment.”
Because almost 75% of the patients received mFOLFOX6 as the chemotherapy, the interaction between the experimental drugs and chemotherapy will be limited, but an analysis is underway. The investigators are also conducting molecular analyses that may identify subsets of patients who did better or worse on either treatment.
Commenting on the data, ESMO spokesperson Dirk Arnold, Director of the Department of Medical Oncology, Tumour Biology Centre in Freiburg, Germany, said: “This was a long awaited phase III trial with a head-to-head comparison of two different molecular approaches: epidermal growth factor receptor (EGFR) blocking by cetuximab on one side and antiangiogenic (anti-vascular endothelial growth factor [VEGF]) inhibiting treatment with bevacizumab on the other side, both in combination with any standard first-line chemotherapy in metastatic colorectal cancer. The trial is important because the primary endpoint was overall survival. The FIRE-3 trial presented last year indicated that there may be an overall survival benefit with cetuximab but overall survival was only a secondary endpoint and data was inconclusive.”
“Each of the monoclonal antibodies, in combination with standard chemotherapy, gave an overall survival of about 30 months: this is the longest overall survival in such a large trial and clearly sets the standard,” Arnold continued. “We now know that using any monoclonal antibody with any standard chemotherapy in first-line treatment may give the patient the likelihood of surviving about 30 months. However there is no clear winner in terms of overall survival.”
“Next we have to see the analyses of the pan RAS cohort. Then we need to find out if different subgroups benefit more from anti-EGFR or anti-VEGF treatment. The type of chemotherapy or localisation of the tumour may also play a role.”
In connection with this trial, results of the now updated phase III CRYSTAL trial and phase II OPUS trial show that adding cetuximab to FOLFIRI or FOLFOX4 in the first-line treatment of metastatic colorectal cancer provides a greater benefit for patients with RAS wild-type tumours compared with the initial analysis with KRAS wild-type selected patients. Patients with RAS tumour mutations did not benefit.
Commenting on the data, Dirk Arnold said: “The CRYSTAL and OPUS trials confirm the results of the PRIME trial of FOLFOX and panitumumab, another anti-EGFR. These trials excluded all mutations in the KRAS and NRAS genes and looked at the benefit of anti-EGFRs in wild-type patients. All three trials consistently show that anti-EGFRs plus chemotherapy do better than chemotherapy alone. And anti-EGFRs in pan wild-type patients do better than anti-EGFRs in only exon 2 wild-type patients.”
He added: “The only issue raising some questions is the fact that patients who bear any mutations may be at risk of a detrimental effect. So genetic testing is not only a prerequisite to ensure the maximum benefit, it is also needed to ensure that we do not harm patients by treating them.”
Notes to Editors
Information contained in this press release was provided by the abstracts authors and reflects the content of the studies. It does not necessarily express ESMO's point of view.
 Abstracts from the 16th ESMO World Congress on Gastrointestinal Cancer are published in Annals of Oncology, Volume 25 suppl 2 June 2014 (Ann Oncol 2014 Jun; 25 (Suppl 2): 1-117)
 Abstract presentation: Saturday, 28 June 2014, 10:50 hrs, Session XVIII: Prevention and screening of colon cancer
CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon
A. Venook1, D. Niedzwiecki2, H.J. Lenz3, F. Innocenti4, M.R. Mahoney5, B. O’Neil6, J. Shaw7, B. Polite8, H. Hochster9, J. Atkins10, R. Goldberg11, R. Mayer12, R. Schilsky13, M. Bertagnolli14, C. Blanke15 , Cancer and Leukaemia Group B16, SWOG and ECOG16
1University of California, San Francisco, USA, 2Duke University, Durham, USA, 3USC Norris Comprehensive Cancer Centre, Los Angeles, USA, 4The University of North Carolina at Chapel Hill, Chapel Hill, USA, 5Mayo Clinic and Mayo Cancer Centre, Rochester, USA, 6Indiana University School of Medicine, Indianapolis, USA, 7Virginia Commonwealth University, Richmond, USA, 8The University of Chicago School of Medicine, Chicago, USA, 9Yale Cancer Centre, New Haven, USA, 10Southeast Cancer Control Consortium, CCOP, Goldsboro, USA, 11Comprehensive Cancer Centre at The Ohio State University, Columbus, USA, 12Dana-Farber Cancer Institute, Boston, USA, 13American Society of Clinical Oncology, Alexandria, USA, 14Brigham and Women’s Hospital, Boston, USA, 15Oregon Health & Science University, Portland, USA, 16 N/A
Background: FOLFIRI or mFOLFOX6, combined with BV or CET, are 1st-line treatments for MCRC. The optimal antibody combination is unknown.
Methods: Pts with KRAS wt (codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomised to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomised to CET, BV or both. In June, 2009, it was amended to include only pts w/KRAS wt tumours (codon 12 and 13) and to delete the combination CET + BV arm. Rxcontinued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks. permitted. Accrual goal was 1142 pts. 1° endpoint was overall survival (OS). Subsequent therapies up to MD.
Results: Between 11/2005 and 3/2012, 3058 unselected pts enrolled, 2334 KRAS wt pts randomised; final N =1137, median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 27%, mFOLFOX6 = 73%. OS analysis planned at 849 events; futility boundary for efficacy crossed at 10th interim analysis. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78,1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 -11.4) v. 10.45 (9.66 - 11.33) mos. 94 pts attained NED status following surgery, median f/u 40 mos (range 8.0 - 86.0). There was no difference in outcomes or serious toxicity based on gender or treatment. A QOL sub-study has been presented. Analyses underway include expanded RAS; chemotherapy – biologic interactions, subsequent therapies, impact of prior adjuvant therapy (9%), pharmacoeconomics.
Conclusion: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in 1st line. Overall OS of 29 + mos in all pts represents a new standard for KRAS wt CRC and confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison although analysis underway. Expanded RAS and other molecular and clinical information may identify subsets of pts who get more or less benefit from specific regimens.
Outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer randomized to FOLFIRI with or without cetuximab as first-line treatment
E. Van Cutsem1, J. Lenz Heinz2, C.H. Köhne3, V. Heinemann4, S. Tejpar5, I. Melezinek6, F. Beier6, K. Duecker6, H. van Krieken7, F. Ciardiello8
1Digestive Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium, 2University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA, 3Onkologie Klinikum Oldenburg, Oldenburg, Germany, 4Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany, 5University Hospital Gasthuisberg, Leuven, Belgium, 6Merck KGaA, Darmstadt, Germany, 7UMCN, Nijmegen, Netherlands, 8Seconda Università Degli Studi Di Napoli, Naples, Italy
Introduction: The randomized phase III CRYSTAL study demonstrated that the addition of cetuximab to FOLFIRI significantly improved progression-free survival, overall survival and response in the first-line treatment of patients with KRAS codon 12/13 (hereinafter, exon 2) wild-type metastatic colorectal cancer (mCRC). Patients with KRAS exon 2 tumor mutations showed no cetuximab treatment benefit.
Methods: Available KRAS exon 2 wild-type tumors from CRYSTAL study patients were screened for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3 and 4) using BEAMing technology, an approach based on polymerase chain reaction (PCR) amplification of single target DNA molecules on individual magnetic beads within an emulsion. Bead-associated PCR products from tumor DNA samples were subsequently typed for the presence of mutant or wild-type sequences using specific fluorescent probes and flow cytometry. Where mutations were detected, this approach allowed for the determination of the ratio of mutant to wild-type RAS DNA molecules in the original tumor DNA sample. As the predictive value of low prevalence RAS mutations in tumors in which the overwhelming majority of cells were wild-type was not clear, and in line with current clinical practice in relation to KRAS exon 2 screening, a 5% diagnostic cutoff was selected for analysis. Treatment outcome was subsequently assessed according to RAS mutation status (RAS wild-type, new RAS mutant, and RAS mutant [KRAS exon 2 or new RAS]). The effect of selecting different diagnostic cutoffs on the predictive value of mutation status in patients receiving FOLFIRI plus cetuximab was further explored.
Results: Mutation status was evaluable in 430/666 (65%) patients with KRAS exon 2 wild-type tumors. Using a 5% diagnostic cutoff, new RAS mutations were scored in 63/430 (15%) patients. In those with RAS wild-type tumors, a significant benefit across efficacy endpoints was associated with the addition of cetuximab to FOLFIRI (Table). In patients with new RAS tumor mutations, no clear difference in efficacy outcomes between treatment groups was seen. In patients with any tumor RAS mutation (KRAS exon 2 or new RAS), no benefit from the addition of cetuximab to FOLFIRI was apparent. Analysis of treatment outcome in new RAS mutant subgroups defined according to a range of sensitivity cutoffs from 20% down to 0.1% supported the use of 5% as a clinically appropriate threshold for defining a subgroup of patients most likely to benefit from the addition of cetuximab to FOLFIRI.
Conclusion: In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a marked benefit across all efficacy endpoints from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not benefit. This finding may allow the further tailoring of cetuximab therapy to maximize patient benefit.
Outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer randomized to FOLFOX4 with or without cetuximab as first-line treatment
C. Bokemeyer1, C.H. Köhne2, F. Ciardiello3, H.J. Lenz4, V. Heinemann5, U. Klinkhardt6, F. Beier6, C. Stroh6, H. van Krieken7, S. Tejpar8
1Dept. of Oncology/Hematology, University Hospital Hamburg, Hamburg, Germany, 2Onkologie Klinikum Oldenburg, Oldenburg, Germany, 3Seconda Universita Degli Studi Di Napoli, Naples, Italy, 4University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA, 5Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany, 6Merck KGaA, Darmstadt, Germany, 7UMCN, Nijmegen, Netherlands, 8University Hospital Gasthuisberg, Leuven, Belgium
Introduction: The randomized phase II OPUS study demonstrated that the addition of cetuximab to FOLFOX4 significantly improved response and progression-free survival in the first-line treatment of patients with KRAS codon 12/13 (hereinafter, exon 2) wild-type metastatic colorectal cancer (mCRC). Patients with KRAS exon 2 tumor mutations showed no such cetuximab benefit, with worse outcome in patients in the FOLFOX4 plus cetuximab arm compared with FOLFOX4 alone arm.
Methods: Available KRAS exon 2 wild-type tumors from OPUS study patients were screened for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3 and 4) using BEAMing technology, an approach based on polymerase chain reaction (PCR) amplification of single target DNA molecules on individual magnetic beads within an emulsion. Bead-associated PCR products from tumor DNA samples were subsequently typed for the presence of mutant or wild-type sequences using specific fluorescent probes and flow cytometry. Where mutations were detected, this approach allowed for the determination of the ratio of mutant to wild-type RAS DNA molecules in the original tumor DNA sample. As the predictive value of low prevalence RAS mutations in tumors in which the overwhelming majority of cells were wild-type was not clear, and in line with current clinical practice in relation to KRAS exon 2 screening, a 5% diagnostic cutoff was selected for analysis. Treatment outcome was subsequently assessed according to RAS mutation status (RAS wild-type, new RAS mutant and RAS mutant [KRAS exon 2 or new RAS]).
Results: Mutation status was evaluable in 118/179 (66%) patients with KRAS exon 2 wild-type tumors. New RAS mutations were detected in 31/118 (26%) patients. In those with RAS wild-type tumors, response was significantly improved by the addition of cetuximab to FOLFOX4 (Table). The treatment effect for those with new RAS tumor mutations could not be definitively assessed due to low patient numbers. In patients with any tumor RAS mutation (KRAS exon 2 or new RAS), no benefit from the addition of cetuximab to FOLFOX4 was seen, with a clear trend for worse outcome.
Conclusion: In the first-line setting, patients with mCRC harboring any activating RAS mutation are unlikely to benefit from the addition of cetuximab to FOLFOX4. Restricting the administration of FOLFOX4 plus cetuximab to patients with tumors wild-type at all such loci might help further tailoring of therapy to maximize patient benefit.