FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study

doi:10.1016/j.clcc.2014.12.003

Clinical Colorectal Cancer

Volume 14, Issue 2, June 2015, Pages 91-98

https://doi.org/10.1016/j.clcc.2014.12.003 Get rights and content

Abstract

Background

This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab.

Patients and Methods

Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups.

Results

Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.

Conclusion

These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.

Introduction

In randomized studies, adding an epidermal growth factor receptor (EGFR) monoclonal antibody to first-line oxaliplatin plus infusional fluorouracil with folinic acid (FOLFOX4), or first-line irinotecan plus infusional fluorouracil with folinic acid (FOLFIRI) improved clinical outcome compared with chemotherapy alone in metastatic colorectal cancer (mCRC) patients whose tumors were wild type (wt) for codons 12 and 13 in KRAS exon 2.1, 2, 3

An updated analysis of the PRIME study investigated the effect of tumor mutations at other loci in KRAS exons 3 and 4, and in NRAS exons 2 to 4 on the efficacy and safety of FOLFOX4 plus panitumumab in patients with KRAS wt (codons 12 and 13) mCRC.⁴ The authors reported that mutations at other RAS loci were negative predictors of benefit for FOLFOX4 in combination with panitumumab. Recent updated analysis of the OPUS study found patients whose tumors contained a mutation at any of the RAS loci examined experienced worse progression-free survival (PFS) and a trend toward worse overall survival (OS) if treated with FOLFOX4 plus cetuximab compared with FOLFOX4 alone.⁵

In the OPUS study, cetuximab was administered as a standard weekly regimen in combination with FOLFOX4 (administered every 2 weeks).² The Central European Cooperative Oncology Group (CECOG)-sponsored randomized phase 2 CORE 1.2.002 study (NCT00479752) reported similar activity and safety profiles for FOLFOX4 with either cetuximab once a week or cetuximab administered in an every-second-week regimen in patients with KRAS wt (codons 12 and 13) mCRC.⁶

This updated analysis of the CECOG/CORE 1.2.002 study aimed to further investigate the effect of tumor mutations at other RAS loci (KRAS and NRAS exons 2 to 5) on efficacy and safety in patients with KRAS wt (codons 12 and 13) mCRC treated with first-line FOLFOX4 plus cetuximab (either once or every second week). In addition, the influence of BRAF gene mutations was investigated. BRAF encodes a downstream effector of KRAS in the mitogen-activated protein kinase pathway.⁷ BRAF mutations are associated with poor prognosis in mCRC patients treated in the first-line setting.3, 4, 8, 9

Section snippets

Study Design

CECOG/CORE 1.2.002 was a multicenter, open-label, parallel-group, phase 2 study. The design and patient eligibility criteria have been described previously.⁶ Briefly, patients with histologically confirmed adenocarcinoma of the colon or rectum not suitable for curative-intent resection, KRAS wt (codons 12 and 13), following a protocol amendment in March 5, 2008, were eligible for randomization (1:1). Patients received cetuximab either once a week (initial dose of 400 mg/m² over 2 hours and

Results

Between September 2007 and September 2009, 163 patients were randomized at 22 sites in 12 countries; of these, 152 eligible patients comprised the KRAS wt (codons 12 and 13) population described previously.⁶ From this population, 148 patient tumors were evaluable for RAS and BRAF mutations. One hundred twenty-four patients (84%) had RAS wt/BRAF wt tumors, 10 patients (7%) had tumors that were BRAF wt but harbored RAS mutations, and 1 of these patients had a tumor mutation in both KRAS (V152M)

Discussion

In this updated analysis of the CECOG/CORE 1.2.002 study, 7% of patients with KRAS wt tumors at codons 12 and 13 harbored a mutation in at least one other RAS loci examined. The frequency of detection of these mutations in patients with KRAS wt (codons 12 and 13) mCRC was lower than that previously reported from studies in mCRC patients treated with first-line chemotherapy with or without an EGFR monoclonal antibody (16% to 31%).4, 5, 12, 13 The reason for this may be explained by the

Acknowledgments

The CORE 1.2.002 study and updated analysis was sponsored by CECOG. Merck KGaA (Darmstadt, Germany) provided CECOG with a grant, which also funded medical writing services. Paul Hoban of Cancer Communications and Consultancy Ltd (Knutsford, England, UK) provided medical writing services to the authors on behalf of CECOG funded from a grant supplied by Merck KGaA. Merck KGaA reviewed the manuscript; however, the views and opinions described in the publication do not necessarily reflect those of

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FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study
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Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials
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Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
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Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial
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J.Y. Douillard et al.
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study
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Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer
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Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: new results from the OPUS study
J Clin Oncol
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There are more references available in the full text version of this article.

Cited by (26)

Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer
2021, European Journal of Cancer
Citation Excerpt :
The studies selected for pooled analysis were required to have been conducted after approval of cetuximab; to have been sponsored by Merck KGaA, Darmstadt or external investigators; to have patient-level data available to Merck KGaA at the time of study initiation; to have their enrolment period completed at the time of initiation of this pooled analysis; to have evaluated the efficacy of cetuximab as a 1L treatment for the main study outcome; and to have included patients with confirmed RAS wt mCRC irrespective of the number/localization of metastatic sites. Based on these criteria, five NIS/CT were selected: two NIS (EREBUS, ERBITAG [intermediate data cutoff, December 7, 2018]) and three CT (CEBIFOX, CECOG/CORE 1.2.002, APEC) (Table 1) [13,15,20–23]. Additional inclusion criteria applied to individual patients are presented in Supplementary Appendix 1.
This study assessed whether cetuximab 500 mg/m² administered every 2 weeks (Q2W), when combined with chemotherapy as a first-line (1L) treatment, was noninferior to the approved dose (400 mg/m² followed by 250 mg/m² once weekly [Q1W]) for overall survival (OS) in adults with RAS wild-type metastatic colorectal cancer (mCRC).
This pooled analysis included patients receiving 1L treatment with cetuximab Q1W or Q2W in combination with chemotherapy from post-authorisation studies with patient-level data available to the sponsor. Baseline characteristics were adjusted with a propensity score using inverse probability of treatment weighting (IPTW). Noninferiority in terms of OS was tested with a noninferiority margin for the hazard ratio (HR) of 1.25 using a Cox proportional hazards regression model. Secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and rates of lung/liver metastases resection and serious adverse events.
OS time was noninferior in the Q2W cohort (n = 554) compared to the Q1W cohort (n = 763), with a HR after IPTW (95% confidence interval) of 0.827 (0.715–0.956) and median OS times of 24.7 (Q1W) and 27.9 (Q2W) months. There were no major differences in PFS (HR: 0.915 [0.804–1.042]). The odds ratios (ORs) after IPTW for ORR (1.292 [1.031–1.617]) and the rates of lung/liver metastases resection (1.419 [1.043–1.932]) favoured the Q2W regimen. No differences were noted in the occurrence rate of any SAE between groups; the OR after IPTW was 1.089 (0.858–1.382).
The cetuximab Q2W regimen was noninferior to the Q1W regimen for OS in the 1L treatment of mCRC.
Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial
2020, Clinical Colorectal Cancer
Citation Excerpt :
Several small phase II trials have demonstrated safety and efficacy of the biweekly administration of cetuximab in combination with chemotherapy.8-13 Only one of these studies reported the impact of extended RAS/BRAF mutational analysis, and none has so far appreciated the impact of primary tumor location.14 The CEBIFOX trial evaluated the efficacy and safety of a biweekly administered combination of cetuximab with FOLFOX6 in patients with KRAS exon 2 wild-type (wt) mCRC.
The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC).
Patients received FOLFOX6 with cetuximab (500 mg/m²) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location.
In total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months.
This study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.
Liver Metastases
2019, Abeloff’s Clinical Oncology
The liver is the most common site of metastatic disease in gastrointestinal and other malignancies. Surgical indications for resecting liver metastases have gradually expanded. Changes in perioperative management and surgical technique have improved oncologic outcomes following hepatic resection for metastatic disease. The most common source of hepatic metastases is colorectal cancer. Hepatic resection is the first-line treatment for patients with resectable liver metastases, with 5-year survival rates of 25% to 58%. Portal vein embolization and two-staged hepatectomy can increase the size of the future liver remnant, making more patients potentially eligible for surgery. Oxaliplatin- and irinotecan-based chemotherapy regimens are the backbones of neoadjuvant and adjuvant chemotherapy. There are multiple liver-directed therapies that can be utilized for patients who are poor operative candidates or who have unresectable disease, including radiofrequency ablation, microwave ablation, and yttirum-90 radioembolization. Neuroendocrine liver metastases are unique in that debulking can improve survival, however recurrence rates are high. Gastrointestinal stromal tumor liver metastasis management has significantly changed since the advent of tyrosine kinase inhibitor therapy, however liver resection is still warranted in select settings of disease progression. Liver resection can be offered to patients with other sources of primary malignancy, however the oncologic outcomes are typically poorer and data is more limited. Early evaluation by multidisciplinary teams with expertise in hepatic metastasis management can maximize patient outcomes.
Improving the genetic signature of prostate cancer, the somatic mutations
2018, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Recent large-scale sequencing efforts such as The Cancer Genome Atlas (TCGA) have revealed a complex landscape of somatic mutations in various cancer types [5]. For example, in colorectal cancer, somatic BRAF V600E mutation is associated with poor outcomes irrespective of the received treatment and regarded as poor prognosis markers [6]. Current data about whole-exome sequencing and whole-genome sequencing have provided a window into the biology, that drives oncogenesis and PC tumors progression, by enabling unbiased exploration of somatic mutations in prostate tumors that span the spectrum of aggressiveness disease [7].
Somatic mutations have been related to the highest incidence of metastatic disease and different treatment responses. The molecular cause of prostate cancer (PC) is still unclear; however, its progression involves alterations in oncogenes and tumor suppressor genes as well as somatic mutations such as the ones in PIK3CA gene. A high percentage of PC is considered sporadic, which means that the damage to the genes occurs by chance after birth (mainly somatic mutations will drive the cancer event). However, little is known about somatic mutations in PC development.
We evaluated prostate biopsies in the main somatic mutations genes (PIK3CA, TP53, EGFR, KIT, KRAS, PTEN, and BRAF) among individuals with PSA values>4 ng/ml (n = 125), including affected and unaffected PC subjects.
Mutations in KIT gene are related to aggressive PC: TNM stages II to III, Gleason score ≥ 7 and D’Amico risk (P = 0.037, 0.040, and 0.017). However, there are no statistical significant results when more than 3 somatic mutations are presented in the same individual. In relation to environmental factors (smoking, diet, alcohol intake, or workplace exposure) there are no significant differences in the effect of environmental exposure and the somatic mutation presence. The most prevalent mutations among patients with PC are c.1621A>C (rs3822214) in KIT, c.38G>C (rs112445441) in KRAS and c.733G>A (rs28934575) in TP53 genes. KRAS, KIT, and TP53 genes are the most prevalent ones in patients with PC.
Somatic alterations predisposing to chromosomal rearrangements in PC remain largely undefined. We show that KIT, KRAS, and TP53 genes have a higher presence among patients with PC and that mutations in KIT gene are related to an aggressive PC. However, we did not find any environmental effect in somatic mutations among PC individuals.
Update on current problems in colorectal liver metastasis
2017, Current Problems in Surgery
Citation Excerpt :
Conversely, BRAF mutations are commonly associated with high-level microsatellite instability (30%), which traditionally carries a good prognosis.109 Despite the association, these patients have the worst prognosis (10-month median OS) and typically demonstrate poor response to all lines of chemotherapy, including Cetuximab.110,111 The outcomes of patients undergoing resection of BRAF-mutant CRLM have traditionally been poor.112
Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study
2017, Clinical Colorectal Cancer
Citation Excerpt :
The APEC study has shown that once-every-2-weeks cetuximab with either FOLFOX or FOLFIRI is effective as a first-line therapy for mCRC in this Asia-Pacific study population. The observed median OS for the KRAS wt and RAS wt populations is similar to those reported in prior first-line pivotal studies involving weekly cetuximab plus FOLFOX or FOLFIRI that enrolled mainly white patients.2,5,14-16 Cetuximab compliance in the APEC study was high, and the overall occurrence of AEs, including grade 3/4 acneiform skin reactions, was similar to historical rates for the weekly administration schedule of cetuximab plus chemotherapy and chemotherapy alone.2,5
In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed.
APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated.
In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations.
The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.

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Clinical Colorectal Cancer

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Study Design

Results

Discussion

Acknowledgments

References (19)

Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study

Ann Oncol

FOLFOX4 plus cetuximab administered weekly or every second week in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer: a randomized phase II CECOG study

Ann Oncol

Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials

Eur J Cancer

Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Lancet

Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial

Lancet Oncol

Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study

J Clin Oncol

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status

J Clin Oncol

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

N Engl J Med

Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: new results from the OPUS study

J Clin Oncol

Cited by (26)

Noninferiority of cetuximab every-2-weeks versus standard once-weekly administration schedule for the first-line treatment of RAS wild-type metastatic colorectal cancer

Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial

Liver Metastases

Improving the genetic signature of prostate cancer, the somatic mutations

Update on current problems in colorectal liver metastasis

Efficacy, Tolerability, and Biomarker Analyses of Once-Every-2-Weeks Cetuximab Plus First-Line FOLFOX or FOLFIRI in Patients With KRAS or All RAS Wild-Type Metastatic Colorectal Cancer: The Phase 2 APEC Study

Original StudyFOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Study Design

Results

Discussion

Acknowledgments

Ann Oncol

Ann Oncol

Eur J Cancer

Lancet

Lancet Oncol

Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study

J Clin Oncol

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status

J Clin Oncol

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

N Engl J Med

Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: new results from the OPUS study

J Clin Oncol

Original Study
FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study