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Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

ABSTRACT: Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC.Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07).This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.

SUBMITTER: Rowland A

PROVIDER: S-EPMC4580381 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

Rowland A A Dias M M MM Wiese M D MD Kichenadasse G G McKinnon R A RA Karapetis C S CS Sorich M J MJ

British journal of cancer 20150519 12

<h4>Background</h4>Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain.<h4>Methods</h4>We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-E ...[more]

PMID: 25989278

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Project description:Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment.In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient.This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response.Implications for practiceIn metastatic colorectal cancer (mCRC), therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of RAS mutations. Cumulative evidence shows that patients with BRAF mutations, who comprise 10% of the mCRC population, do not benefit from anti-EGFR-antibody treatment. Although guidelines state that evidence for BRAF as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of BRAF as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected.

Project description:BackgroundEpidermal growth factor receptor gene copy number (EGFR GCN) has been heavily investigated as a potential predictive biomarker for the treatment of metastatic colorectal cancer (mCRC) with anti-EGFR monoclonal antibodies (MAbs). The objective of this study was to systematically review current evidences on this issue.MethodsPubMed, EMBASE, The Cochrane Library, Chinese Biomedical Literature Database, Wanfang Data, and the conference abstracts of American Society of Clinical Oncology and European Society of Medical Oncology were comprehensively searched. Studies that reported the objective response rate (ORR), progression-free survival, and/or overall survival of mCRC patients treated with anti-EGFR MAbs, stratified by EGFR GCN status, were included. The effect measures for binary outcome (response) and time-to-event outcomes (progression-free survival and overall survival) were risk difference and hazard ratio, respectively. Statistical heterogeneity among the studies was assessed by the Cochran's Q-test and the I2 statistic. If appropriate, a quantitative synthesis of data from different studies would be conducted with a random-effects model.ResultsNineteen eligible studies were identified. The criteria for increased EGFR GCN (GCN+) were highly inconsistent across different studies. The prevalence of GCN?+?ranged from 6.9% to 88.9%, and the difference in ORR between patients with GCN?+?and those with non-increased EGFR GCN (GCN-) varied from -28% to 84%. Because of the significant heterogeneity, no quantitative synthesis of data was performed. There was a general trend towards higher ORR in patients with GCN+. The difference in ORRs between patients with GCN?+?and those with GCN- was even greater in KRAS wild-type patients, while in KRAS mutated patients the difference often did not exist. Almost all patients with EGFR amplification responded to the treatment. However, the prevalence of EGFR amplification was generally low. Incomplete data on progression-free survival and overall survival seemingly supported the findings on ORR.ConclusionsAlthough increased EGFR GCN is generally associated with a better outcome of anti-EGFR MAbs treatment, especially among patients with wild-type KRAS, the clinical utility of this biomarker for selecting recipients of anti-EGFR MAbs would be severely limited by the heterogeneous scoring system and the poor reproducibility of EGFR GCN enumeration due to technical reasons.

Project description:The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis.RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3.The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR?=?0.70; 95% confidence interval [CI]: 0.59-0.82; P?<?.0001), OS (HR?=?0.79; 95%CI: 0.67-0.92; P?=?.003), and ORR (OR?=?2.56; 95% CI: 1.77-3.70; P?<?.00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR?=?0.77; 95% CI: 0.61-0.98; P?=?.03; PFS, HR?=?0.68; 95% CI: 0.57-0.82; P?<?.00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P?=?.0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P?=?.53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients.So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.

Project description:BackgroundAn over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC). METHODS: This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5-15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study. RESULTS: From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type KRAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T1/2) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%-44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%-68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6-5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached).ConclusionsSCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC.Trial registrationThis study was registered with ClinicalTrials.gov ( NCT02211443 ).

Dataset Information

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

Publications

Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.

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