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Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking.We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort.In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07).Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

Patients' characteristics of JACCRO CC-05/06 and 05/06AR trials

Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.

Consort flow diagram of the study

Supplementary Figures S1-S4 and Supplementary Tables S1-S4

Purpose:OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site.Experimental Design:Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden.Results:Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10.Conclusions:Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.

PURPOSE Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

Primary tumor site and genomic status are utilized for regimen selection in metastatic colorectal cancer; however, the impact on clinical practice is not well known.We aimed to clarify the impact of primary tumor site and genomic status on clinical practice in metastatic colorectal cancer.The relationship between primary tumor site, genomic alterations, and clinical outcomes was evaluated in patients with untreated metastatic colorectal cancer using real-world data of a prospective observational study, SCRUM-Japan GI-SCREEN with clinical and genomic data set in 1011 patients enrolled from February 2015 to March 2017.Five hundred and sixty-one patients were eligible for this study. Patients with right-sided tumors had a significantly worse survival, left-sided tumors with wild-type RAS had favorable outcomes when treated with anti-epidermal growth factor receptor monoclonal antibodies, and cecum tumors had poor prognosis when treated with bevacizumab. The rate of gene alterations varied considerably depending on the primary site. In addition, gene alterations of KRAS, BRAF, SMAD4, or TP53 had individually different contributions to survival from site to site. KRAS, BRAF, PTEN, or SMAD4 mutations were associated with efficacy of bevacizumab or anti-epidermal growth factor receptor monoclonal antibodies.Primary tumor site is a clinically useful biomarker to predict survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. Moreover, the prognostic or predictive value of several gene alterations by primary tumor site should be considered in clinical practice.

The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/mIn total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Objective Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. Methods Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. Results We enrolled 102 patients with a median age of 80 years (range, 75–88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, −0.06; P = 0.56) adverse events. Conclusions The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Tumor mutational burden (TMB) is a genomic biomarker associated with the benefits of immune checkpoint inhibitors (ICIs). Detection of elevated blood TMB (bTMB) in circulating tumor DNA represents a compelling noninvasive approach. However, the validity and utility of this emerging biomarker across cancer types has not been established. To better understand bTMB landscape, a preliminary analysis of bTMB was performed in a large clinical cohort and MONSTAR-SCREEN. There was higher agreement between TMB and bTMB in samples with higher levels of plasma tumor fraction (TF). Among patients with bTMB-high treated with ICIs, there was a trend toward a higher response rate and longer progression-free survival, which was more pronounced among patients with TF≥10%. Our findings suggest elevated bTMB is correlated with elevated TMB and represents a pragmatic biomarker for assessing ICIs benefits. The utility of this biomarker is likely to be associated with high TF levels, informing future prospective investigations.

Purpose: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the RAS status by metastatic sites in patients with a single metastatic site. Experimental Design: Data from previous Spanish and Japanese studies investigating the concordance of the RAS status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden. Results: Patients had metastases in the liver (n = 151), peritoneum (n = 25), or lung (n = 45) with concordance rates of 91% (95% confidence interval, 85%–95%), 88% (68%–97%), and 64% (49%–78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number (P = 0.004), and sample collection interval (P = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10. Conclusions: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' RAS status with only peritoneal or lung metastases.

PURPOSE Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.

Purpose Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC.Methods Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay.Results The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within one year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC.Conclusion NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variants should be further investigated as a favorable prognostic marker.

FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted., High FLT3 amplification may function not only as a prognostic factor but a promising treatment target in metastatic colorectal cancer.

Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman’s correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P

Background Regorafenib or trifluridine/tipiracil as third-line treatment have limited efficacy in metastatic colorectal cancer (mCRC). Methods This Phase 2 trial evaluated the efficacy and safety of irinotecan plus cetuximab rechallenge as third-line treatment in KRAS wild-type mCRC patients who achieved clinical benefit with first-line cetuximab-containing therapy. The primary endpoint was 3-month progression-free survival (PFS) rate. A sample size was calculated; 30 patients with a 3-month PFS rate of 45% deemed promising and 15% unacceptable. Patients with greater and less than the cut-off value of cetuximab-free intervals (CFIs) were classified into the long and short CFI groups, respectively, in subgroup analyses. Results Among 34 eligible patients who received treatment at least once, 3-month PFS rate was 44.1% (95% confidence interval, 27.4–60.8%). The median PFS and overall survival (OS) were 2.4 and 8.2 months, respectively. The response and disease control rates were 2.9 and 55.9%, respectively. PFS and OS were significantly longer in the long- than in the short CFI group. Conclusions Irinotecan plus cetuximab rechallenge as third-line treatment for KRAS wild-type mCRC was safe and had promising activity, especially in those with a long CFI, warranting further investigation in a Phase 3 randomised trial. Clinical trial registration UMIN000010638

IntroductionA new concept of ‘NeoRAS wild-type (WT)’, which means conversion of RAS status from RAS mutant to RAS WT after treatment, has been reported. Previous observational and proof-of-concept studies have demonstrated the efficacy of epidermal growth factor receptor inhibitors in patients with NeoRAS WT metastatic colorectal cancer (mCRC). Moreover, posthoc biomarker analyses of these studies have suggested that not only the RAS status in the circulating tumour DNA (ctDNA) but also other gene mutational status may be useful as biomarkers of epidermal growth factor receptor inhibitors for NeoRAS WT mCRC.Methods and analysisThis trial is a multicentre, single-arm, phase II trial to assess the efficacy and safety of panitumumab plus irinotecan therapy for patients with NeoRAS mCRC. The key eligibility criteria include RAS mutant mCRC initially proven in tumour tissue refractory or intolerant to fluoropyrimidine, oxaliplatin and irinotecan; RAS WT in ctDNA (defined as plasma mutant allele frequencies of all RAS ≤0.1%) within 28 days before enrolment and Eastern Cooperative Oncology Group performance status ≤2. The primary endpoint is the response rate. The target sample size is 30 patients. Biomarker analyses are planned to be performed using next-generation sequencing-based ctDNA analysis.Ethics and disseminationThis study was approved by the certified review board of National Cancer Center Hospital. The main results of the trial will be presented in international meetings and in medical journals.Trial registration numbers031210565.

The aim of this phase II study was to evaluate the efficacy and safety of combination therapy with five-cycle CAPOX (capecitabine plus oxaliplatin) plus bevacizumab, followed by five-cycle maintenance therapy with capecitabine plus bevacizumab and reintroduction of CAPOX plus bevacizumab for five cycles, with a preplanned intermittent oxaliplatin strategy in metastatic colorectal cancer (mCRC). Patients with untreated mCRC were administered CAPOX (130 mg/m2 oxaliplatin on day 1, 2000 mg/m2/day capecitabine on days 1–14, every 21 days) + bevacizumab (7.5 mg/kg) every 3 weeks for five cycles, maintenance treatment without oxaliplatin for five cycles, and CAPOX + bevacizumab reintroduction for five cycles or upon tumor progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the time to treatment failure (TTF), overall survival, response rate (RR), and safety. Forty-seven patients who fulfilled the inclusion criteria were enrolled in the evaluation of efficacy and safety. Median PFS was 14.1 months (95% confidence interval [CI], 8.6–19.5), and median TTF was 12.3 months (95% CI, 10.3–14.3). The objective RRs were 51.1% (24/47) during induction therapy, 58.3% (21/36) during maintenance therapy, and 63.6% (14/22) during reintroduction therapy. The frequency of patients with neutropenia, diarrhea, peripheral sensory neuropathy, venous thromboembolism, or grade ≥ 3 allergic reactions was 2.1%. CAPOX plus bevacizumab therapy with a preplanned intermittent oxaliplatin strategy consisting of brief five-cycle induction therapy, five-cycle maintenance therapy with capecitabine plus bevacizumab, and five-cycle reintroduction therapy consisting of CAPOX plus bevacizumab is safe and effective for mCRC patients. UMIN ID: 000,005,732, date of registration: June 7, 2011. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000006695

Aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second‐line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty‐two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy‐eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor‐stroma interaction. Plasma levels of biomarkers at baseline and at pre‐dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre‐dose 3 (adjusted P

Background OncoBEAMTM RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA. Methods mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma- and tissue-based RAS mutational status were determined by BEAMing, respectively. Results A total of 280 patients from eight institutions were eligible. The overall agreement between plasma- and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma- and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma- and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions. Conclusion The clinical validity of OncoBEAMTM RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions.

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

A striking resection rate and survival benefit of first-line cetuximab-containing chemotherapy were demonstrated in patients with mCRC who were classified into the potentially resectable group., Objective We aimed to clarify the clinical practice and outcomes of first-line cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Efficacy and safety were evaluated in each group classified by the European Society for Medical Oncology Guidelines 2012. Methods This prospective observational study included patients with previously untreated metastatic colorectal cancer from 158 centers in Japan who started first-line cetuximab-containing chemotherapy from January 2012 to June 2013 and were followed for up to 3 years. The resection rates after chemotherapy were calculated and the overall survival was estimated using the Kaplan–Meier method for Group 1 (G1, potentially resectable), Group 2 (G2, not resectable and tumor-related symptoms) and Group 3 (G3, not resectable and asymptomatic). Results Of 578 patients, 562 were classified into G1 (n = 165), G2 (n = 224) or G3 (n = 173). The resection rate of any site was higher in G1 (57.0%) than in G2 (11.2%) and G3 (11.6%). G1, G2 and G3 showed median overall survivals (95% confidence interval) of 45.9 (38.1–not available), 16.7 (14.5–18.8) and 30.6 (23.2–34.8) months, respectively (P < 0.0001). The common tumor-related symptoms in G2 were pain, fatigue and anorexia, from which 31.7, 22.2 and 14.8% of the patients suffered at baseline. Conclusions The expected efficacy and safety of first-line cetuximab-containing chemotherapy were demonstrated in patients with metastatic colorectal cancer under clinical practice in Japan. Registered clinical trial numbers UMIN000007275

3530 Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]

3571 Background: In colorectal cancer (CRC), mutations in KRAS, NRAS, and BRAF predict resistance to anti-EGFR therapies. In pancreatic ductal adenocarcinoma (PDAC), ~90% of patients harbor KRAS mutations, while KRAS wild-type tumors often have clinically actionable fusion alterations. Thus, in both cancers, the accurate ascertainment of RAS and BRAF driver status is essential. Sequencing of cell-free DNA (cfDNA) from plasma allows convenient assessment of a tumor’s molecular profile, but sensitivity can be limited by low ctDNA shedding. We sought to establish a ctDNA shedding threshold at which actionable driver mutations can be reliably detected. Methods: Molecular reports and matched clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA and GI-SCREEN. CRC or PDAC patients with a pathogenic KRAS, NRAS, or BRAF activating point mutation (“driver”) present on tissue next-generation sequencing (NGS) assays and who also had cfDNA assay available were included. Tissue NGS included Foundation One CDx and Oncomine Comprehensive Assay. Guardant 360 (G360) was the sole plasma cfDNA assay. 131 CRC and 24 PDAC cases with 189 total G360 assays met criteria and were included. Samples were analyzed according to detection of the driver mutation and the maximum mutant allele frequency (MAF) of non-driver mutations on G360. An optimal cut-point for max MAF was explored among the CRC and PDAC patients using a maximally selected Wilcoxon rank statistic method. Results: 76.8% of driver mutations were in KRAS, 22.6% in BRAF, and 1.9% in NRAS with an overlap of 1 BRAF and 1 NRAS mutation with a KRAS mutation. Overall sensitivity of G360 for drivers was 83.0% for CRC and 54.2% for PDAC. No variants were detected on G360 in 9.1% of CRC and 37.5% of PDAC. Sensitivity for driver mutations increased with higher maximum non-driver MAF, with MAF > 1% predicting sensitivity > 98% (Table). Optimal cut-point analysis identified MAF of > 0.34% (p < 0.0001), above which the driver was identified in 97% of patients and below which only 27%. Conclusions: In our study, non-driver MAF > 1% on cfDNA NGS predicts high sensitivity for RAS and BRAF mutations and thus is adequate to guide clinical decisions such as anti-EGFR therapy in CRC, evaluation for fusions in PDAC, and validity in clinical trials. MAF ≤0.34% is a clear threshold to consider an assay inadequate and thus seek alternative testing. Sensitivity rises for MAF between 0.35 and 1% but will require greater patient numbers to establish clinically relevant sensitivity thresholds. These results will be updated with additional data for final presentation. [Table: see text]

3586 Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p

Detection of RAS and BRAF mutations is essential to determine the optimal treatment strategy for metastatic colorectal cancer (CRC). We prospectively evaluated the MEBGEN RASKET-B KIT (RASKET-B), a novel multiplex kit, simultaneously detecting 48 types of RAS mutations and the BRAF V600E mutation using Luminex xMAP technology. The aim was to obtain market approval for RASKET-B as an in vitro diagnostic (IVD) option in Japan. Genomic DNA was extracted from 302 formalin-fixed paraffin-embedded tissues obtained from CRC patients. The primary endpoints were the concordance rate (CR) between the results from RASKET-B and the previously approved IVD kit (RASKET) for RAS mutations, and CR between the results from RASKET-B and direct sequencing (DS) for BRAF mutations. The secondary endpoints included the CR between RASKET-B and DS for RAS mutations and between RASKET-B and the pyrosequencing (PYRO) for the BRAF V600E mutation. Among the 302 samples, 142 RAS mutations (47%) and 18 BRAF V600E mutations (6.0%) were detected by RASKET-B. All mutations detected in the recruited patients were mutually exclusive. Both RAS and BRAF mutation rates were statistically higher in right-sided than left-sided CRC. The CR between RASKET-B and RASKET for RAS gene and RASKET-B and DS for BRAF V600E mutation was 100% for both (95% CI: 99%-100%). The results from RASKET-B were also highly concordant with DS for RAS (97.4%) and with PYRO for the BRAF (V600E) gene (99.7%). RASKET-B thus provides rapid, precise, and simultaneous detection of RAS and BRAF mutations in CRC.

High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer.Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate.This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P = .018). The low-expression (cutoff 15%) TK1 group experienced a smaller OS benefit (9.3 vs. 7.4 months; hazard ratio = 0.88; 95% confidence interval, 0.63-1.23; P = .45). For patients who received placebo, the high-expression TK1 group had a slightly worse prognosis than the low-expression TK1 group. The tendency of FTD/TPI efficacy concerning progression-free survival and disease control rate was not similar to that concerning OS between groups.Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship.

Background: In the first-line treatment of metastatic colorectal cancer (mCRC) patients with CAPOX plus bevacizumab, the optimal duration of maintenance treatment without oxaliplatin to avoid discontinuation of therapy due to peripheral sensory neuropathy (PSN) remains unknown. The aim of this phase II study was to evaluate the efficacy and safety of combination therapy with five-cycle CAPOX (capecitabine plus oxaliplatin) plus bevacizumab, followed by five-cycle maintenance therapy with capecitabine plus bevacizumab and reintroduction of CAPOX plus bevacizumab for five cycles, with a preplanned oxaliplatin intermittent strategy in mCRC.Methods: Patients with untreated mCRC were administered CAPOX [oxaliplatin 130 mg/m2 and capecitabine (2000 mg/m2 daily) as intermittent treatment for 14 days, followed by a 7-day treatment-free interval, every 3 weeks] + bevacizumab (7.5 mg/kg) every 3 weeks for five cycles, maintenance treatment without oxaliplatin for five cycles, and CAPOX + bevacizumab reintroduction for five cycles or upon tumor progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the time to treatment failure (TTF), overall survival, response rate (RR), and safety.Results: Forty-seven patients who fulfilled the inclusion criteria were enrolled in the evaluation of efficacy and safety. The relative dose intensity and the cumulative dose of oxaliplatin during the overall treatment period were 649.1 mg/m2 and 1132.5 mg, respectively. Median PFS was 14.1 months (95% confidence interval [CI], 8.6–19.5), and median TTF was 12.3 months (95% CI, 10.3–14.3). The objective RRs were 51.1% (24/47) during induction therapy, 58.3% (21/36) during maintenance therapy, and 63.6% (14/22) during reintroduction therapy. The frequency of patients with neutropenia, diarrhea, PSN, venous thromboembolism, or grade ≥ 3 allergic reactions was 2.1%.Conclusion: CAPOX plus bevacizumab therapy with a preplanned intermittent oxaliplatin strategy consisting of brief five-cycle induction therapy, five-cycle maintenance therapy with capecitabine plus bevacizumab, and five-cycle reintroduction therapy consisting of CAPOX plus bevacizumab is safe and effective for mCRC patients.Trial registration: This trial was registered with the University Hospital Medical Information Network on 7 June 2011 (UMIN ID: 000005732).

AIM The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. METHODS In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. RESULTS With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P

Background/aim In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear. Patients and methods The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities. Results Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed. Conclusion Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib.

Oxaliplatin (OX) and irinotecan (IRI) are used as key drugs for the first‐line treatment of metastatic colorectal cancer (mCRC). However, no biomarkers have been identified to decide which of the drugs is initially used. In this translational research (TR) of the TRICOLORE trial, the advanced colorectal cancer subtype (aCRCS) was analyzed as a potential biomarker for the selection of OX or IRI. We collected 335 (68.8%) formalin‐fixed, paraffin‐embedded (FFPE) primary tumor specimens from 487 patients registered in the TRICOLORE trial and performed direct sequencing and immunohistochemical staining of CRC‐related genes, comprehensive gene‐expression analysis, and genome‐wide methylation analysis. The progression‐free survival (PFS) of the IRI group was significantly better compared with the OX group in BRAF wild‐type (WT), PTEN‐positive, and aCRCS A1 patients. Among the molecular factors, aCRCS were only associated with the PFS of OX and IRI groups. The PFS of the IRI group was significantly better compared with the OX group in aCRCS A1 + B1 (hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.41‐0.82; P = .0023). In contrast, the OX group had better PFS compared with the IRI group in aCRCS B2, although this was not statistically significant (HR = 1.66; 95% CI = 0.94‐2.96; P = .083). Nearly half of patients with mCRC (46.8%, aCRCS A1 + B1) respond well to IRI, while only about 18.5% (aCRCS B2) of patients with mCRC responded well to OX. In conclusion, the aCRCS might be a predictive factor for the clinical outcomes of OX‐based and IRI‐based therapies., From translational research of TRICOLORE trail, the advanced colorectal cancer subtypes (aCRCS) can help to select oxaliplatin‐based or irinotecan‐based therapy for first‐line metastatic colorectal cancer treatment.

Neoadjuvant chemotherapy has been performed for locally advanced colorectal cancer with invasion to other organs or lateral lymph node metastasis in to control local recurrence and distant metastasis. We evaluated the treatment results and the significance of surgery in 53 patients(36 rectal cancer cases and 17 sigmoid colon cancer cases)who underwent surgery after chemotherapy by XELOX plus bevacizumab for 3 months. As pretreatment diagnosis, 42 cases were T4b and 39 cases were lymph node positive. Combined resection was performed in 34 cases including 12 cases of total pelvic exenteration. Pathological diagnosis showed 27 cases of ypT4b and 34 cases of ypN0. Pathological curative resection was performed in 90.4%. Histological effect by chemotherapy was 31 cases in Grade(Gr)1a, 10 cases in Gr 1b, 8 cases in Gr 2, and 4 cases in Gr 3, respectively. The 5-year survival rate was 60.9% in Gr 1a or lower and 100% in Gr 1b or higher. Tumor markers( CEA and CA19-9)were reduced into normal range after neoadjuvant chemotherapy in all 4 patients with Gr 3. Pathological CR could not be predicted from clinical findings after neoadjuvant chemotherapy. It was suggested that neoadjuvant chemotherapy for locally advanced rectal cancer with invasion to other organs or lateral lymph node metastasis is useful for improving the prognosis, surgical resection is indispensable as a multidisciplinary treatment, and that the pathological therapeutic effect leads to prognosis prediction.

Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in theData from previous Spanish and Japanese studies investigating the concordance of thePatients had metastases in the liver (Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients'

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P

Background: The randomized phase II WJOG6510G study demonstrated the non-inferiority of panitumumab to cetuximab in terms of progression-free survival (PFS) in patients with wild-type KRAS exon 2 metastatic colorectal cancer. In this study, we performed exploratory analyses of updated survival data using the KRAS exon 2 and RAS/BRAF statuses. Methods: Patients with wild-type KRAS exon 2 metastatic colorectal cancer who experienced progression after the failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive panitumumab or cetuximab in combination with irinotecan. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence-specific oligonucleotide method. Results: In the updated analysis of 121 enrolled patients after a median follow-up of 31.3 months, the median PFS was 5.4 months in the panitumumab arm, versus 4.3 months in the cetuximab arm (hazard ratio [HR]=0.68). The median overall survival (OS) times were 14.9 and 12.5 months in the panitumumab and cetuximab arms, respectively (HR=0.68). In 83 analyzed patients, RAS/BRAF testing identified 19 (23%) and 4 patients (5%) with RAS and BRAF mutations, respectively. In the wild-type RAS and BRAF population, trends of better PFS (6.5 months versus 4.6 months; HR=0.57) and OS (15.3 months versus 11.8 months; HR=0.77) were observed for panitumumab. Conclusions: In this updated analysis, panitumumab was associated with a modest survival benefit versus cetuximab in patients with centrally confirmed wild-type KRAS exon 2 metastatic colorectal cancer as well as in the wild-type RAS and BRAF population.