Clinical outcome in patients with metastatic colorectal cancer harboring KRAS p.G13D mutation treated with cetuximab.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 448-448 ◽  
Author(s):  
H. Bando ◽  
T. Yoshino ◽  
E. Shinozaki ◽  
S. Yuki ◽  
T. Nishina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Therapeutic Benefit ◽  
Combination Regimen ◽  
Wild Type ◽  
Kras Status ◽  
Clinical Benefits ◽  
Colorectal Cancer Patients

448 Background: Metastatic colorectal cancer patients with KRAS codon 12 or 13 mutated tumors are presently excluded from treatment with cetuximab (Cmab). On the other hand, a few patients who have mutated KRAS status occasionally respond to Cmab. The tumors of those patients predominantly had codon 13 mutation, and all codon 13 responder have mutation of p.G13D. We now compared the efficacy of Cmab among patients with p.G13D- mutant, other KRAS mutant and KRAS wild-type colorectal cancer. Methods: The patients from 9 Japanese institutions were retrospectively collected and analyzed. All patients were refractory to fluoropyrimidine, oxaliplatin and irinotecan, and were treated with Cmab and irinotecan combination regimen. Response rate (RR), progression-free survival (PFS) and overall survival (OS) were calculated respectively according to KRAS status. Results: Ninety four patients were treated with combination therapy. Among 94 cases, 7 cases were p.G13D-mutant KRAS, 23 cases were other mutant KRAS and 63 cases were wild-type KRAS. Baseline characteristics by each subset were well-balanced. While one partial response (PR) and 4 stable diseases (SD) cases were found in 7 p.G13D-mutated cases, no PR was found in other KRAS mutated cases. Median PFS of the patients with p.G13D-mutant, other KRAS mutant and KRAS wild-type were 4.5 months (95%CI 1.7-), 2.3 months (95%CI 1.9-4.3), 4.6 months (95%CI 3.5-6.5) respectively. And median OS of the patients with p.G13D- mutant, other KRAS mutant and KRAS wild-type were 9.3months (95%CI 8.5- 11.8), 7.4 months (95%CI 4.5-9.4), 12.2 months (95%CI 8.7-19.8) respectively. Although statistical significance was not found between the two mutated groups, there are trends that the patients with p.G13D-mutant may have received better clinical benefits from Cmab than the patients with other KRAS mutant. Conclusions: Cmab may have therapeutic benefit in the patients with KRAS p.G13D-mutant colorectal cancer although further evaluation is warranted. No significant financial relationships to disclose.

The Association of FCGR2A and FCGR3A polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 633-633
Author(s):  
Daniel Shepshelovich ◽  
Amanda Rose Townsend ◽  
Osvaldo Espin-Garcia ◽  
Lidija Latifovic ◽  
Christopher J. O'Callaghan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Wild Type ◽  
Genotype Combination ◽  
Trial Analysis ◽  
Germline Polymorphism ◽  
Intermediate Outcomes ◽  
Colorectal Cancer Patients

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.

Circulating tumor cells as predictive marker in panitumumab after progression of cetuximab in Japanese patients with KRAS wild-type metastatic colorectal cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 440-440
Author(s):  
Yoshihito Ohhara ◽  
Satoshi Matsusaka ◽  
Eiji Shinozaki ◽  
Mitsukuni Suenaga ◽  
Nobuyuki Mizunuma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Salvage Therapy ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Wild Type ◽  
Predictive Role

440 Background: Panitumumab has a high affinity for epidermal growth factor receptor. Its utility as a salvage therapy is unknown in cetuximab-resistant colorectal cancer. We assessed the prognostic and predictive role of circulating tumor cells (CTC) in KRAS wild-type metastatic colorectal cancer (mCRC) patients treated with panitumumab after progression of cetuximab. Methods: Panitumumab (6 mg/kg, every 2 weeks) was administered as a salvage therapy to cetuximab-resistant mCRC. CTCs of whole blood at baseline were isolated and enumerated using immunomagnetics. Results: Nineteen patients were enrolled in this prospective study between July 2010 and March 2011. Five patients had stable disease (SD) with a response rate of 0%. Four patients reached long SD, which was defined as continuous SD of more than 120 days. All of the four patients had <2 CTC. <2 CTC showed an independent predictive role for progression-free survival (PFS) at multivariate analysis (HR; 7.275, p=0.013). Patients with >2 CTC had shorter median PFS than those with <2 CTC (1.8 and 3.6 months, p=0.008). There was no statistical significance in median OS between patients with <2 CTC and those with >2 CTC (3.2 and 6.7 months, p=0.164). Conclusions: Panitumumab may be effective for patients with <2 CTC, KRAS-wild-type mCRC after progression of cetuximab.

scholarly journals Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5715
Author(s):  
Davide Ciardiello ◽  
Vincenzo Famiglietti ◽  
Stefania Napolitano ◽  
Lucia Esposito ◽  
Nicola Normanno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Metastatic Colorectal Cancer ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Circulating Tumor Dna ◽  
Wild Type ◽  
Line Of Therapy

The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.

scholarly journals Negative Hyperselection of Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy

2019 ◽  
Vol 37 (33) ◽  
pp. 3099-3110 ◽  
Author(s):  
Federica Morano ◽  
Salvatore Corallo ◽  
Sara Lonardi ◽  
Alessandra Raimondi ◽  
Chiara Cremolini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Wild Type ◽  
Primary Resistance ◽  
Molecular Alterations ◽  
Status Interaction ◽  
Colorectal Cancer Patients

PURPOSE We assessed the prognostic/predictive role of primary tumor sidedness and uncommon alterations of anti–epidermal growth factor receptor (EGFR) primary resistance (primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies [PRESSING] panel) in patients with RAS/ BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who were randomly assigned to panitumumab plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) induction followed by maintenance with panitumumab with or without fluorouracil (FU) plus leucovorin (LV); Valentino trial (ClinicalTrials.gov identifier: NCT02476045 ). PATIENTS AND METHODS This prespecified retrospective analysis included 199 evaluable patients with RAS/ BRAF wt. The PRESSING panel included the following: immunohistochemistry (IHC) and in situ hybridization for HER2/MET amplification, IHC with or without RNA sequencing for ALK/ROS1/NTRKs/RET fusions, next-generation sequencing for HER2/ PIK3CAex.20/PTEN/ AKT1 and RAS mutations with low mutant allele fraction, and multiplex polymerase chain reaction for microsatellite instability. PRESSING status (any positive biomarker v all negative) and sidedness were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the study population and by treatment arm. RESULTS Overall, left- and right-sided tumors were 85.4% and 14.6%, respectively, and PRESSING-negative and -positive tumors were 75.4% and 24.6%, respectively. At a median follow-up of 26 months, inferior outcomes were consistently observed in right- versus left-sided tumors for ORR (55.2% v 74.1%; P = .037), PFS (8.4 v 11.5 months; P = .026), and OS (2-year rate: 50.2% v 65.1%; P = .062). Similar results were observed in the PRESSING-positive versus PRESSING-negative subgroup for ORR (59.2% v 75.3%; P = .030), PFS (7.7 v 12.1 months; P < .001), and OS (2-year rate: 48.1% v 68.1%; P = .021). The PFS benefit of FU plus LV added to panitumumab maintenance, reported in the study, was independent from sidedness and PRESSING status (interaction for PFS P = .293 and .127, respectively). However, outcomes were extremely poor in patients who received single-agent panitumumab and had right-sided tumors (median PFS, 7.7 months; 2-year OS, 38.5%) or PRESSING-positive tumors (median PFS, 7.4 months; 2-year OS, 47.0%). CONCLUSION The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with RAS/ BRAF–wt mCRC who had inferior benefit from initial anti-EGFR–based regimens, particularly after maintenance with single-agent anti-EGFRs.

Clinical benefits of bevacizumab in metastatic colorectal cancer depending on KRAS status.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 636-636
Author(s):  
Keisuke Kurimoto ◽  
Kiyoshi Ishigure ◽  
Yoshiyasu Kato ◽  
Yasuyuki Asai ◽  
Nobutake Tanaka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Reduction Rate ◽  
Wild Type ◽  
Mutant Type ◽  
Drug Benefits ◽  
Kras Status ◽  
Clinical Benefits ◽  
Mutation Type

636 Background: KRAS status is the therapeutic marker of anti-EGFR drug, and may be the prognostic marker of metastatic colorectal cancer (mCRC). However, there is no consensus whether bevacizumab (anti-VEGF drug) benefits patients with mutated KRAS in mCRC. We investigated the clinical benefits of bevacizumab treatment in mCRC depending on KRAS status, retrospectively. Methods: We investigated 49 patients who received chemotherapies with bevacizumab as first-line treatment for mCRC from May 2008 through June 2013. We evaluated response rate (RR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tumor reduction rate and the adverse events (CTCAE v4.0 - JCOG) depending on KRAS status. Results: The median age of the patients was 66 years (range; 36 - 80). Forty-five patients received oxaliplatin-based chemotherapies with bevacizumab and four patients received irinotecan-based chemotherapies with bevacizumab. KRAS status of 30 patients was wild type and that of 19 patients was mutation type. There was no difference in patient characteristics between KRAS wild type (WT) and mutation type (MT). In all 49 patients, RR was 62.5%. DCR was 91.7%. The median PFS was 10.9 months. In RR, patients with KRAS wild type tumors had better outcome than patients with mutant type tumors (WT : MT, 69.0% : 52.6%, no statistically difference). A similar tendency was seen in DCR (WT : MT, 96.6% : 84.2%, no statistically difference). The average reduction rate in KRAS WT was 42.7% and in KRAS MT was 32.3% (p = 0.309). In the KRAS wild patients, the median PFS was longer than that in the KRAS mutant patients (WT : MT, 11.8 : 8.9 months, Log Rank p = 0.583), but there is no statistically difference between two groups. In median OS, there was no difference between two groups (WT : MT, 21.0 : 20.8 months, Log Rank p = 0.393). The incidence of severe adverse events was not statistically different between KRAS WT group and MT group. Conclusions: Regardless of KRAS status, bevacizumab provides clinical benefits for patients with mCRC.

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract 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.

Tumor bulk as a prognostic biomarker and predictor of benefit from anti-EGFR therapy in patients with metastatic colorectal cancer: Analysis of 476 patients from the ARCAD Clinical Trials Program.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 108-108
Author(s):  
Benjamin Adam Weinberg ◽  
Manel Rakez ◽  
Benoist Chibaudel ◽  
Tim Maughan ◽  
Richard Adams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Performance Status ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Wild Type ◽  
Cox Models ◽  
Study Results

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]

scholarly journals Cetuximab versus bevacizumab maintenance following prior 8-cycle modified FOLFOXIRI plus cetuximab in Asian postmenopausal women with treatment-naive KRAS and BRAF wild-type metastatic colorectal cancer

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052093044
Author(s):  
Baomin Chen ◽  
Donghua Zheng ◽  
Weiguang Yu ◽  
Cuiping Huang ◽  
Junxing Ye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Postmenopausal Women ◽  
Induction Therapy ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Wild Type ◽  
Clinical Endpoints ◽  
Treatment Naïve

Objective To assess the efficacy and safety of cetuximab (CE) versus bevacizumab (BE) maintenance treatment after prior 8-cycle modified 5-fluorouracil, folinate, oxaliplatin, and irinotecan (FOLFOXIRI) plus CE induction therapy in treatment-naive KRAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC). Methods From 2012 to 2017, prospectively maintained databases were reviewed to assess Asian postmenopausal women with treatment-naive KRAS and BRAF wt mCRC who underwent modified FOLFOXIRI plus CE induction therapy, followed by CE or BE maintenance until disease progression or death. Co-primary clinical endpoints were progression-free survival (PFS) and overall survival (OS). Results A total of 222 women were included (CE n = 110 and BE n = 112). At a median follow-up of 27.0 months (interquartile range, 6.5–38.6 months), median PFS was 21.9 months (95% confidence interval [CI] 16.4–24.4) and 17.7 months (95% CI 11.3–19.0) for CE and BE groups, respectively (hazard ratio [HR] 0.31, 95% CI 0.15–0.46); median OS was 26.0 months (95% CI 23.4–28.7) and 22.7 months (95% CI 21.2–24.3) for CE and BE groups, respectively (HR 0.22, 95% CI 0.11–0.37). Conclusions CE maintenance treatment is more poorly tolerated but has a slightly more modest survival benefit compared with BE maintenance treatment in mCRC.

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