KRAS mutation status to predict response in first-line capox and bevacizumab therapy for metastatic colorectal cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 536-536
Author(s):  
You Yone ◽  
Mohammad Abdallah ◽  
Saad Sabih Tahir ◽  
Selim Cellek ◽  
Jufen Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Response ◽  
Response Rate ◽  
Quantitative Polymerase Chain Reaction ◽  
Tumour Response ◽  
Ffpe Tissue ◽  
First Line ◽  
Large Patient ◽  
Kras Status

536 Background: Capecitabine and Oxaliplatin (CAPOX) combined with the humanised anti-vascular endothelial growth factor Bevacizumab represents a standard first-line treatment for metastatic colorectal cancer (mCRC). However, the response rate is only approximately 50% and currently there is no biomarker to predict treatment response. This study aims to correlate KRAS status with response to CAPOX and Bevacizumab (CAPOX-Bev). Methods: Forty-five patients with mCRC were retrospectively screened between January 2012 and December 2015 at Broomfield Hospital, UK. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples (Qiagen FFPE tissue kit). Twelve types of mutations in Exons 2, 3 and 4 of the KRAS gene were analysed using a real-time quantitative polymerase chain reaction (qPCR) assay (EntroGen). Treatment response was assessed according to RECIST criteria version 1.1 by comparing pre-treatment and post-treatment radiological CT scans. The KRAS status was correlated with CT tumour response (responders: partial response and complete response; non-responders: progressive disease and stable disease). A Chi-square test was used to determine the correlation between KRAS status and tumour response. Results: 19/45 patients were KRAS wild type (WT, 42%) and 26 were KRAS mutant (MT, 58%). 8/19 (42%) KRAS WT patients were responders, compared to 3/26 (12%) KRAS MT patients. Conversely 11/19 (58%) of WT patients were non-responders, compared to 23/26 (88%) MT patients. The correlation of treatment response and KRAS status was statistically significant (p = 0.018), with a 31% difference in response rate between KRAS WT (42%) and KRAS MT (12%) groups. Conclusions: Within this pilot retrospective analysis, KRAS mutations demonstrated clinical value in identifying patients who are more likely to respond to first-line CAPOX-Bev in advanced colorectal cancer. This finding requires prospective evaluation within a large patient cohort powered to further detect potential differences in overall and progression free survival. [Table: see text]

Effect of the addition of bevacizumab to first-line FOLFOX on efficacy, including response rate, progression-free survival, and overall survival, in patients with metastatic colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 588-588
Author(s):  
M. Suenaga ◽  
N. Mizunuma ◽  
S. Matsusaka ◽  
E. Shinozaki ◽  
M. Ogura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Survival Benefit ◽  
Response Rate ◽  
Progression Free Survival ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
First Line Treatment

588 Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Used in combination with chemotherapy, BV has been shown to improve survival in both first- and second-line treatment for metastatic colorectal cancer (mCRC). However, it was reported that addition of BV to FOLFOX conferred only little survival benefit (Saltz et al. JCO2008). The aim of this study was to assess the efficacy of addition of BV to FOLFOX in first-line treatment for patients with mCRC. Methods: Bevacizumab was approved for mCRC in July 2007 in Japan. This study was conducted at a single institution and comprised 217 consecutive patients receiving first-line treatment for mCRC between 2005 and 2009. The primary objective was to compare survival benefit in patients treated with FOLFOX4 (FF) between 2005 and 2007 with that in patients receiving FOLFOX4+BV 5 mg/kg (FF+BV) between 2007 and 2009. Results: Total number of patients in the FF and FF+BV groups was 132 and 85, respectively. Characteristics of patients were as follows (FF vs. FF+B): median age, 62 yrs (range 28-76 yrs) vs. 60 yrs (range16-74 yrs); ECOG PS0, 98.8% vs. 81.8%; and median follow-up time, 20.8 months vs. 24.4 months. Median progression-free survival (PFS) in the FF and FF+BV groups was 10 months (95% CI, 8.7-11.3) and 17 months (95% CI, 10.2-14.1), while median overall survival (OS) was 21 months (95% CI, 17.9-24.1) and not reached, respectively. Response rate was 46% (95% CI, 37- 54) in FF, and 62% (95% CI, 51-73) in FF+BV. Addition of BV to FOLFOX4 significantly improved PFS (p=0.002) and OS (p<0.001). Conclusions: The additive effect of BV for first-line FOLFOX was reconfirmed. These data indicate potential survival benefits from the addition of BV to FOLFOX in first-line treatment of mCRC. In addition, PFS may be a sensitive indicator of outcome prior to post-treatment. No significant financial relationships to disclose.

FOLFIRI-3/bevacizumab induction, then capecitabine/bevacizumab maintenance as front-line strategy for metastatic colorectal cancer: A phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14007-e14007
Author(s):  
Stefano Chong Hun Kim
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Predictive Factors ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Line Treatment ◽  
Front Line ◽  
First Line ◽  
First Line Treatment

e14007 Background: Bevacizumab with FOLFIRI or FOLFOX regimen is the standard of care in metastatic colorectal cancer (mCRC). As second line regimen after FOLFOX, FOLFIRI-3 has showed a significantly better PFS in comparison with other irinotecan-based regimen. We therefore evaluated the safety, efficacy and possible predictive factors for FOLFIRI-3 in combination with bevacizumab as initial treatment for mCRC. Secondarily, we evaluated the feasibility of Capecitabine-Bevacizumab maintenance. Methods: We conducted a phase II, multicentric trial of FOLFIRI-3 regimen (irinotecan 100mg/m2 day 1, LV 200mg/m2 day 1, 5-FU bolus 400 mg/m2 day 1 followed by a 36-h 5-FU continuous infusion 2400 mg/m2, irinotecan 100mg/m2 day 3) with bevacizumab (5mg/kg day 1) repeated every 2 weeks, as first-line treatment in mCRC for 6 months, followed by maintenance treatment with bevacizumab (7.5 mg/kg day 1) and capecitabine (1000 mg/m2 day 1 to 14), repeated every 3 weeks. The primary endpoint was objective response rate (ORR). Secondary endpoints were PFS, overall survival (OS), and biologic analysis of potential predictive factors of response to treatment. Results: From October 2007 to July 2009, 61 patients were enrolled for treatment. The ORR was 66.7% (8.3% of complete response and 58.3% of partial response). Stable disease was observed in 25% of patients (disease control rate of 91.7%). PFS was 12 months, and OS was 33 months. Forty patients entered to maintenance phase. Favorable tolerance profile was observed. Median PFS was 14 months, and OS was 36 months. Its efficacy was maintained in patients recently exposed to oxaliplatin. Conclusions: As front-line regimen in mCRC, FOLFIRI3-bevacizumab is maybe the best among irinotecan-5FU-bevacizumab based regimens to obtain objective response rate. PFS and OS are high but it can be secondary to high complete resection rate in our trial. In recently oxaliplatin-exposed patients, FOLFIRI3-bevacizumab regimen should be considered as first line treatment. Capecitabine-bevacizumab maintenance is clearly feasible and its encouraging result should be validated in a large phase III trial.

Cetuximab with irinotecan or oxaliplatin for first-line metastatic colorectal cancer: Effectiveness in the EREBUS cohort compared to pivotal trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14542-e14542
Author(s):  
Annie Fourrier-Réglat ◽  
Magali Rouyer ◽  
Pernelle Noize ◽  
Emmanuelle Bignon ◽  
Alise Le Monies ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Initiation ◽  
Response Rate ◽  
Real Life ◽  
Wild Type ◽  
First Line ◽  
Multicenter Cohort Study ◽  
Baseline Characteristics ◽  
One Year

e14542 Background: Cetuximab (CTX) has demonstrated improved survival outcomes in metastatic colorectal cancer (mCRC) but information from real-life use is sparse. Here, CTX survival and safety outcomes in real-life are compared to those observed in OPUS and CRYSTAL trials. Methods: EREBUS is a French multicenter cohort study that included over two years (2009-2010) patients with unresectable mCRC and wild-type KRAS initiating CTX as 1st-line therapy in 65 centres and followed for 12 months from treatment initiation. Results: We included 389 patients treated with a combination of CTX with irinotecan-based (56.0%) or CTX with oxaliplatin-based (37.8%) chemotherapy. The main characteristics, safety, response rate, and one year survival of this cohort are presented in the Table below in parallel with results obtained in pivotal trials. Conclusions: Despite differences in baseline characteristics between real-life and pivotal trials (such as ECOG status), the response rate and PFS were comparable in mCRC patients with wt KRAS treated with 1st-line CTX. The nature of adverse events was in-line with the trials but the frequency was lower probably owing to under-notification in real-life. [Table: see text]

scholarly journals MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ho Wai Derrick Siu ◽  
Niall Tebbutt ◽  
Lorraine Chantrill ◽  
Chris Karapetis ◽  
Christopher Steer ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Tumour Response ◽  
Trial Registration ◽  
First Line ◽  
The Impact

Abstract Background Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a “lighter” treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. Methods/design MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. Discussion MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12618000233224, prospectively registered 14 February 2018.

Analysis of survival and prognostic factors in metastatic colorectal cancer patients treated with first line bevacizumab.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15009-e15009 ◽  
Author(s):  
Nazim Demircan ◽  
Faysal Dane ◽  
Mehmet Akif Ozturk ◽  
Mehmet Besiroglu ◽  
Nalan Babacan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Prognostic Factors ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
First Line ◽  
Right Colon Cancer ◽  
Kras Status ◽  
Colorectal Cancer Patients ◽  
Left Colon Cancer

e15009 Background: Colorectal cancer is a major cause of mortality worldwide. Survival has been improved by usage of bevacizumab. Our study aimed to analyze survival and prognostic factors in metastatic colorectal cancer patients treated with first-line bevacizumab. Methods: Files of patients were examined retrospectively and 360 patients treated with first-line bevacizumab were included. Data regarding age, gender, family history, location of the primary, histopathology, KRAS status, surgery and chemotherapy were acquired from the files. Overall response rates (ORR) to chemotherapy, progression and exitus dates or dates of last examination were recorded. Median progression-free and overall survival (PFS and OS) were calculated. Survival was analyzed with Kaplan-Meier method. Log-rank test and Cox regression model were used for univariate and multivariate analysis, respectively. Results: 201 (%55,8) of the patients were male and 159 (%44,2) were female. Median age at the time of the diagnosis was 59.5. 260 patients (%72,2) had initially stage IV disease. KRAS was mutant in 125 patients (%34,7). Median PFS was 8.5 months, median OS was 25.3 months and ORR was %51,4. Median PFS was 8.2 and 9.5 months, median OS was 30.4 and 28.1 months, ORR was %62,6 and %58.4 in KRAS wild type and mutant groups, respectively. In patients with left colon cancer median PFS and OS (9.6 and 27.1 months) were superior compared to patients with right colon cancer (7.3 and 19.4 months) (p = 0.005 and 0.016, respectively). Location of the primary, histopathologic grade, primary surgery, metastasectomy and KRAS status affected overall survival significantly (p < 0.05) in univariate analysis. In multivariate analysis, histopathologic grade (p = 0.034) and metastasectomy (p = 0.001) were independent prognostic factors. Conclusions: In our study, response rates and survival of metastatic colorectal cancer patients treated with first-line bevacizumab were similar to previous studies. Left colon cancer patients had superior median PFS and OS compared to right colon cancer patients as shown in recent studies. Histopathologic grade and metastasectomy were independent prognostic factors in correlation with literature.

Influence of BRAF mutations and RAC1b/RAC1 mRNA expression ratio on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3553-3553
Author(s):  
Virginia Alonso-Espinaco ◽  
Maribel Marmol ◽  
Vicente Alonso ◽  
Pilar Escudero ◽  
Carlos Horndler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mrna Expression ◽  
Braf Mutation ◽  
Response Rate ◽  
Braf V600e ◽  
Significant Variable ◽  
First Line ◽  
Expression Ratio ◽  
Potential Marker

3553 Background: Metastatic colorectal cancer (mCRC) patients (pts), with BRAF tumor mutation (V600E) present poor overall survival (OS). RAC1b, a RAC1 spliced variant, is overexpressed in CRC, and impairs apoptosis by activation of nuclear-factor-KB. Because RAC1b and BRAF (V600E) are significantly associated in CRC (Matos et al, 2008), we evaluated if RAC1b/RAC1 mRNA expression ratio (RNA ER) was an independent prognostic factor in mCRC. Methods: We analyzed tumor samples from 186 mCRC pts, treated in first-line therapy with FOLFOX or CAPOX in three Spanish hospitals. We examined BRAF (V600E) mutational status by allelic discrimination, RAC1b/RAC1 expression ratio by mRNA RT-PCR (quantitative real time polymerase chain reaction) and mismatch repair (MMR) deficiency by microsatellite instability (MSI) analysis. We assessed whether these biomarkers were independently predictive of response rate (RR), progression free survival (PFS) or OS. Results: 88% of samples were informative for BRAF, 75% for MMR status and 85% for RAC1b/RAC1 (RNA ER). BRAF (V600E) was found in 7%, MSI-H in 5% and high >0.9-fold RAC1b/RAC1 (RNA ER) in 20% of pts. Five of 11 pts (46%) with BRAF mutation had high RAC1b/RAC1 (RNA ER) compared with 25/144 (18%) without BRAF mutation (p=0.036). All pts with BRAF mutation were MMR and none of the MSI-H pts, showed high RAC1b/RAC1 (RNA ER). Patients with low RAC1b/RAC1 (RNA ER) and BRAF WT had higher response rate (68% vs 43%; p=0.035). Response rate were not different according BRAF mutation (64% WT vs 63% mutant) (p=NS). The multivariate regression analysis identified ECOG PS (HR: 4.2 (CI 1.4-12.7) as a significant variable for PFS and LDH levels (HR: 2.26 (CI 1.3-3.8), PS (HR: 3.85 (CI 1.5-9.8) and high RAC1b/RAC1 (RNA ER) (HR: 2.6 (CI 1.1-5.9) for OS in WT BRAF pts. Conclusions: High RAC1b/RAC1 (RNA ER) constitutes a marker of poor OS and a potential marker of acquired chemo-resistance in WT BRAF mCRC pts treated with first-line oxaliplatin-based therapy.

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

2011 ◽  
Vol 29 (15) ◽  
pp. 2011-2019 ◽  
Author(s):  
Eric Van Cutsem ◽  
Claus-Henning Köhne ◽  
István Láng ◽  
Gunnar Folprecht ◽  
Marek P. Nowacki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Poor Prognosis ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Mutation Status ◽  
Kras Status ◽  
First Line Treatment

Purpose The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients and Methods Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. Results The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. Conclusion The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

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