FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. LBA391-LBA391 ◽  
Author(s):  
Thomas Brodowicz ◽  
Damir Vrbanec ◽  
Klaus Kaczirek ◽  
Tudor-Eliade Ciuleanu ◽  
Regina Knittelfelder ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Exon 2 ◽  
The Impact ◽  
Kras Exon

LBA391^ Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

scholarly journals A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients

2019 ◽  
Vol 121 (5) ◽  
pp. 378-383 ◽  
Author(s):  
Elena Elez ◽  
Carles Pericay ◽  
Manuel Valladares-Ayerbes ◽  
Inmaculada Bando ◽  
Maria Jose Safont ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Salvage Therapy ◽  
Phase 2 ◽  
Wild Type ◽  
Exon 2 ◽  
Phase 2 Study ◽  
Colorectal Cancer Patients ◽  
Kras Exon

scholarly journals Sequential cetuximab/bevacizumab therapy is associated with improved outcomes in patients with wild‐type KRAS exon 2 metastatic colorectal cancer

2019 ◽  
Vol 8 (7) ◽  
pp. 3437-3446 ◽  
Author(s):  
Hung‐Chih Hsu ◽  
Yu‐Chun Liu ◽  
Chuang‐Wei Wang ◽  
Wen-Chi Chou ◽  
Yu-Jen Hsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Wild Type ◽  
Exon 2 ◽  
Improved Outcomes ◽  
Kras Exon

Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3).

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA3506-LBA3506 ◽  
Author(s):  
Volker Heinemann ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
Alexander Kiani ◽  
Ursula Vehling-Kaiser ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Study Endpoint ◽  
Primary Study ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Duration Of Treatment ◽  
First Line Treatment

LBA3506 Background: In patients (pts) with KRAS, wild-type metastatic colorectal cancer (mCRC) a head to head comparison of anti-EGFR- and anti-VEGF-directed first-line therapy has not been reported with regard to the FOLFIRI backbone. The AIO KRK-0306 study was therefore designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in mCRC pts not pretreated for metastatic disease. Methods: Pts were randomized to FOLFIRI (Tournigand regimen) every two wks plus cetuximab (400 mg/m² day 1, followed by 250 mg/m² wkly = arm A) or bevacizumab (5 mg/kg every two wks = arm B). The intent-to-treat (ITT) population comprised all pts who had at least completed one application of therapy. While recruitment initially was independent of KRAS status, an amendment confined inclusion to KRAS wildtype (WT) tumors. Recruitment was completed in October 2012. The primary study endpoint was objective response rate (ORR, investigators read). Results: Among 735 pts of the ITT-population, KRAS-WT was identified in 592. Of these, 297 pts were randomized to arm A and 295 to arm B. Median age was 64 years, 66% of pts were male, and ECOG PS 0-1 was observed in 98% of pts. Median duration of treatment was 4.7 mo vs 5.3 mo, respectively. While in the ITT analysis, ORR was comparable in arms A vs B (62% vs 57%, odds ratio 1.249), a significant superiority was found for assessable pts in arm A. Median PFS of the ITT population was nearly identical (10.3 vs 10.4 mo, HR 1.04, p=0.69), however, overall survival (OS) showed a significantly better outcome in arm A vs arm B (28.8 vs 25.0 mo, HR 0.77, p=0.0164, 95% CI: 0.620-0.953). Sixty-day mortality was low in both arms (1.01% vs 2.71%). Conclusions: ORR was comparable between arms in the ITT analysis, but favored arm A in assessable pts. Significantly superior OS was observed in KRAS-WT patients receiving cetuximab plus FOLFIRI as first-line treatment. Clinical trial information: NCT00433927.

PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS776-TPS776 ◽  
Author(s):  
Takayuki Yoshino ◽  
Hiroyuki Uetake ◽  
Katsuya Tsuchihara ◽  
Kohei Shitara ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Phase Iii ◽  
Type I ◽  
Line Treatment ◽  
Wild Type ◽  
First Line ◽  
Exon 2 ◽  
First Line Treatment

TPS776 Background: Optimal combination of monoclonal antibody (anti-VEGF vs. anti-EGFR antibody) with standard chemotherapy as first-line treatment in patients (pts) with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. FIRE-3 study demonstrated a significant improvement in overall survival (OS) with anti-EGFR over bevacizumab in pts with KRAS exon 2 wild type mCRC, while CALGB 80405 study did not. PARADIGM study is designed to compare panitumumab vs. bevacizumab combined with mFOLFOX6 in pts with RAS wild-type chemotherapy-naive mCRC. Methods: Eligible pts are aged 20-79 years with ECOG performance status (PS) 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. 800 pts will be randomly assigned in a 1:1 ratio to mFOLFOX6 plus panitumumab or bevacizumab, and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil (5-FU) iv 400 mg/m2 at day 1, 5-FU civ 2400 mg/m2 at day 1-3, and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg at day 1 every two weeks. The primary endpoint is the OS; the study was designed to detect the OS hazard ratio of 0.76, with a one-sided type I error of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. One interim analysis is planned for the OS when approximately 70% of the targeted 570 events has been observed. Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations using tumor tissue and circulating tumor DNA (Study ID: NCT02394834). As of August 2015, 21 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02394795.

Sign in / Sign up

Export Citation Format

Share Document