scholarly journals Management of BRAF Gene Alterations in Metastatic Colorectal Cancer: From Current Therapeutic Strategies to Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Hiroyuki Takeda ◽  
Yu Sunakawa
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Therapeutic Strategies ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Future Perspectives ◽  
Poor Prognostic Factor

BRAF mutations constitute an important poor prognostic factor in metastatic colorectal cancer (mCRC) and the development of treatments in this context is of great necessity to prolong patient survival. Although the association between BRAF mutations and microsatellite instability (MSI) has been known for several years, previous clinical trials have revealed that the former has a limited prognostic impact and that immune checkpoint inhibitors offer a significant survival benefit to mCRC patients with both characteristics. Furthermore, the genomic classification of BRAF mutations according to their molecular functions enables greater understanding of the characteristics of mCRC patients with BRAF mutations, with therapeutic strategies based on this classification made more ideal to improve poor prognosis through the delivery of targeted therapies. Recently, a phase III trial was conducted in previously treated mCRC patients with BRAF V600E–mutated tumors and revealed that the combination therapy approach of BRAF inhibition and anti–epidermal growth factor receptor antibody therapy with or without MEK inhibition was more efficacious than standard chemotherapy alone. This review discusses current treatment strategies and future perspectives in BRAF-mutated mCRC.

scholarly journals The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 137
Author(s):  
Gianluca Mauri ◽  
Erica Bonazzina ◽  
Alessio Amatu ◽  
Federica Tosi ◽  
Katia Bencardino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Braf Inhibitor ◽  
Current Treatment ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
Poor Prognostic Factor

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen

2012 ◽  
Vol 30 (28) ◽  
pp. 3499-3506 ◽  
Author(s):  
Eric Van Cutsem ◽  
Josep Tabernero ◽  
Radek Lakomy ◽  
Hans Prenen ◽  
Jana Prausová ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Survival Times ◽  
Previously Treated

Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. Conclusion Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.

Consensus molecular subtypes and RAS status as biomarker of treatment intensity with fluoropyrimidine, bevacizumab, and irinotecan in metastatic colorectal cancer (XELAVIRI, AIO KRK 0110).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
Arndt Stahler ◽  
Volker Heinemann ◽  
Veronika Schuster ◽  
Annabel Helga Sophie Alig ◽  
Laura Elisabeth Fischer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regression Model ◽  
Metastatic Colorectal Cancer ◽  
Cox Regression ◽  
Molecular Subtypes ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Multinomial Regression ◽  
Multinomial Regression Model

3552 Background: Prognostic biomarkers beside RAS/BRAF status are necessary to identify metastatic colorectal cancer (mCRC) patients who benefit from combined (COMB) versus sequential (SEQ) treatment with fluoropyrimidine, bevacizumab and irinotecan (randomized phase III XELAVIRI trial). Methods: mRNA was extracted from formalin-fixed paraffin embedded (FFPE) tumor tissue of 337 patients, gene expression was measured by the Nanostring PanCancer Progression Panel. Consensus molecular subtypes (CMS) classification was re-derived using a multinomial regression model. Data of Guinney et al. (Nat. Med. 2015. 21:1350-6) and FIRE-3 served as training and validation set. RAS/BRAF MUT were assessed by pyrosequencing. Median overall (OS) and progression free survival (PFS), hazard ratios (HR) and 95% confidence interval (CI) were estimated by Kaplan-Meier method and univariate Cox regression. Results: The multinomial regression model employed in the present analysis correctly predicted CMS labels in 98.3 % of the original Guinney- and 100.0 % of FIRE-3 population. In XELAVIRI, CMS subgroups were predicted as follows: CMS1: n = 62 (18.4 %); CMS2: n = 174 (51.6 %); CMS3: n = 9 (2.7 %); CMS4: n = 92 (27.3 %). A general prognostic impact of CMS was not observed when all patients were analysed. In RAS/BRAF WT mCRC patients, substantial benefit of COMB versus SEQ treatment was shown for OS and PFS in CMS2 and CMS4, but not in CMS1. Conversely, OS was significantly longer for COMB treatment in patients with RAS MUT and CMS1 mCRC, while SEQ treatment was not inferior in RAS MUT and CMS2 or CMS4 subgroups (see TABLE). Additional data for overall response rates, early tumor shrinkage and sidedness might be presented at the meeting. Conclusions: This retrospective analysis of XELAVIRI suggests that CMS may serve as biomarker that predicts response to initially combined versus less intensive sequential chemotherapy in patients with RAS/BRAF WT mCRC.[Table: see text]

scholarly journals BRAF, MEK and EGFR inhibition as treatment strategies in BRAF V600E metastatic colorectal cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592199297
Author(s):  
Javier Ros ◽  
Iosune Baraibar ◽  
Emilia Sardo ◽  
Nuria Mulet ◽  
Francesc Salvà ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Therapeutic Strategies ◽  
Braf V600e ◽  
Driver Mutations ◽  
Braf Mutations ◽  
Egfr Inhibition ◽  
Braf Inhibition

Introduction: BRAF driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of BRAF kinase and sustained RAS/RAF/MEK/ERK pathway signaling. BRAF mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with BRAF inhibition in BRAF mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates. Areas covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and EGFR signaling in BRAF V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented. Expert opinion: Exploiting knowledge of the mechanisms of resistance to BRAF inhibitors has been crucial to developing effective therapeutic strategies in BRAF-V600E mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated BRAF V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.

EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer

2008 ◽  
Vol 26 (14) ◽  
pp. 2311-2319 ◽  
Author(s):  
Alberto F. Sobrero ◽  
Joan Maurel ◽  
Louis Fehrenbacher ◽  
Werner Scheithauer ◽  
Yousif A. Abubakr ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Study Groups ◽  
Phase Iii ◽  
Severe Toxicity ◽  
Open Label ◽  
Number Of Patients ◽  
Post Trial

PurposeTo determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.Patients and MethodsThis multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m2day 1 followed by 250 mg/m2weekly) plus irinotecan (350 mg/m2every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).ResultsMedian OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms.ConclusionCetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

scholarly journals Therapeutic Targets of KRAS in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6233
Author(s):  
Shafia Rahman ◽  
Shimon Garrel ◽  
Michael Gerber ◽  
Radhashree Maitra ◽  
Sanjay Goel
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Unmet Need ◽  
Therapeutic Strategies ◽  
Personalized Therapy ◽  
Prognostic Impact ◽  
Kras Mutations ◽  
Therapy Approach ◽  
Predictive Role

Patients with metastatic colorectal cancer have a 5-year overall survival of less than 10%. Approximately 45% of patients with metastatic colorectal cancer harbor KRAS mutations. These mutations not only carry a predictive role for the absence of response to anti-EGFR therapy, but also have a negative prognostic impact on the overall survival. There is a growing unmet need for a personalized therapy approach for patients with KRAS-mutant colorectal cancer. In this article, we focus on the therapeutic strategies targeting KRAS- mutant CRC, while reviewing and elaborating on the discovery and physiology of KRAS.

scholarly journals Emerging Treatment Options for the Management of Metastatic Colorectal Cancer

2020 ◽  
Vol 18 (7.5) ◽  
pp. 949-952
Author(s):  
Dustin A. Deming
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Performance Status ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Nccn Guidelines ◽  
Molecular Alterations ◽  
Molecular Landscape

An improved understanding of the molecular landscape of metastatic colorectal cancer (CRC) has opened the door for new treatment options. Clinicians should test for molecular alterations that predict resistance to epidermal growth factor receptor (EGFR) inhibitors, such as KRAS and NRAS, and additionally clinically actionable alterations, including BRAF V600 mutations, HER2 amplification, NTRK fusions, and mismatch repair deficiency. Improved outcomes can be achieved with precision treatment strategies for the various CRC subtypes, although clinical features, such as tumor bulk and patient performance status, still help to guide treatment choice. Immune therapies have also produced impressive results in patients with mismatch repair–deficient/microsatellite instability–high tumors. These newer approaches were recently incorporated into the NCCN Guidelines for Colon and Rectal Cancers. In the future, these newer approaches may be used in earlier treatment settings.

scholarly journals Chemotherapy With or Without Anti-EGFR Agents in Left- and Right-Sided Metastatic Colorectal Cancer: An Updated Meta-Analysis

2019 ◽  
Vol 17 (7) ◽  
pp. 805-811 ◽  
Author(s):  
Zi-Xian Wang ◽  
Hao-Xiang Wu ◽  
Ming-Ming He ◽  
Ying-Nan Wang ◽  
Hui-Yan Luo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Meta Analysis ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Phase Iii ◽  
Left And Right ◽  
Meta Analyses

AbstractBackground: Previous meta-analyses have suggested primary tumor location as a predictive factor for efficacy of anti–epidermal growth factor receptor (EGFR) therapies in patients with metastatic colorectal cancer (mCRC). However, the recent phase III TAILOR trial addressing this issue was not included in those analyses. This meta-analysis incorporated data from the TAILOR trial to evaluate the efficacy of chemotherapy plus anti-EGFR agents (cetuximab [Cet] or panitumumab [Pani]) versus chemotherapy alone for RAS wild-type (wt) right- and left-sided mCRC. Patients and Methods: A PubMed-based literature search was conducted to identify randomized controlled trials (RCTs) studying the additional efficacy of Cet/Pani in combination with chemotherapy versus chemotherapy alone in RAS wt left- and right-sided mCRC. Study-level pooled analyses of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for objective response rate (ORR) were performed. Results: Three first-line RCTs (CRYSTAL, PRIME, and TAILOR) and one second-line RCT (20050181) were included. Significant OS benefits from Cet/Pani were observed in the left-sided (HR, 0.76; 95% CI, 0.66–0.86) but not right-sided subgroups (HR, 0.99; 95% CI, 0.78–1.27). However, the addition of Cet/Pani to chemotherapy significantly improved PFS and ORR in both the left-sided (HR, 0.70; 95% CI, 0.57–0.86, and OR, 3.28; 95% CI, 1.95–5.51, respectively) and right-sided subgroups (HR, 0.76; 95% CI, 0.59–0.99, and OR, 1.78; 95% CI, 1.08–2.93, respectively). Conclusions: The addition of Cet/Pani to chemotherapy significantly benefits PFS and ORR in patients with RAS wt right-sided mCRC, indicating that anti-EGFR therapies may remain an option for selected patients.

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