scholarly journals BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer—A Case Series Study Target Therapy of BRAF-Mutated mCRC

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1339
Author(s):  
Jen-Hao Yeh ◽  
Hsiang-Lin Tsai ◽  
Yen-Cheng Chen ◽  
Ching-Chun Li ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Case Series ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Free Survival ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1–26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1–2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.

scholarly journals Phase II study of lenvatinib for metastatic colorectal cancer refractory to standard chemotherapy: the LEMON study (NCCH1503)

ESMO Open ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. e000776 ◽  
Author(s):  
Satoru Iwasa ◽  
Natsuko Okita ◽  
Aya Kuchiba ◽  
Gakuto Ogawa ◽  
Mamiko Kawasaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Vegf Receptor ◽  
Free Survival

BackgroundLenvatinib inhibits tyrosine kinases, including vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor alpha, RET proto-oncogene and KIT proto-oncogene, receptor tyrosine kinase. We assessed the efficacy and safety of lenvatinib in patients with metastatic colorectal cancer after failure of standard chemotherapies.Patients and methodsThis was an open-label, single centre, single-arm, phase 2 study. Eligible patients had unresectable metastatic colorectal adenocarcinoma, refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, trifluridine/tipiracil, anti-VEGF therapy and anti-epidermal growth factor receptor therapy (for tumours with wild-type RAS). Patients were treated with oral lenvatinib at 24 mg one time a day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was centrally assessed disease control rate. Secondary endpoints included safety, response rate, progression-free survival and overall survival. The planned sample size was 30 patients to expect a disease control rate of 60% with a threshold disease control rate of 35%, one-sided alpha of 5% and power of 80%ResultsBetween 24 October 2016 and 23 January 2018, 30 patients were enrolled; 11 (37%) and 19 (63%) had received 3 or ≥4 lines of prior chemotherapy for metastatic disease, respectively. The median number of lenvatinib cycles was 4 (range 1–13). The centrally assessed disease control rate was 70.0% (21/30, 90% CI 53.5% to 83.4%, one-sided p=0.0001); 2 patients had a partial response and 19 had a stable disease. Median progression-free survival was 3.6 months (95% CI 2.6 to 3.7). Median overall survival was 7.4 months (95% CI 6.4 to 10.8). The most common grade ≥3 adverse events were hypertension (53%), thrombocytopenia (10%), increased alanine aminotransferase and anorexia (7% each).ConclusionsLenvatinib showed promising clinical activity and was tolerated in patients with metastatic colorectal cancer after failure of standard chemotherapies.Trial registration numberUMIN-CTR, UMIN000023446 and JAMCCT-CTR, JMA-IIA00261.

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.

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.

scholarly journals Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer

2010 ◽  
Vol 14 (Suppl 2) ◽  
pp. 47-53
Author(s):  
S Whyte ◽  
A Pandor ◽  
M Stevenson ◽  
A Rees
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Absolute Difference ◽  
First Line ◽  
Open Label ◽  
Open Label Study ◽  
Free Survival

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer based on the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one phase III, multicentre, multinational, randomised, open-label study (NO16966 trial). This two-arm study was originally designed to demonstrate the non-inferiority of oral capecitabine plus oxaliplatin (XELOX) compared with 5-fluorouracil plus folinic acid plus oxaliplatin (FOLFOX)-4 in adult patients with histologically confirmed metastatic colorectal cancer who had not previously been treated. Following randomisation of 634 patients, the open-label study was amended to include a 2 × 2 factorial randomised (partially blinded for bevacizumab) phase III trial with the coprimary objective of demonstrating superiority of bevacizumab in combination with chemotherapy compared with chemotherapy alone. Measured outcomes included overall survival, progression-free survival, response rate, adverse effects of treatment and health-related quality of life. The manufacturer’s primary pooled analysis of superiority (using the intention-to-treat population) showed that after a median follow-up of 28 months, the addition of bevacizumab to chemotherapy significantly improved progression-free survival and overall survival compared with chemotherapy alone in adult patients with histologically confirmed metastatic colorectal cancer who were not previously treated [median progression-free survival 9.4 vs 7.7 months (absolute difference 1.7 months); hazard ratio (HR) 0.79, 97.5% confidence interval (CI) 0.72 to 0.87; p = 0.0001; median overall survival 21.2 vs 18.9 months (absolute difference 2.3 months); HR 0.83, 97.5% CI 0.74 to 0.93; p = 0.0019]. The NO16966 trial was of reasonable methodological quality and demonstrated a significant improvement in both progression-free survival and overall survival when bevacizumab was added to XELOX or FOLFOX. However, the size of the actual treatment effect of bevacizumab is uncertain. The ERG believed that the modelling structure employed was appropriate, but highlighted several key issues and areas of uncertainty. At the time of writing, NICE was yet to issue the guidance for this appraisal.

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