Aflibercept in the treatment of metastatic colorectal cancer.
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ABSTRACT:
SUBMITTER: Wang TF
PROVIDER: S-EPMC3256978 | biostudies-other | 2012
REPOSITORIES: biostudies-other
Publications
Aflibercept in the treatment of metastatic colorectal cancer.
Wang Tzu-Fei TF Lockhart Albert Craig AC
Clinical Medicine Insights. Oncology 20120104
Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel a ...[more]
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Project description:The combination of cytotoxic chemotherapy and antiangiogenic agents has become a conventional treatment option for patients with metastatic colorectal cancer. Ziv-aflibercept is a fusion protein which acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF); it was approved in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin-containing fluoropyrimidine-based regimen. Herein we review the role of tumor angiogenesis as the rationale for antiangiogenic therapy, the clinical data associated with ziv-aflibercept, and its current role as a treatment option compared to other antiangiogenic agents, such as bevacizumab and regorafenib.
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Project description:Worldwide, colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Metastatic disease develops in more than half of the patients and carries a poor prognosis. Over the past three decades, significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). The development of new cytotoxic agents and the incorporation of target-specific agents in first-, second-, third-, and nowadays even fourth-line treatment has prolonged median overall survival up to 24-28 months. However, 5-year survival rates remain disappointingly low. This review summarizes the currently available cytotoxic treatment options for mCRC, and highlights the further emerging role of vascular endothelial growth factor (VEGF)-inhibiting strategies, emphasizing the role of aflibercept. Aflibercept is a recombinant fusion protein with high VEGF affinity, and is the second antiangiogenic agent to obtain registration in the treatment of mCRC.
| S-EPMC3873022 | biostudies-other
Project description:Inhibition of angiogenesis is an established adjunct in the treatment of metastatic colorectal cancer. Bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) A, improves clinical outcomes when added to standard chemotherapy for metastatic colorectal cancer. Unfortunately, the development of resistance is inevitable, and novel therapeutic strategies are needed. Aflibercept is an intravenously administered fusion protein of the human vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 extracellular domains. This antiangiogenic agent binds to VEGF A, VEGF B, and placental growth factor 1 (PlGF1) and PlGF2 with high affinity and inhibits downstream signaling. Common side effects of single agent aflibercept are similar to other antiangiogenic drugs and include hypertension, proteinuria, fatigue, and headache. Recent clinical data regarding the efficacy of aflibercept with standard chemotherapy for metastatic colorectal cancer, associated adverse events, and future areas of research are reviewed.
| S-EPMC3808572 | biostudies-literature
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| S-EPMC8345481 | biostudies-literature
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| S-EPMC6700318 | biostudies-literature
Project description:Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.
| S-EPMC6398889 | biostudies-literature
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Project description:BackgroundThe VELOUR study demonstrated a survival benefit for FOLFIRI + aflibercept versus FOLFIRI + placebo in metastatic colorectal cancer (mCRC) patients who progressed on oxaliplatin-based chemotherapy. Continued divergence of overall survival (OS) curves in the intension to treat (ITT) population, with the survival advantage persisting beyond median survival time, suggested subpopulations might have different magnitudes of survival gain. Additionally, 10% of patients within VELOUR had recurrence during or within 6 months of completing oxaliplatin-based adjuvant therapy (adjuvant fast relapsers)--previously identified as having poorer survival outcomes.MethodsTo determine which patients received the greatest benefit from FOLFIRI-aflibercept, a post hoc multivariate analysis of the VELOUR ITT population was conducted. Prognostic factors identified were applied to the ITT population, excluding adjuvant fast relapsers, to derive OS prognostic profiles.ResultsThe better efficacy subgroup was identified as patients within VELOUR exclusive of adjuvant fast relapsers and had performance status (PS) 0 with any number of metastatic site or PS 1 with <2 metastatic site. A significant improvement in efficacy outcome was observed with aflibercept in the better efficacy subgroup. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo:16.2 and 13.1 months (adjusted Hazard Ratio [HR] = 0.73; 95% confidence interval [CI]: 0.61-0.86); median progression free survival (PFS): 7.2 and 4.8 months (adjusted HR = 0.68; 95% CI: 0.57-0.80); and objective response rate (ORR): 24% versus 11% respectively. Poorer efficacy subgroup comprised of adjuvant fast relapsers or patients with PS2 or PS1 with ≥ 2 metastatic sites. In poorer efficacy subgroup, no benefit was seen with aflibercept. Median OS for FOLFIRI-aflibercept and FOLFIRI-placebo: 10.4 and 9.6 months (adjusted HR = 0.97; 95% CI: 0.78-1.21) respectively with no improvement in PFS or ORR.ConclusionThis analysis suggests that within VELOUR, patients in the better efficacy subgroup may derive enhanced benefit from treatment with FOLFIRI-aflibercept. These prognostic criteria may guide practitioners toward optimal use of targeted biologicals in appropriate second-line mCRC patients.
| S-EPMC4149045 | biostudies-literature
Project description:Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.
| S-EPMC6825011 | biostudies-literature
Project description:BackgroundSafety and effectiveness of aflibercept with 5-fluorouracil/levofolinate/irinotecan have not been reported in Japanese patients with metastatic colorectal cancer (mCRC) in a real-world clinical setting.MethodsThis post-marketing surveillance enrolled patients with un-resectable advanced or recurrent mCRC who were prescribed aflibercept from December 2017 to June 2019 in Japan. Data, collected up to 1 year from starting treatment, included patient background, safety, and effectiveness assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or physician's evaluation.ResultsOf 261 patients registered from 64 centers, 235 [53.2% male with a median age of 67 years (range 28-84)] received treatment and were included in the safety analysis. Aflibercept was received at 1st, 2nd, and ≥ 3rd line in 1.3%, 48.1%, and 50.2% of patients, respectively. Median number of treatment cycles was 6 (range 1-22) and relative dose intensity was 75.4% (range 14.3-101.8%). Adverse events (all grades) were reported in 88.5% of patients, including neutropenia (34.5%), proteinuria (24.7%), hypertension (17.0%), diarrhea (17.0%), and decreased appetite (15.3%). Three treatment-related deaths occurred by perforation of the digestive tract, pneumonia and gastrointestinal bleeding, and sudden death. The effectiveness analysis included 198 patients. Overall response rate was 6.1% (1st line, 0%; 2nd line, 10.1%; ≥ 3rd line, 2.1%) and disease control rate was 47.5% (1st line, 100%; 2nd line, 58.6%; ≥ 3rd line, 34.4%).ConclusionNo new risks of aflibercept were identified in real clinical practice. Effectiveness in patients at the 2nd line was consistent with previous reports.
| S-EPMC9823052 | biostudies-literature