scholarly journals Aflibercept in the Treatment of Metastatic Colorectal Cancer

2012 ◽  
Vol 6 ◽  
pp. CMO.S7432 ◽  
Author(s):  
Tzu-Fei Wang ◽  
Albert Craig Lockhart
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
The Third ◽  
Common Cancer ◽  
The Us

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 angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept.

Phase III Trial of Infusional Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan (FOLFOXIRI) Compared With Infusional Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) As First-Line Treatment for Metastatic Colorectal Cancer: The Gruppo Oncologico Nord Ovest

2007 ◽  
Vol 25 (13) ◽  
pp. 1670-1676 ◽  
Author(s):  
Alfredo Falcone ◽  
Sergio Ricci ◽  
Isa Brunetti ◽  
Elisabetta Pfanner ◽  
Giacomo Allegrini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Peripheral Neurotoxicity ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Secondary Resection ◽  
Phase Iii Study ◽  
Grade 3

Purpose The Gruppo Oncologico Nord Ovest (GONO) conducted a phase III study comparing fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI [irinotecan 165 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 200 mg/m2 day 1, fluorouracil 3,200 mg/m2 48-hour continuous infusion starting on day 1, every 2 weeks]) with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI). Methods Selection criteria included unresectable metastatic colorectal cancer, age 18 to 75 years, and no prior chemotherapy for advanced disease. The primary end point was response rate (RR). Results A total of 244 patients were randomly assigned. An increase of grade 2 to 3 peripheral neurotoxicity (0% v 19%; P < .001), and grade 3 to 4 neutropenia (28% v 50%; P < .001) were observed in the FOLFOXIRI arm. The incidence of febrile neutropenia (3% v 5%) and grade 3 to 4 diarrhea (12% v 20%) were not significantly different. Responses, as assessed by investigators, were, for FOLFIRI and FOLFOXIRI, respectively, complete, 6% and 8%; and partial, 35% and 58%, (RR, 41% v 66%; P = .0002). RR confirmed by an external panel was 34% versus 60% (P < .0001). The R0 secondary resection rate of metastases was greater in the FOLFOXIRI arm (6% v 15%; P = .033, among all 244 patients; and 12% v 36%; P = .017 among patients with liver metastases only). Progression-free survival (PFS) and overall survival (OS) were both significantly improved in the FOLFOXIRI arm (median PFS, 6.9 v 9.8 months; hazard ratio [HR], 0.63; P = .0006; median OS, 16.7 v 22.6 months; HR, 0.70; P = .032). Conclusion The FOLFOXIRI regimen improves RR, PFS, and OS compared with FOLFIRI, with an increased, but manageable, toxicity in patients with metastatic colorectal cancer with favorable prognostic characteristics. Further studies of FOLFOXIRI in combination with targeted agents and in the neoadjuvant setting are warranted.

Ziv-aflibercept: A novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer

2013 ◽  
Vol 70 (21) ◽  
pp. 1887-1896 ◽  
Author(s):  
Clement Chung ◽  
Nisha Pherwani
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Performance Status ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Second Line ◽  
Patient Response ◽  
Line Setting

Abstract Purpose The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of ziv-aflibercept in combination therapy for metastatic colorectal cancer (mCRC) are reviewed. Summary Ziv-aflibercept (Zaltrap, Regeneron Pharmaceuticals and sanofi-aventis) is a novel recombinant fusion protein that targets the angiogenesis signaling pathway of tumor cells by blocking vascular endothelial growth factor (VEGF) receptors that play a key role in tumor growth and metastasis; it is a more potent VEGF blocker than bevacizumab. Ziv-aflibercept is approved by the Food and Drug Administration for use in combination with fluorouracil, irinotecan, and leucovorin (the FOLFIRI regimen) for second-line treatment of patients with mCRC who have disease progression during first-line oxaliplatin-based chemotherapy. A Phase III trial demonstrated that relative to FOLFIRI therapy alone, the use of ziv-aflibercept was associated with significantly improved patient response, overall survival, and progression-free survival in patients with good performance status at baseline, including some who had received prior bevacizumab therapy. The most common grade 3 or 4 adverse effects associated with ziv-aflibercept use in clinical studies were neutropenia, hypertension, and diarrhea; the U.S. product labeling warns of potential hemorrhage and other treatment-related risks. Conclusion Current clinical data are insufficient to directly compare ziv-aflibercept and bevacizumab when used with standard combination chemotherapy as first- or second-line regimens for mCRC. The role of ziv-aflibercept is currently limited to the second-line setting in combination with irinotecan-based regimens in mCRC patients who have not received irinotecan previously. The role of ziv-aflibercept in chemotherapy for other tumor types is yet to be determined.

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.

Neoadjuvant imatinib in patients with locally advanced GIST in the prospective BFR14 trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10551-10551 ◽  
Author(s):  
P. A. Cassier ◽  
A. A. Blesius ◽  
D. Perol ◽  
I. Ray-Coquard ◽  
A. Adenis ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Primary Tumor ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Primary Gist ◽  
Advanced Gist

10551 Background: The role of surgery in the management of patients with advanced gastrointestinal stromal tumors (GIST) in the era of imatinib mesylate (IM) remains unknown. We sought to assess the outcome of patients with locally advanced primary GIST tumors without metastases treated with IM in the neoadjuvant setting within the prospective BFR14 phase III trial. Methods: The data base of the BFR14 trial was searched for patients with locally advanced disease and no metastases. Patients with recurrent disease were excluded. Results: Twenty five patients (9 females, 16 males) met these criteria. Twenty patients were PS 0 or 1, primary tumor sites were: small intestine (n=7), peritoneum (n=7), rectum (n=4), stomach (n=4), esophagus (n=2), and pelvis (n=1). Nine of the 25 patients underwent surgical resection of the primary tumor after a median of 7.3 (range 3.4–12.1) months of treatment with IM. There was a significant improvement in progression-free survival (PFS) for patient who underwent surgical resection versus those who did not: median PFS: 28.7 month vs 12.9 months respectively (p=0.0463) this benefit did not however translate into a significant benefit in overall survival (OS), although the trend favoured the resected group: median OS median not reached vs 29.4 months (p=0.0677). Conclusions: Surgery may increase progression-free survival in patients with locally advanced GIST who become resectable following treatment with IM. [Table: see text]

A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3519-3519 ◽  
Author(s):  
Daisuke Takahari ◽  
Yasuhide Yamada ◽  
Hiroshi Matsumoto ◽  
Hideo Baba ◽  
Kazuhiro Yoshida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Open Label ◽  
Phase Iii Trial ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

3519 Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.

Capecitabine, Bevacizumab, and Mitomycin in First-Line Treatment of Metastatic Colorectal Cancer: Results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study

2010 ◽  
Vol 28 (19) ◽  
pp. 3191-3198 ◽  
Author(s):  
Niall C. Tebbutt ◽  
Kate Wilson ◽  
Val J. Gebski ◽  
Michelle M. Cummins ◽  
Diana Zannino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Free Survival ◽  
Treatment Regimens ◽  
The United Kingdom

Purpose To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. Patients and Methods Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). Results Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. Conclusion Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL.

On-treatment progression-free survival analysis of ziv-aflibercept/FOLFIRI treatment within 28 days of end of treatment in metastatic colorectal cancer: Updated efficacy results from the VELOUR study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3573-3573
Author(s):  
David Ferry ◽  
Tae Won Kim ◽  
Tormod Kyrre Guren ◽  
Jayesh Desai ◽  
Luis Marcelo Villanueva ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Rank Test ◽  
Free Survival

3573 Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent ziv-aflibercept (known as aflibercept outside the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate vs placebo/FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive ziv-aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test and were stratified by Eastern Cooperative Oncology Group performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment analysis showed significantly increased PFS for patients treated with ziv-aflibercept/FOLFIRI compared with placebo/FOLFIRI (Table). More patients were censored in the ziv-aflibercept arm due to adverse events. Conclusions: The on-treatment PFS analysis demonstrates a significantly improved treatment effect of the addition of ziv-aflibercept to FOLFIRI (HR=0.55) over what was observed in the primary analysis suggesting that continuing treatment with ziv-aflibercept up to disease progression provides additional benefit. Clinical trial information: NCT00561470. [Table: see text]

scholarly journals Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E–Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study

2019 ◽  
Vol 37 (17) ◽  
pp. 1460-1469 ◽  
Author(s):  
Eric Van Cutsem ◽  
Sanne Huijberts ◽  
Axel Grothey ◽  
Rona Yaeger ◽  
Pieter-Jan Cuyle ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Phase Iii ◽  
Cancer Trial ◽  
Free Survival

PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non– BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study

2008 ◽  
Vol 26 (12) ◽  
pp. 2013-2019 ◽  
Author(s):  
Leonard B. Saltz ◽  
Stephen Clarke ◽  
Eduardo Díaz-Rubio ◽  
Werner Scheithauer ◽  
Arie Figer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Placebo Group ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival

PurposeTo evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).Patients and MethodsPatients with MCRC were randomly assigned, in a 2 × 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS).ResultsA total of 1,401 patients were randomly assigned in this 2 × 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials.ConclusionThe addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

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