Phase III Trial of Cetuximab, Bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX-Bevacizumab in Colorectal Cancer

Saltz, Leonard B.; Badarinath, Suprith; Dakhil, Shaker R.; Bienvenu, Bryan J.; Harker, W. Graydon; Birchfield, George; Tokaz, Laurence K.; Barrera, David; Conkling, Paul; O’Rourke, Mark Allen; Richards, Donald A.; Reidy, Diane Lauren; Solit, David B.; Vakiani, Efsevia; Capanu, M.; Scales, Amy; Zhan, Feng; Boehm, Kristi A.; Asmar, Lina; Cohn, Allen Lee

doi:10.1016/j.clcc.2011.05.006

Cited by 64 publications

(32 citation statements)

References 12 publications

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“…However, Phase III clinical trials have shown that the addition of cetuximab to bevacizumab and chemotherapy did not improve the survival of patients with advanced colorectal cancer compared to bevacizumab and chemotherapy alone. [22][23][24] These findings were unexpected as preclinical studies using combination therapy targeting both angiogenesis and EGFR showed encouraging results. [14][15][16][17] However, none of these early preclinical studies used the combination of bevacizumab and cetuximab.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 Therefore, the combination of chemotherapy with anti-EGFR antibodies has been studied in Phase III clinical trials. The combination of chemotherapy and bevacizumab with cetuximab 22,23 or panitumumab 24 did not result in improved progression-free survival compared to patients who received chemotherapy and bevacizumab alone. The study of Hecht et al 24 even showed a significantly reduced survival for patients receiving the combination of antibodies.…”

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confidence: 99%

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Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

Heskamp

Boerman

Molkenboer-Kuenen

et al. 2013

Intl Journal of Cancer

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Bevacizumab (antivascular endothelial growth factor [anti‐VEGF]) and cetuximab (antiepidermal growth factor receptor [anti‐EGFR]) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of bevacizumab on targeting of anti‐EGFR and insulin‐like growth factor 1 receptor (IGF‐1R) antibodies in tumors with single‐photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF‐1R‐expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled cetuximab or R1507, an anti‐IGF‐1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF‐1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 ± 1.1 %ID/g to 19.8 ± 5.7 %ID/g (p = 0.009) for untreated and bevacizumab‐treated tumors, respectively. A similar effect was found for 111In‐R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF‐1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti‐EGFR and anti‐IGF‐1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

Heskamp

Boerman

Molkenboer-Kuenen

et al. 2013

Intl Journal of Cancer

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“…According to the inclusion criteria of each trial, patients were required to have adequate hepatic, renal and hematological function. Underlying malignancies included colorectal cancer (eleven trials) [14,15,[22][23][24][25][26][27][28][29][30][31], non-small-cell lung cancer (seven trials) [32][33][34][35][36][37][38], head and neck cancer (four trials) [5,13,39,40], breast cancer (one trial) [41], urothelial carcinoma (one trial) [42], pancreatic cancer (one trial) [43] and esophagogastric cancer (one trial) [44].…”

Section: Search Resultsmentioning

confidence: 99%

Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis

Qi¹,

Zhang³

et al. 2014

BMC Medicine

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Background: Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are potentially life-threatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs. Methods: The databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies.

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“…It has been hypothesized that inconsistencies in outcomes with mAbs could also be related to their high specificity, which may make them susceptible to resistance through redundant signaling pathways (11). Attempts to broaden activity by combining different mAbs have not proven fruitful in mCRC (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

Tabernero

Garcia-Carbonero

Cassidy

et al. 2013

Clinical Cancer Research

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Purpose: This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).Experimental Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR ¼ 0.88; 95% CI, 0.64-1.23; P ¼ 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.Conclusion: This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.

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Phase III Trial of Cetuximab, Bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX-Bevacizumab in Colorectal Cancer

Cited by 64 publications

References 12 publications

Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

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