Bevacizumab Avastin Research Articles

The combination of bevacizumab/Avastin and erlotinib/Tarceva is relevant for the treatment of metastatic renal cell carcinoma: the role of a synonymous mutation of the EGFR receptor.

Metastatic clear cell renal cell carcinomas (mRCC) over-express the vascular endothelial growth factor (VEGF). Hence, the anti-VEGF antibody bevacizumab/Avastin (BVZ) combined with interferon alpha (IFN) was approved for the treatment of mRCC. However, approval was lost in July 2016 due to the absence of sustained efficacy. We previously showed that BVZ accelerates tumor growth in experimental models of mRCC in mice, results in part explained by down-regulation of the phospho tyrosine phosphatase receptor kappa (PTPRκ) in tumor cells. The epidermal growth factor receptor (EGFR) is a direct target of PTPRκ. Its down-regulation leads to constitutive activation of EGFR, an observation which prompted us to test the effect of the EGFR inhibitor erlotinib/Tarceva (ERLO) in addition to BVZ/IFN. The influence of the long non-coding RNA, EGFR-AS1, on ERLO efficacy was also addressed.Methods: The effect of BVZ/IFN/ERLO was tested on the growth of experimental tumors in nude mice. The presence of germline mutation in the EGFR was evaluated on cell lines and primary RCC cells. In vitro translation and transfections of expression vectors coding the wild-type or the EGFR mutated gene in HEK-293 cells were used to test the role of EGFR mutation of the ERLO efficacy. Correlation between EGFR/EGFR-AS1 expression and survival was analyzed with an online available data base (TCGA).Results: Tumor growth was strongly reduced by the triple combination BVZ/IFN/ERLO and linked to reduced levels of pro-angiogenic/pro-inflammatory cytokines of the ELR+CXCL family and to subsequent inhibition of vascularization, a decreased number of lymphatic vessels and polarization of macrophages towards the M1 phenotype. Cells isolated from surgical resection of human tumors presented a range of sensitivity to ERLO depending on the presence of a newly detected mutation in the EGFR and to the presence of EGFR-AS1.Conclusions: Our results point-out that the BVZ/IFN/ERLO combination deserves testing for the treatment of mRCC that have a specific mutation in the EGFR.

Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies.

Tumor growth relies on oxygen and blood supply depending on neo-vascularization. This process is mediated by the Vascular Endothelial Growth Factor (VEGF) in many tumors. This paradigm has led to the development of specific therapeutic approaches targeting VEGF or its receptors. Despite their promising effects, these strategies have not improved overall survival of patients suffering from different cancers compared to standard therapies. We hypothesized that the existence of anti-angiogenic forms of VEGF VEGFxxxb which are still present in many tumors limit the therapeutic effects of the anti-VEGF antibodies bevacizumab/Avastin (BVZ). To test this hypothesis, we generated renal cell carcinoma cells (RCC) expressing VEGF165b. The incidence of tumors xenografts generated in nude mice and their growth were inferior to those obtained with control cells. Whereas BVZ had no effect on control tumors, it slowed-down the growth of tumor generated with VEGF165b expressing cells. A prophylactic immunization against the domain discriminating VEGF from VEGFxxxb isoforms inhibited the growth of tumor generated with two different syngenic tumor cell lines (melanoma (B16 cells) and RCC (RENCA cells)). Purified immunoglobulins from immunized mice also slowed-down tumor growth of human RCC xenografts in nude mice, producing a potent effect compared to BVZ in this model. Furthermore, down-regulating the serine-arginine-rich splicing factor 1 (SRSF1) or masking SRSF1 binding sites by 2’O-Methyl RNA resulted in the increase of the VEGFxxxb/VEGF ratio. Therefore, a vaccine approach, specific antibodies against pro-angiogenic forms of VEGF, or increasing the VEGFxxxb/VEGF ratio may represent new prophylactic or pro-active anti-cancer strategies.

Molecular Imaging of Antiangiogenic Agents

Many novel antiangiogenic agents are currently in various phases of clinical testing. These agents tend to be cytostatic, and therefore few responses are observed with conventional imaging by computerized tomography. Furthermore, toxicity with these agents is seen when the maximum-tolerated dose is combined with chemotherapy. Hence, there is a need to develop imaging strategies that can determine the minimum and optimum biologically active doses. There is increasing awareness of the need to obtain evidence of drug activity through the use of surrogate markers of the biologic mechanism of action during early clinical trials, in addition to determining the pharmacokinetics, toxicity profile, and maximum-tolerated dose. One of the major impediments to the rapid development of antiangiogenic agents in the past has been the lack of validated assays capable of measuring an antiangiogenic effect directly in patients. Recently, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has emerged as a useful technique for noninvasive imaging of tumor vasculature in preclinical and clinical models. The problem of tumor heterogeneity remains to be addressed. The major challenge is the standardization of the technique worldwide for the purpose of early clinical studies that are likely to be multicenter. Convincing data on correlations between changes observed through molecular imaging and changes in tumor angiogenesis, and hence tumor biology, are still lacking. Whether this would translate into a survival advantage remains to be seen. The ultimate test of the surrogate biological end points determined by molecular imaging will occur in randomized phase III trials. Results of the first randomized trial that showed a survival advantage in favor of antiangiogenic agents were released at the American Society of Clinical Oncology meeting in 2003. There it was reported that the combination of 5-fluorouracil, leucovorin, and irinotecan (Camptosar; Pfizer Pharmaceuticals; New York, NY) with anti-vascular endothelial growth factor antibody (bevacizumab-Avastin; Genentech, Inc.; South San Francisco, CA) was superior to the chemotherapy regimen alone when used to treat patients with metastatic colorectal cancer. However, until further phase III clinical trials confirm these results, surrogate end points of clinical efficacy of the newer agents are urgently needed so that development of ineffective drugs can be halted early. This review briefly discusses the role of molecular imaging in general, and DCE-MRI in particular, in relation to treatment with antiangiogenic agents and highlights some of the difficulties encountered in this area.

Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab

3702 Background. Bevacizumab [Avastin (BV)] is a humanized monoclonal antibody directed against vascular endothelial growth factor. A recent randomized, double-blinded, Phase III trial showed that the addition of BV to bolus irinotecan, 5-FU, leucovorin (IFL) increased survival compared with bolus IFL alone in subjects with metastatic colorectal cancer (CRC). Since BV is an antiangiogenic agent, we undertook an analysis of wound healing in subjects treated with BV plus bolus IFL and BV plus 5-FU/leucovorin versus those receiving bolus IFL alone. Methods. Wound healing and bleeding complications were analyzed within the 60-day post-operative period in subjects who underwent surgery during the study period of the trial. Many of these surgeries were emergent, particularly for bowel obstruction. Adverse events reported as abnormal healing, wound dehiscence, ecchymosis, and hemorrhage following major surgery (requiring general anesthesia) were studied. Results. During the course of the study, 25 subjects in the bolus IFL arm underwent major surgery compared with 40 subjects in the BV plus bolus IFL arm and 15 subjects in the BV plus 5-FU/LV arm. Of these subjects, 0 in the bolus IFL arm, 4 in BV plus bolus IFL arm, and 1 in the BV plus 5-FU/LV arm had post-operative wound healing or bleeding complications. These adverse events were anastomotic bowel dehiscence (2 subjects), thoracotomy wound dehiscence (1), hemothorax following lung resection (1), and ecchymosis and bleeding along a surgical incision after revision of a colostomy (1). Prior to their complication, these subjects had been off BV therapy for 13, 89, 32, 47, and 39 days, respectively. Discussion. This study suggests that metastatic CRC subjects who undergo surgery after having received BV have a small incidence of wound healing and/or bleeding complications within 60 days after surgery. Investigators should consider the risks and benefits of surgery when subjects are receiving treatment with BV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.

Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab

3702 Background. Bevacizumab [Avastin (BV)] is a humanized monoclonal antibody directed against vascular endothelial growth factor. A recent randomized, double-blinded, Phase III trial showed that the addition of BV to bolus irinotecan, 5-FU, leucovorin (IFL) increased survival compared with bolus IFL alone in subjects with metastatic colorectal cancer (CRC). Since BV is an antiangiogenic agent, we undertook an analysis of wound healing in subjects treated with BV plus bolus IFL and BV plus 5-FU/leucovorin versus those receiving bolus IFL alone. Methods. Wound healing and bleeding complications were analyzed within the 60-day post-operative period in subjects who underwent surgery during the study period of the trial. Many of these surgeries were emergent, particularly for bowel obstruction. Adverse events reported as abnormal healing, wound dehiscence, ecchymosis, and hemorrhage following major surgery (requiring general anesthesia) were studied. Results. During the course of the study, 25 subjects in the bolus IFL arm underwent major surgery compared with 40 subjects in the BV plus bolus IFL arm and 15 subjects in the BV plus 5-FU/LV arm. Of these subjects, 0 in the bolus IFL arm, 4 in BV plus bolus IFL arm, and 1 in the BV plus 5-FU/LV arm had post-operative wound healing or bleeding complications. These adverse events were anastomotic bowel dehiscence (2 subjects), thoracotomy wound dehiscence (1), hemothorax following lung resection (1), and ecchymosis and bleeding along a surgical incision after revision of a colostomy (1). Prior to their complication, these subjects had been off BV therapy for 13, 89, 32, 47, and 39 days, respectively. Discussion. This study suggests that metastatic CRC subjects who undergo surgery after having received BV have a small incidence of wound healing and/or bleeding complications within 60 days after surgery. Investigators should consider the risks and benefits of surgery when subjects are receiving treatment with BV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.

Lack of effect of bevacizumab on wound healing/bleeding complications when given 28–60 days following primary cancer surgery

3530 Background: Bevacizumab [Avastin (BV)] is a humanized monoclonal antibody directed against vascular endothelial growth factor. A recent randomized, double-blinded, Phase III trial showed that addition of Avastin to chemotherapy (bolus irinotecan, 5-FU, leucovorin -IFL) increased survival compared with IFL alone. Antiangiogenic therapy has previously shown delay in wound healing in preclinical models. Therefore, we undertook an analysis of wound healing in subjects receiving BV plus bolus IFL and BV plus 5-FU/LV versus those that received bolus IFL alone. Methods: Wound healing and bleeding complications were analyzed in subjects who underwent primary cancer surgery (i.e., colonic or rectal resection to remove tumor) within 28–60 days of starting study treatment. Sixty-day post-operative adverse events reported as abnormal healing, wound dehiscence, delayed wound healing, bowel perforation, fistula, abscess, and hemorrhage were studied. Results: A total of 150 subjects receiving BV plus bolus IFL and 37 subjects receiving BV plus 5-FU/LV underwent prior cancer surgery before initial use of BV plus chemotherapy compared with 155 subjects who received bolus IFL alone. The incidence of Grade 3 / 4 wound healing / bleeding in subjects was 1 subject (0.65 %) in the bolus IFL arm alone, 3 subjects (2.0 %) in the BV + bolus IFL arm, and no subjects (0 %) in the BV + 5-FU/LV arm. Conclusions:These results suggest that surgery in subjects within 28–60 days before the initial use of Avastin does not lead to a significantly increased incidence of wound healing / bleeding complications. These results are encouraging for the planned evaluation of Avastin in adjuvant colorectal trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Bais; Genentech; Pfizer; USON Genentech Genentech Genentech; GlaxoSmithKline; Pfizer; Roche

Lack of effect of bevacizumab on wound healing/bleeding complications when given 28–60 days following primary cancer surgery

3530 Background: Bevacizumab [Avastin (BV)] is a humanized monoclonal antibody directed against vascular endothelial growth factor. A recent randomized, double-blinded, Phase III trial showed that addition of Avastin to chemotherapy (bolus irinotecan, 5-FU, leucovorin -IFL) increased survival compared with IFL alone. Antiangiogenic therapy has previously shown delay in wound healing in preclinical models. Therefore, we undertook an analysis of wound healing in subjects receiving BV plus bolus IFL and BV plus 5-FU/LV versus those that received bolus IFL alone. Methods: Wound healing and bleeding complications were analyzed in subjects who underwent primary cancer surgery (i.e., colonic or rectal resection to remove tumor) within 28–60 days of starting study treatment. Sixty-day post-operative adverse events reported as abnormal healing, wound dehiscence, delayed wound healing, bowel perforation, fistula, abscess, and hemorrhage were studied. Results: A total of 150 subjects receiving BV plus bolus IFL and 37 subjects receiving BV plus 5-FU/LV underwent prior cancer surgery before initial use of BV plus chemotherapy compared with 155 subjects who received bolus IFL alone. The incidence of Grade 3 / 4 wound healing / bleeding in subjects was 1 subject (0.65 %) in the bolus IFL arm alone, 3 subjects (2.0 %) in the BV + bolus IFL arm, and no subjects (0 %) in the BV + 5-FU/LV arm. Conclusions:These results suggest that surgery in subjects within 28–60 days before the initial use of Avastin does not lead to a significantly increased incidence of wound healing / bleeding complications. These results are encouraging for the planned evaluation of Avastin in adjuvant colorectal trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Bais; Genentech; Pfizer; USON Genentech Genentech Genentech; GlaxoSmithKline; Pfizer; Roche

Bevacizumab in combination with 5-FU/leucovorin improves survival in patients with metastatic colorectal cancer: A combined analysis

3616 Background: Bevacizumab [Avastin (BV)], a recombinant, humanized monoclonal antibody against VEGF, improves survival in combination with chemotherapy for first line treatment of metastatic colorectal cancer (CRC). In a randomized, placebo-controlled phase III study, the addition of BV to irinotecan/5-FU/Leucovorin (IFL) resulted in significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.6 months to 20.3 months). BV has been combined with 5-FU/leucovorin (LV) alone in 3 randomized studies (see table). In the phase III study, a third treatment arm of BV/5-FU/LV was included until the safety of IFL/BV was demonstrated in a pre-specified analysis. BV/5-FU/LV has been studied in 2 randomized phase II studies. In the larger phase II study, patient characteristics were similar to those in the phase III study with the exception that median age was 71 compared with 60 years, and ECOG performance status ≥ 1 was 72% versus 41% of patients. Combining the patien...

Bevacizumab in combination with 5-FU/leucovorin improves survival in patients with metastatic colorectal cancer: A combined analysis

3616 Background: Bevacizumab [Avastin (BV)], a recombinant, humanized monoclonal antibody against VEGF, improves survival in combination with chemotherapy for first line treatment of metastatic colorectal cancer (CRC). In a randomized, placebo-controlled phase III study, the addition of BV to irinotecan/5-FU/Leucovorin (IFL) resulted in significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.6 months to 20.3 months). BV has been combined with 5-FU/leucovorin (LV) alone in 3 randomized studies (see table). In the phase III study, a third treatment arm of BV/5-FU/LV was included until the safety of IFL/BV was demonstrated in a pre-specified analysis. BV/5-FU/LV has been studied in 2 randomized phase II studies. In the larger phase II study, patient characteristics were similar to those in the phase III study with the exception that median age was 71 compared with 60 years, and ECOG performance status ≥ 1 was 72% versus 41% of patients. Combining the patient data from these 3 studies allows a more robust evaluation of efficacy and safety of BV/5-FU/LV in comparison with a combined control of 5-FU/LV and IFL. Methods: The combined control group included patients with metastatic CRC randomized to 5-FU/LV or to IFL. The comparator arm included patients randomized in these same studies to BV/5-FU/LV. BV dosing was 5mg/kg every 2 weeks in all patients evaluated. Results: The efficacy results are shown below. There was a 26% reduction in daily risk of death with BV/5-FU/LV compared with 5-FU/LV or IFL alone (hazard ratio 0.742; 95% CI: 0.59, 0.93). Adverse events were consistent with those previously reported. Conclusion: This large combined analysis confirms that the combination of Bevacizumab with 5 FU/LV improves survival and progression-free survival compared with 5-FU/LV or IFL alone. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech

Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) to prolong progression-free survival in first-line colorectal cancer (CRC) in subjects who are not suitable candidates for first-line CPT-11

3516 Background: Bevacizumab [Avastin (BV)] is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor. As presented at ASCO 2003, the addition of BV to IFL chemotherapy prolonged median survival from 15.61 months to 20.34 months (p = 0.00004). This was a companion trial that studied the addition of BV to FU/LV chemotherapy in subjects who were not optimal candidates for first-line irinotecan because of age or performance status. Methods: Approximately 200 patients were to be randomized to receive the Roswell Park regimen of FU/LV placebo or FU/LV/BV (5 mg/kg every two weeks). The primary efficacy endpoint was survival; secondary efficacy endpoints included progression free survival (PFS), objective response rate (ORR) and duration of response. Results: 209 patients were randomized between September 7, 2000 and May 6, 2002. For the two groups, FU/LV/Placebo and FU/LV/BV, baseline characteristics were similar. Efficacy and selected safety results are as follows: Conclusions: The addition of BV to FU/LV chemotherapy, in subjects who are not optimal candidates for first-line CPT-11 resulted in a clinically meaningful and statistically significant prolongation of progression-free survival and trends towards improved response rate,duration of response, and survival as compared with FU/LV chemotherapy alone. The addition of BV to FU/LV was well tolerated; Grade 3 hypertension, easily managed with oral medications was increased with BV, The uncommon but life-threatening event of gastrointestinal perforation occurred in 2 patients in the FU/LV/BV arm Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.

Bevacizumab plus irinotecan/5-FU/leucovorin for treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patient subgroups

3617 Background. Bevacizumab [Avastin (BV)], a recombinant, humanized monoclonal antibody against VEGF, has demonstrated efficacy and safety when added to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy as first-line therapy for metastatic colorectal cancer (CRC). The results of the primary analysis of a randomized phase III trial demonstrated that the addition of BV to IFL resulted in significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.61 to 20.34 months). Additional sub-group analyses were performed to evaluate the effects of baseline risk factors on survival. Methods. The effects of demographic and baseline prognostic characteristics and selected baseline laboratory values on duration of survival, PFS, and objective response rate were examined. Patient characteristics included baseline ECOG performance status, number of organ sites with metastases, site of primary tumor, age, sex, race, prior adjuvant chemotherapy, prior radiotherapy, duration of metastatic disease, years since diagnosis of CRC, baseline sum of longest diameters of target lesions, baseline levels of albumin, alkaline phosphatase, and LDH. Descriptive summaries of duration of survival and PFS were produced for each level of the categorical variables listed above for each treatment arm. These descriptive summaries consisted of the hazard ratio from unstratified Cox regression and Kaplan-Meier estimates of median time to the event. Results. 815 patients were randomized to receive either IFL + placebo or IFL + BV. A survival benefit in the IFL/BV arm was seen across all patient subgroups compared with the IFL/placebo arm (see table). Conclusion. The addition of Bevacizumab to IFL chemotherapy results in prolonged survival in multiple sub-groups. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech Genentech

Post-progression therapy (PPT) effect on survival in AVF2107, a phase III trial of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC)

3517 Background: Bevacizumab [Avastin (BV)], a recombinant humanized monoclonal antibody against VEGF, significantly prolongs overall survival (OS) when added to 1st-line chemotherapy for mCRC. BV ...

Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) to prolong progression-free survival in first-line colorectal cancer (CRC) in subjects who are not suitable candidates for first-line CPT-11

3516 Background: Bevacizumab [Avastin (BV)] is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor. As presented at ASCO 2003, the addition of BV to IFL chemotherapy prolonged median survival from 15.61 months to 20.34 months (p = 0.00004). This was a companion trial that studied the addition of BV to FU/LV chemotherapy in subjects who were not optimal candidates for first-line irinotecan because of age or performance status. Methods: Approximately 200 patients were to be randomized to receive the Roswell Park regimen of FU/LV placebo or FU/LV/BV (5 mg/kg every two weeks). The primary efficacy endpoint was survival; secondary efficacy endpoints included progression free survival (PFS), objective response rate (ORR) and duration of response. Results: 209 patients were randomized between September 7, 2000 and May 6, 2002. For the two groups, FU/LV/Placebo and FU/LV/BV, baseline characteristics were similar. Efficacy and selected safety results are as follows: Conclusions: The addition of BV to FU/LV chemotherapy, in subjects who are not optimal candidates for first-line CPT-11 resulted in a clinically meaningful and statistically significant prolongation of progression-free survival and trends towards improved response rate,duration of response, and survival as compared with FU/LV chemotherapy alone. The addition of BV to FU/LV was well tolerated; Grade 3 hypertension, easily managed with oral medications was increased with BV, The uncommon but life-threatening event of gastrointestinal perforation occurred in 2 patients in the FU/LV/BV arm Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc. Genentech, Inc. Genentech, Inc.

Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) does not increase the incidence of venous thromboembolism when added to first-line chemotherapy to treat metastatic colorectal cancer

3529 Background: Venous thromboembolism has been reported as a potential risk of anti-angiogenic and anti-VEGF therapy. To clarify the true risk, studies of bevacizumab [Avastin (BV)] included special case report forms and “real-time” assessment of the incidence and characteristics of thromboembolism. An analysis was performed from two completed randomized, controlled, double-blind trials. Methods: Study AVF2107g was a large, randomized, controlled, double-blinded Phase III trial testing the efficacy and safety of adding BV to bolus-IFL as first-line chemotherapy for metastatic colorectal cancer. The addition of BV to IFL chemotherapy resulted in a prolongation of median survival from 15.6 mos to 20.3 mos (p=0.00004). Study AVF2192g was a randomized, controlled, double-blinded Phase II trial testing the efficacy and safety of adding BV to FU/LV as first-line chemotherapy in CRC for subjects who were not optimal candidates for first-line CPT- II. The addition of BV to FU/LV chemotherapy resulted in prolongation of median progression-free survival from 5.5 to 9.2 months (p=0.0002). Results: The incidences and types of thrombembolic events in the two trials is shown below: Conclusions: The addition of BV to either standard first-line chemotherapy was not associated with an increase in venous thromboembolism in either study AVF2107g or study AVF2192g. There may be a small increase in arterial thromboembolic events. These data emphasize the high background rate of thromboembolism associated with mCRC and standard chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech; Pfizer Genentech, Inc. Genentech, Inc. AstraZeneca; Genentech, Inc.; GlaxoSmithKline

Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) does not increase the incidence of venous thromboembolism when added to first-line chemotherapy to treat metastatic colorectal cancer

3529 Background: Venous thromboembolism has been reported as a potential risk of anti-angiogenic and anti-VEGF therapy. To clarify the true risk, studies of bevacizumab [Avastin (BV)] included special case report forms and “real-time” assessment of the incidence and characteristics of thromboembolism. An analysis was performed from two completed randomized, controlled, double-blind trials. Methods: Study AVF2107g was a large, randomized, controlled, double-blinded Phase III trial testing the efficacy and safety of adding BV to bolus-IFL as first-line chemotherapy for metastatic colorectal cancer. The addition of BV to IFL chemotherapy resulted in a prolongation of median survival from 15.6 mos to 20.3 mos (p=0.00004). Study AVF2192g was a randomized, controlled, double-blinded Phase II trial testing the efficacy and safety of adding BV to FU/LV as first-line chemotherapy in CRC for subjects who were not optimal candidates for first-line CPT- II. The addition of BV to FU/LV chemotherapy resulted in prolongation of median progression-free survival from 5.5 to 9.2 months (p=0.0002). Results: The incidences and types of thrombembolic events in the two trials is shown below: Conclusions: The addition of BV to either standard first-line chemotherapy was not associated with an increase in venous thromboembolism in either study AVF2107g or study AVF2192g. There may be a small increase in arterial thromboembolic events. These data emphasize the high background rate of thromboembolism associated with mCRC and standard chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech; Pfizer Genentech, Inc. Genentech, Inc. AstraZeneca; Genentech, Inc.; GlaxoSmithKline

Bevacizumab plus irinotecan/5-FU/leucovorin for treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patient subgroups

3617 Background. Bevacizumab [Avastin (BV)], a recombinant, humanized monoclonal antibody against VEGF, has demonstrated efficacy and safety when added to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy as first-line therapy for metastatic colorectal cancer (CRC). The results of the primary analysis of a randomized phase III trial demonstrated that the addition of BV to IFL resulted in significant improvement in survival compared with IFL alone (p=0.00004; median survival increased from 15.61 to 20.34 months). Additional sub-group analyses were performed to evaluate the effects of baseline risk factors on survival. Methods. The effects of demographic and baseline prognostic characteristics and selected baseline laboratory values on duration of survival, PFS, and objective response rate were examined. Patient characteristics included baseline ECOG performance status, number of organ sites with metastases, site of primary tumor, age, sex, race, prior adjuvant chemotherapy, prior radiotherapy, durati...