Bevacizumab with Gemcitabine Shows Activity in Phase II Pancreatic Cancer Trial
Abstract & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC and is Editor of Clinical Oncology Alert. Dr. Ershler is on the speaker’s bureau for Amgen and does research for Ortho Biotech.
Synopsis: In a phase II trial of bevacizumab and gemcitabine in patients with advanced pancreatic cancer, responses were observed in 21% and stable disease in 46%. Although the median overall survival was not dramatically superior to that reported for gemcitabine alone, there is rationale for proceeding to larger scale phase III trial of this combination.
Source: Kindler HL, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005;23:8033-8040.
Kindler and colleagues coordinated a multi-center phase II trial of bevacizumab given in combination with gemcitabine for patients with previously untreated advanced pancreatic cancer. The goals of the study were to determine the objective tumor response rate, overall and progression-free survival rates and toxicity profile of this combination.
Fifty-two patients were enrolled at 7 centers between November 2001 and March 2004 and were treated with gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. All patients also received bevacizumab (Avastin®, Genentech, South San Francisco, CA) 10 mg/kg on days 1 and 15, after the gemcitabine infusion.
Of the 52 patients, 11 (21%) had confirmed partial responses and 24 (46%) had stable disease. The 6-month survival rate was 77%, the median survival was 8.8 months, and the median progression-free survival was 5.4 months. Pretreatment plasma VEGF levels did not correlate with outcome. Grade 3 and 4 toxicities included hypertension in 19%, thrombosis in 13%, visceral perforation in 8%, and bleeding in 2%.
Detailed in the current paper are a relatively high occurrence of toxicities, although most of which did not reach grade 3. For example, 44% developed hypertension, but this reached grade 3 in just 19% (and none experienced hypertensive crisis). Similarly, proteinuria occurred in 36% of patients, but was grade 3 in only 2% and bleeding episodes occurred in 31% (epistaxis in 23%), but severe bleeding occurred only in one patient.
The investigators concluded that this combination (gemcitabine and bevacizumab) and schedule was sufficiently positive with regard to clinical outcomes to warrant additional, larger-scale investigation.
Commentary
The treatment of pancreatic cancer remains disappointing. Although in phase II trials, the addition of second agents (eg, 5 fluorouracil, oxaliplatin, cisplatin, and others) have shown promise, in larger Phase III trials, the combinations have shown no advantage over gemcitabine alone.1-3 In the current trial, bevacizumab was tested in combination with gemcitabine in patients with previously untreated pancreatic cancer. Bevacizumab is a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), which has been shown to promote the growth and spread of a number of human tumors, including pancreatic cancer.4 The rationale for this trial was strengthened by the observations that pancreatic cells grown in culture were stimulated by VEGF5 and inhibitors of VEGF reduced angiogenesis and tumor growth in animal models of pancreatic cancer.6 Thus, the current trial has great appeal, for the utilization of bevacizumab is based upon solid rationale and the treatment directed at a population distinctly in need of a therapeutic breakthrough. The results, although modest by phase II standards, are sufficient to warrant a larger scale investigation and it is gratifying to see that the Cancer and Leukemia Group B has undertaken such a trial comparing gemcitabine plus bevacizumab vs gemcitabine plus placebo. Until the findings are reported, however, it would seem the risks and expense may not warrant incorporation into community standard practice.
References
1. Berlin JD, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270-3275.
2. Rocha Lima CM, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004;22:3776-3783.
3. Louvet C, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005;23:3509-3516.
4. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer. 2003;2:8.
5. Itakura J, et al. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000;85:27-34.
6. Baker CH. Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res. 2002;62:1996-2003.
In a phase II trial of bevacizumab and gemcitabine in patients with advanced pancreatic cancer, responses were observed in 21% and stable disease in 46%. Although the median overall survival was not dramatically superior to that reported for gemcitabine alone, there is rationale for proceeding to larger scale phase III trial of this combination.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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