Avastin: Effect on Lung Cancer Survival

NASHVILLE, Tenn. Dec. 13- Avastin (bevacizumab) added to chemotherapy for non-squamous cell, non-small-cell lung cancer (NSCLC) increased survival by two months, but treatment-related deaths rose.

The median survival was 12.3 months in the group that received a Avastin-chemotherapy combination versus 10.3 months for patients randomized to Taxol (paclitaxel) and Paraplatin (carboplatin) alone (P=0.003), Alan Sandler, M.D., of the Vanderbilt-Ingram Cancer Center in Nashville reported in the Dec. 14 issue of the New England Journal of Medicine.

But, Dr. Sandler and colleagues pointed out, there were 15 treatment related deaths in the Avastin arm versus two in the Taxol/Paraplatin arm.

The response rate was 35% in Avastin add-on arm versus 15% in the Taxol-Paraplatin arm (P<0.001), but 4.4% of the Avastin patients developed clinically significant bleeding events versus 0.7% (P<0.001), and five of the 15 deaths were caused by pulmonary hemorrhage.

The Easter Cooperative Oncology Group trial recruited 878 patients with stage IIIB or IV NSCLC from July 2001 to April 2004. Four hundred and thirty-four patients were assigned to the Avastin-Taxol/Paraplatin arm and 444 to the Taxol-Paraplatin arm, including one patient who later withdrew consent.

Patients in the Avastin/Taxol-Paraplatin arm received six cycles of Taxol/Paraplatin chemotherapy followed by Avastin monotherapy every three weeks until evidence of disease progression or discontinuation to toxic effects. Patients in the control arm received six cycles of Taxol/Paraplatin.

Four hundred and seventeen patients from the Avastin/Taxol-Paraplatin arm were included in the analysis, as were 433 from the Taxol/Paraplatin arm.

Among the findings:

• The one-year survival rate was 51% in the Avastin/Taxol-Paraplatin arm versus 44% in the Taxol-Paraplatin arm and two-year survival rates were 23% versus 15%, respectively.
• Median progression-free survival was 6.2 months in the Avastin-Taxol/Paraplatin arm versus 4.5 month in the Taxol-Paraplatin arm (HR 0.66, 95% CI, 0.57-0.77, P<0.001).
• Avastin improved both survival and progression-free survival irrespective of whether the patients had measurable or nonmeasurable disease, prior radiation therapy, weight loss, disease stage, or recurrent disease.
• Of the 15 deaths in the Avastin group five were attributable to pulmonary hemorrhage, five to complications of febrile neutropenia, two to cerebrovascular event and two gastrointestinal hemorrhage, and one to probable pulmonary embolus.
• The most common grade 3 or 4 toxic effects for 215 patients continued on Avastin monotherapy were hypertension, proteinuria, fatigue, and dyspnea.

Dr. Sandler and colleagues said the improved response rate observed in the Avastin arm was "not anticipated a priori, since antiangiogenic drugs were not considered to have a cytotoxic effect."

The significant improvement in response rate "supports the hypothesis that [Avastin] improves drug delivery to the tumor."

They said that response was consistent across all study groups "with the possible exception of survival among women."

In this study the median survival was 13.3 months for women in the Avastin arm versus 13.1 for women in the Taxol-Paraplatin arm, while for men the rates were 11.7 versus 8.7 months.

The authors concluded that the addition of Avastin "conferred a significant improvement in overall survival, progression-free survival, and response rate in patients with non-squamous cell carcinoma and a good performance status."

Those results, however, need to be balanced against increased toxic, and sometimes fatal, side effects of Avastin.

Dr. Sandler reported receiving grant support form Genentech, OSI, Pfizer, Eli Lilly, Sunesis, Novartis, and Wyeth. He also received lecture fees form Genentech, and Bristol-Myers Squibb, and consulting fees form Genentech, OSI, Bristol-Myers Squibb, Eli Lilly, Sanofi-Aventis, Pfizer, Bayer, AstraZeneca, Novartis, Wyeth, Amgen, and Cyclacel. His co-authors report financial support from those same entities as well as Schering-Plough, Berlex, Ortho-Biotech, Merck, Mederex, Abbott, Glaxo-SmithKline, Cell Pathways, Immunex, Millenium, Cell Genesys, Battelle, and Zivena. One co-author, Michael C. Perry, M.D. disclosed equity ownership in Genentech, and Joan H. Schiller, M.D., serves on the advisory board of EMD Pharmaceuticals.