ASCO: Jury Still Out on Bevacizumab (Avastin) With Chemotherapy for SCLC

CHICAGO, June 6 -- Bevacizumab (Avastin) added to chemotherapy for bulky small-cell lung cancer led to modest anticancer activity without clinically significant hemoptysis, investigators reported here.

Yet the three-agent regimen of cisplatin, irinotecan, and bevacizumab failed to reach the goal of exceeding a median survival of 12.8 months achieved in a Japanese study of chemotherapy alone for extensive-stage SCLC (N Engl J Med. 2002;346:85-91). Progression-free and median survival were nominally improved compared with results from recent trials conducted in the U.S.

"The progression-free survival is promising, but we have to wait for the final results to decide whether they justify carrying this regimen forward in a phase III trial," said Neal Ready, M.D., of Duke at the American Society of Clinical Oncology meeting. "We hope to have that data within another three to six months."

Several lines of evidence provided a rationale for adding bevacizumab to cisplatin-irinotecan chemotherapy for extensive SCLC, said Dr. Ready. VEGF is expressed in about 80% of SCLC. Combining bevacizumab with chemotherapy has led to improved outcomes in advanced colorectal cancer, non-small cell lung cancer, and breast cancer. The combination if cisplatin and irinotecan has demonstrated activity in untreated extensive-stage SCLC.

Because SCLC often resides adjacent to major airways, the proposed use of bevacizumab raised some concern about the possibility of treatment-induced hemoptysis. Evaluation of the anti-VEGF antibody in a 10-patient safety cohort revealed no such adverse effect.

The nonrandomized, single-arm study involved 72 patients with measurable extensive-stage SCLC. The patients had no history of chemotherapy, and radiation therapy had to be completed at least a week prior to beginning the bevacizumab-cisplatin-irinotecan protocol. Patients with a recent history of hemoptysis and those on chronic aspirin, other antiplatelet therapy, or anticoagulation were excluded.

The study regimen consisted of:

• Cisplatin at 30 mg/m² on days one and eight.
• Irinotecan at 65 mg/m² on days one and eight.
• Bevacizumab at 15 mg/kg on day one.

The regimen was repeated every 21 days for a maximum of six cycles without maintenance bevacizumab. The primary endpoint was a 12-month survival of 57% (median survival ?15 months).

The most common grade 3+ adverse events were neutropenia (25%), diarrhea (16%), dehydration (12%), leukopenia (11%), and thrombocytopenia, diarrhea, and fatigue (10% each). One patient died of left-ventricular systolic dysfunction, one of brain hemorrhage, and one of pneumonitis/pulmonary infiltrates. The only adverse event considered possibly related to bevacizumab was the hemorrhage, which initially presented as a thrombotic-embolic stroke with no evidence of bleeding on a CT scan, according to Dr. Ready.

The treatment regimen resulted in three complete responses and 48 partial responses, for an overall response rate of 75%. Eleven other patients had stable disease. The 12-month overall survival was 48.9%, and median survival was 11.7 months. The 12-month progression-free survival was 18.3%, with a median of 7.1 months. Monitoring of VEGF and platelet-derived growth factor levels revealed no correlation with response, overall survival, or progression-free survival.

Although the results did not exceed those of the Japanese study of combination chemotherapy, they compared favorably with recent U.S. studies involving untreated extensive-stage SCLC. Those trials demonstrated progression-free survival ranging from 4.1 to 6.0 months, and median survival of 8.6 to 10.2 months, Dr. Ready reported.