Results of randomized, multicenter, double-blind phase III trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients

Background and objective: Endostar™ (rh-endostatin, YH-16) is a new recombinant human endostatin developed by Medgenn Bioengineering Co. Ltd., Yantai, Shandong, P. R. China. Pre-clinical study indicated that YH-16 could inhibit tumor endothelial cell proliferation, angiogenesis and tumor growth. Phase I and phase II studies revealed that YH-16 was effective as single agent with good tolerance in clinical use. The current study was to compare the response rate, median time to progression (TTP), clinical benefit and safety in patients with advanced non-small cell lung cancer (NSCLC), who were treated with YH-16 plus vinorelbine and cisplatin (NP) or placebo plus NP. Methods: Four hundred and ninety-three histologically or cytologically confirmed stage III B and IV NSCLC patients, with life expectancy > 3 months and ECOG performance status 0-2, were enrolled in a randomized, double-blind, placebo-controlled, multicenter trial, either trial group: NP plus YH-16 (vinorelbine 25 mg/m ² on day 1 and day 5, cisplatin 30 mg/m² on days 2 to 4, YH-16 7.5 mg/m² on days 1 to 14) or control group; NP plus placebo (vinorelbine 25 mg/m² on day 1 and day 5, cisplatin 30 mg/m ² on days 2 to 4, 0.9% sodium-chloride 3.75 ml on days 1 to 14) every 3 weeks for 2-6 cycles. The trial endpoints included response rate, clinical benefit rate, time to progression, quality of life and safety. Results: Of 486 assessable patients, overall response rate was 35.4% in trial group and 19.5% in control group (P = 0.0003). The median TTP was 6.3 months and 3.6 months for trial group and control group respectively (P<0.001). The clinical benefit rate was 73.3% in trial group and 64.0% in control group (P = 0.035). In untreated patients of trial group and control group, the response rate was 40.0% and 23.9% (P = 0.003), the clinical benefit rate was 76.5% and 65.0% (P = 0.023), the median TTP was 6.6 and 3.7 months (P = 0.0000), respectively. In pretreated patients of trial group and control group, the response rate was 23.9% and 8.5% (P = 0.034), the clinical benefit rate was 65.2% and 61.7% (P = 0.68), the median TTP was 5.7 and 3.2 months (P = 0.0002), respectively. The relief rate of clinical symptoms in trial group was higher than that of those in control group, but no significance existed (P>0.05). The score of quality of life in trial group was significantly higher than that in control group (P = 0.0155) after treatment. There were no significant differences in incidence of hematologic and non-hematologic toxicity, moderate and severe side effects between trial group and control group. Conclusion: The addition of YH-16 to NP regimen results in significantly and clinically meaningful improvement in response rate, median time to tumor progression, and clinical benefit rate compared with NP alone in advanced NSCLC patients. YH-16 in combination with chemotherapy shows a synergic activity and a favorable toxic profile in advanced cancer patients.