Final results of a multicenter phase II study of irinotecan (CPT), cisplatin (CIS), and bevacizumab (BEV) in patients with metastatic gastric or gastroesophageal (GEJ) adenocarcinoma (NCI #6447)

Abstract

4020 Background: BEV improves survival in several solid tumors when combined with chemotherapy. CPT/CIS is active in gastric and GEJ cancers with a median time to progression(TTP) of 4.2 months, response rate(RR) of 30%, and median survival of ∼7 months (Pozzo Ann Onc 2004). Anti-angiogenic therapy for upper GI cancers is of concern due to a potential increased risk of perforation or GI bleed. We evaluated the efficacy and safety of the combination of CPT, CIS, and BEV in the treatment of gastric and GEJ cancers. Methods: 47 patients with previously untreated metastatic gastric or GEJ adenocarcinomas were treated with BEV 15mg/kg day 1, CPT 65mg/m2 and CIS 30mg/m2 days 1 and 8, every 21 days. The primary endpoint was TTP, with 90% power to demonstrate a 50% improvement in TTP (eg. from 5 to 7.5 months) over historical control. Safety, response, and survival were secondary endpoints. Results: Patient characteristics: median age 59 (range 25–75), KPS 90% (70%-100%), Male 34, Gastric/GEJ 27:20. With a median follow up of 9.0 months, median TTP is 9.9 months (95%CI: 6.5–11.8 months). In 33 patients with measurable disease, the RR (partial + complete) is 66.7% (95%CI: 51–83%). Median survival is 12.6 months (95%CI: 10.1–17.1 months). We observed no change in expected CPT/CIS related toxicity: eg. grade 3/4 neutropenia (29%), nausea/vomiting (10%), and diarrhea (13%). Possible BEV related toxicity includes 2 gastric perforations, 1 grade 3 peri-rectal fistula, 2 cardiac events(1 ischemia, 1 reduced ejection fraction), and 10 patients with grade 3/4 hypertension. Although the primary tumor was unresected in 35 patients, we observed only 1 patient with an upper GI bleed. Grade 3/4 thromboembolic events occurred in 25%. Conclusions: The combination of CPT/CIS/BEV is active in gastric and GEJ cancers. The toxicity profile is acceptable. The primary endpoint of improving TTP was exceeded by 100% with median TTP 9.9 months. Despite the majority of patients having their primary tumor unresected, GI bleeding was not significant. The thromboembolic and perforation rates with CPT/CIS are similar with or without BEV (Shah et al JCO 2005). Further development of BEV in gastric and GEJ cancers is clearly warranted. [Table: see text]