A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer

Abstract

4007 Background: Pemetrexed (P) (ALIMTA) is a multitargeted antifolate with broad antitumor activity in solid tumors, including pancreas cancer (PC). Gemcitabine (G) (GEMZAR) is the current standard of care for inoperable PC. The combination of G and P has shown preclinical synergy and activity in a phase II study in PC [Kindler et al., ASCO 2002]. Methods: This study compared G 1250 mg/m2 day (d)1 & d 8 and P 500 mg/m2 d 8 q 3 weeks to G 1000 mg/m2 d 1, 8, 15 q 4 weeks in chemonaive patients (pts). Primary objective was overall survival (OS); secondary objectives were progression-free survival (PFS), time to progressive disease (TTP), response rate (RR), quality of life (QoL), and toxicity. Pts were stratified for performance status, disease stage, baseline homocysteine levels and investigational centers. Results: 565 pts (GP 283; G 282) were randomized. Baseline characteristics were well balanced (GP/G) with median age (63/63), stage IV disease (90%/91%), ECOG PS 0–1 (85%/88%), and liver metastasis (63%/63%). Median treatment duration was 12 weeks in both arms. There was no statistical difference in OS (p=0.848; censoring rate 16.3%; median 6.2 months (m) for GP and 6.3 m for G). RR was significantly better (p=0.006) for GP (18.3%; 42/230) than G (9.1%,20/220) as was median TTP (5.2 m for GP vs 3.6 m, p=0.042). PFS (3.9 m vs 3.3 m; p=0.11) and 1-year survival (21.4 vs 20.1%; p=0.718) were similar in both arms. Second-line therapy was given to 39% of the pts (PG 34%; G 43%). Of the planned doses, 75.3% of G and 86.9% of P in the GP arm were given, 86.5% in the G arm. Weekly mean dose of G was similar in both arms (628 vs 610 mg/m2). There were 3 treatment-related deaths in the PG arm. More grade 3/4 toxicity was seen for PG: neutropenia (45.1% vs 12.8%), thrombocytopenia (17.9% v 6.2%), anemia (13.9% v. 2.9%), febrile neutropenia (9.9% vs 0.4%), all differences p<0.001, and fatigue (15% vs 6.6%, p<0.05). Otherwise, both treatments were well tolerated. Overall QoL was well preserved in both treatment arms. Conclusions: PG improved TTP and RR, but not survival. Gemcitabine monotherapy remains the global standard of care for inoperable PC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company