MAESTRO: A randomized, double-blind phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC).

Abstract

Background: Hypoxia in PDAC is associated with disease progression and poor prognosis. Evo is a hypoxia-activated prodrug of Br-IPM that is preferentially activated under hypoxic conditions. The addition of Evo to Gem significantly improved PFS in a randomized phase II trial in advanced PDAC (NCT01144455 ). Methods: MAESTRO was an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo (Pbo)/Gem in pts with locally advanced unresectable or metastatic PDAC (NCT01746979 ). Evo 340 mg/m2 or matched Pbo and Gem 1,000 mg/m2 were administered IV on days 1, 8, and 15 of a 28-day cycle. Key eligibility criteria included ECOG PS 0/1. The primary endpoint was overall survival (OS). 660 patients were to be randomized 1:1 to obtain 508 events (deaths) to assure 90% power to detect a hazard ratio (HR) of 0.75 for OS with a two-sided a of 0.05. Secondary endpoints included PFS and objective response rate (ORR). Results: From Jan 2013 to Nov 2014, 693 pts were randomized (346 Evo/Gem, 347 Pbo/Gem). Baseline characteristics were balanced. Median OS was 8.7 mo with Evo/Gem vs 7.6 mo with Pbo/Gem; HR = 0.84 (95% CI: 0.71-1.01, p = 0.059). Median PFS was 5.5 mo with Evo/Gem vs 3.7 mo with Pbo/Gem; HR = 0.77 (95% CI: 0.65-0.92, p = 0.004). Best ORR was 20% with Evo/Gem vs 16% with Pbo/Gem; odds ratio (OR) = 1.32 (95% CI: 0.88-1.97, p = 0.17). Confirmed ORR was 15% with Evo/Gem vs 9% with Pbo/Gem; OR = 1.90 (95% CI: 1.16 - 3.12, p = 0.009). Most common non-hematologic AEs of nausea (47%), decreased appetite (35%) and vomiting (33%) were similar across arms. Hematologic AEs of neutropenia, thrombocytopenia and anemia were more frequent with Evo/Gem. AEs leading to death were 9% with Evo/Gem vs 11% with Pbo/Gem. AEs leading to treatment discontinuation were 17.9% on Evo/Gem and 15.6% on Pbo/Gem. Conclusions: The primary endpoint was not met as difference in OS time was not statistically significant. Evo/Gem showed signs of antitumor activity with longer PFS and higher ORR. The safety profile was similar to that previously reported.