A double-blind, randomized, placebo-controlled, phase 2 study of maintenance
enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line
therapy for metastatic colorectal cancer.
Author(s): Wolff RA, Fuchs M, Di Bartolomeo M, Hossain AM, Stoffregen C, Nicol S, Heinemann
Affiliation(s): The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Publication date & source: 2012, Cancer. , 118(17):4132-8
BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor
effects and, in phase 1 studies, the combination was well tolerated. This phase 2
study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as
maintenance therapy for metastatic colorectal cancer (MCRC).
METHODS: Patients with locally advanced or MCRC and stable or responding disease
after completing 6 cycles of first-line chemotherapy randomly received a loading
dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo.
Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2)
intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2)
IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was
progression-free survival (PFS), from randomization. Overall survival (OS) and
PFS were also assessed from start of first-line therapy. Enrollment was stopped,
and the final analysis was conducted after 73 PFS events.
RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo.
For the enzastaurin and placebo arms, respectively, the median cycles received
were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR],
1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not
calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The
median PFS from start of first-line therapy was 8.9 months for enzastaurin and
11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin
patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%;
P = .008). One possibly enzastaurin-related death occurred because of arrhythmia.
CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable,
but does not improve PFS during maintenance therapy in patients with MCRC
compared with bevacizumab-based therapy alone.