Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer.

Abstract

To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with <i>RAS</i>-mutated, methyl-guanine methyltransferase (<i>MGMT</i>)-methylated metastatic colorectal cancer (mCRC). In this randomized, phase II trial, we enrolled patients with <i>RAS</i>-mutated, <i>MGMT</i>-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed <i>MGMT</i> methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A. Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (<i>n</i> = 43) or arm B (<i>n</i> = 43). After a median follow-up of 30.5 months (interquartile range, 12.2-36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided <i>P</i> = 0.223). Progression-free survival and overall survival were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) in arm A versus 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B [HR = 1.19 (0.82-1.72) and HR = 0.97 (0.58-1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM. Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.