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

Filippo Pietrantonio, Riccardo Lobefaro, Maria Antista, Sara Lonardi, Alessandra Raimondi, Federica Morano, Stefania Mosconi, Lorenza Rimassa, Sabina Murgioni, Andrea Sartore-Bianchi, Gianluca Tomasello, Raffaella Longarini, Gabriella Farina, Fausto Petrelli, Stefania Gori, Giovanni Randon, Salvatore Corallo, Filippo Pagani, Vincenzo Guarini, Federica PalermoAntonia Martinetti, Marco Macagno, Ludovic Barault, Federica Perrone, Elena Tamborini, Massimo Milione, Federica Di Nicolantonio, Massimo Di Maio, Giovanni Fucà, Maria Di Bartolomeo, Filippo de Braud

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PURPOSE: To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl-guanine methyltransferase (MGMT)-methylated metastatic colorectal cancer (mCRC).EXPERIMENTAL DESIGN: In this randomized, phase II trial, we enrolled patients with RAS-mutated, MGMT-methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed MGMT 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.RESULTS: Between November 2014 and May 2019, 86 patients were randomly assigned to arm A (n = 43) or arm B (n = 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 P = 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.CONCLUSIONS: Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.
Original languageEnglish
JournalClin. Cancer Res.
Publication statusPublished - Nov 18 2019


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