TY - JOUR
T1 - Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer
AU - Pietrantonio, Filippo
AU - Lobefaro, Riccardo
AU - Antista, Maria
AU - Lonardi, Sara
AU - Raimondi, Alessandra
AU - Morano, Federica
AU - Mosconi, Stefania
AU - Rimassa, Lorenza
AU - Murgioni, Sabina
AU - Sartore-Bianchi, Andrea
AU - Tomasello, Gianluca
AU - Longarini, Raffaella
AU - Farina, Gabriella
AU - Petrelli, Fausto
AU - Gori, Stefania
AU - Randon, Giovanni
AU - Corallo, Salvatore
AU - Pagani, Filippo
AU - Guarini, Vincenzo
AU - Palermo, Federica
AU - Martinetti, Antonia
AU - Macagno, Marco
AU - Barault, Ludovic
AU - Perrone, Federica
AU - Tamborini, Elena
AU - Milione, Massimo
AU - Di Nicolantonio, Federica
AU - Di Maio, Massimo
AU - Fucà, Giovanni
AU - Di Bartolomeo, Maria
AU - de Braud, Filippo
N1 - ©2019 American Association for Cancer Research.
PY - 2019/11/18
Y1 - 2019/11/18
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-19-3024
DO - 10.1158/1078-0432.CCR-19-3024
M3 - Article
JO - Clin. Cancer Res.
JF - Clin. Cancer Res.
SN - 1078-0432
ER -