Capecitabine and temozolomide versus FOLFIRI in RAS mutated, MGMT methylated metastatic colorectal cancer
Mené sur 86 patients atteints d'un cancer colorectal de stade métastatique présentant des mutations du gène RAS et une méthylation du promoteur du gène MGMT, cet essai de phase II compare l'efficacité, du point de vue de la survie sans progression, et la toxicité d'un traitement combinant capécitabine et témozolomide et d'une chimiothérapie de type FOLFIRI (irinotécan, leucovorine et fluorouracile) (durée médiane de suivi : 30,5 mois)
Purpose : To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin and fluorouracil (FOLFIRI) in patients with RAS mutated, MGMTmethylated metastatic colorectal cancer.
Experimental design : In this randomized, phase 2 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 and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was progression-free survival 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 (IQR 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 immunohistochemistry did not benefit from CAPTEM.
Conclusions : Temozolomide-based therapy warrants further investigation in molecularly hyper-selected subgroups
Clinical Cancer Research , résumé, 2018