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

Purpose: To determine whether second-line therapy with cape citabine and temozolomide was superior to irinotecan, leucovorin,
and fluorouracil (FOLFIRI) in patients with RAS-mutated, methyl guanine methyltransferase (MGMT)-methylated metastatic colo rectal cancer (mCRC).
Patients and Methods: 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 progres sion-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 ¼ 43) or arm B (n ¼ 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 ¼
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 ¼ 1.19 (0.82–1.72) and HR ¼ 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.