Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

Abstract

Background

Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients.

Patients and methods

Key inclusion criteria were: centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval (IFI) >3 months. TEMIRI (TMZ 150mg/sqm on days 1-5 plus irinotecan 100mg/sqm on days1,15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary endpoint was overall response rate (ORR). Exploratory translational analyses included MGMT immunoistochemistry (IHC) and methylBEAMing (MB).

Results

Between December 2014 and June 2017, 25 patients were enrolled. The primary endpoint was met, since 6 patients achieved a partial response (ORR 24%, 95% CI, 11%-43%). At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only 4 (16%) patients had ≥ grade 3 adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; HR = 0.29, 95%CI, 0.02-0.41; p = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy.

Conclusions

TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.