Phase II study of temozolomide (TMZ) in metastatic colorectal cancer (mCRC) patients molecularly selected by MGMT promoter hypermethylation.

583 Background: O(6)-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein. About 40% of mCRC display MGMT deficiency due to promoter hypermethylation, leading to susceptibility to treatment with cytotoxic alkylating agents. We previously reported that objective clinical response to dacarbazine is confined to tumors harboring MGMT promoter hypermethylation (Amatu et al. Clin Cancer Res 2013). Based on these findings, we conducted a phase II study with TMZ in MGMT-deficient mCRCs after failure of standard therapies (EudraCT 2012-003338-17). Methods: We screened mCRC patients for MGMT promoter hypermethylation on archival FFPE specimens by methylation-specific PCR (MSP). All eligible patients underwent tumor biopsy prior to start of treatment. Patients received TMZ 200 mg/m 2 po qd days 1-5 q28 until progression or intolerable toxicity. We used a Fleming single-stage design to determine whether PFS rate at 12 week would be ≥35% (H 0 ≤15%, type I error=0.059 (1-sided) and power=0.849). Secondary endpoints included response rate (RR), disease control rate (DCR), overall survival (OS), and association of clinical outcomes with quantitative MGMT evaluation in serum and fresh tissue. Results: 150 patients were screened: 54 (36%) presented MGMT promoter hypermethylation and 29 were eligible and enrolled from December 2012 to May 2014 (M 69%, median age 60y [38-77], mean number of previous treatment lines 5.6). A median of 2 cycles of TMZ were administered (range 1-5). Primary endpoint was not achieved, since PFS rate at 12 weeks was 10.3% (90% CI: 2.9-24.6). DCR was 48.3% (90% CI: 32.0-64.8), median OS 6.2 months (95% CI: 3.7-7.6), and median PFS 2.6 months (95% CI: 1.4-2.7). G3/4 toxicities occurring in ≥10% of patients included: thrombocytopenia (10.3/13.8%), neutropenia (0/10.3%) and increased bilirubin (11.1/0%). Exploratory MGMT quantitative analysis is in progress. Conclusions: In mCRC patients treated with TMZ, selection according to MGMT promoter hypermethylation by MSP did not provide meaningful PFS rate at 12 weeks. Biomarkers analyses on serum and fresh tumor biopsy are ongoing to identify the subgroup of mCRCs benefiting from treatment. Clinical trial information: 2012-003338-17.