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

Backgroud Metastatic colorectal cancer (mCRC) pts bearing promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (), are suitable for treatment with temozolomide (TMZ) with an expected response rate up to 10% even in the chemorefractory setting. Additionally, the reintroduction of a previously used chemoterapeutic agent with potentially retained sensitivity is often used. We hypothesized that the combination of irinotecan, another DNA damaging agent, and TMZ (TEMIRI regimen) in pts with irinotecan-sensitive, methylated, microsatellite stable (MSS) mCRC may be a novel treatment approach. Methods Pts with mCRC bearing methylation were identified in two Italian institutions. Key inclusions criteria were: MSS mCRC, progression after at least two prior chemotherapy lines for advanced disease, irinotecan free interval (IFI) ≥ 3 months, as defined by the time elapsed from the last irinotecan-based regimen and the time of progressive disease. promoter methylation and MSS status were confirmed centrally. Eligible pts received a maximum of 6 cycles of TEMIRI regimen (TMZ 150mg/sqm on days 1-5 plus irinotecan 100mg/sqm on days1,15 every 28 days) followed by maintenance with single-agent TMZ until progression, unacceptable toxicity or consent withdrawal. Primary endpoint of the study was overall response rate (ORR). Setting p0 = 10%, and p1 = 35%, with 1-sided-α and β errors of 0.05 and 0.20, 25 patients were required. Null hypothesis would have been rejected if RECIST response had been observed in at least 6 patients. Exploratory endpoints included the correlation of activity/efficacy parameters with biomarkers, including immunohistochemistry (IHC) and MethylBEAMing (MB). Results Twenty-five pts were enrolled between December 2014 and June 2017. Seventeen pts (68%) had extensive metastatic disease. The majority of pts was heavily pretreated: 68% received more than 3 lines of therapy. Median IFI was 6.8 months. The primary endpoint was met: partial responses (PR) according to RECIST v1.1 were detected in six out of 25 patients (ORR 24%, 95% CI, 11%-43%). Median progression free survival (PFS) and overall survival (OS) were of 4.4 and 13.8 months, respectively. Treatment was well tolerated with neutropenia being the most common G3-G4 adverse event (8%) followed by diarrhea (4%). IHC had a negative predictive value of 100% as all pts whose cancer was -positive were non-responders. Additionally, pts with -negative/low tumors had a significantly longer mPFS than those with -positive ones (6.9 versus 2.0 months; HR=0.29, 95%CI, 0.02-0.41; p=0.003) while no significant difference in OS was observed (17.3 versus 13.8 months; HR=0.56, 95%CI: 0.13-1.85; p=0.303). Similarly, patients with methylation percentage ≥63 by MB had a significantly longer mPFS than others (6.6 versus 3.8 months; HR=0.46, 95% CI, 0.13-0.95; p=0.049), with no OS differences (15.5 versus 12.7 months; HR=0.75, 95% CI 0.24-2.11; p=0.327). Conclusions Given the disappointing results of the available treatments in the chemorefractory setting, TEMIRI regimen is a safe and promising approach for pretreated -methylated, MSS mCRC pts