Abstract CT095: Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients (pts) bearing MGMT methylation
Authors: Morano Federica , Corallo Salvatore , Barault Ludovic , Niger Monica , Berenato Rosa , Moretto Roberto , Fucà Giovanni , Randon Giovanni , Antista Maria , Belfiore Antonino , Raimondi Alessandra , Nichetti Federico , Vita Francesca , Perrone Federica , Milione Massimo , Pruneri Giancarlo , Falcone Alfredo , Bartolomeo Maria Di , Nicolantonio Federica Di , Braud Filippo De , Cremolini Chiara , Pietrantonio Filippo 
Published: August 2018

Abstract
Backgroud
Metastatic colorectal cancer (mCRC) pts bearing promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), 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, MGMT methylated, microsatellite stable (MSS) mCRC may be a novel treatment approach.
Methods
Pts with mCRC bearing MGMT 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. MGMT 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 MGMT 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%). MGMT IHC had a negative predictive value of 100% as all pts whose cancer was MGMT-positive were non-responders. Additionally, pts with MGMT-negative/low tumors had a significantly longer mPFS than those with MGMT-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 MGMT-methylated, MSS mCRC pts
Citation Format: Federica Morano, Salvatore Corallo, Ludovic Barault, Monica Niger, Rosa Berenato, Roberto Moretto, Giovanni Fucà, Giovanni Randon, Maria Antista, Antonino Belfiore, Alessandra Raimondi, Federico Nichetti, Francesca Vita, Federica Perrone, Massimo Milione, Giancarlo Pruneri, Alfredo Falcone, Maria Di Bartolomeo, Federica Di Nicolantonio, Filippo De Braud, Chiara Cremolini, Filippo Pietrantonio. Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients (pts) bearing MGMT methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT095.