F Morano1, S Corallo1, M Niger1, L Barault2, M Milione3, R Berenato1, R Moretto4, G Randon1, M Antista1, A Belfiore3, A Raimondi1, F Nichetti1, A Martinetti1, L Battaglia5, F Perrone3, G Pruneri6, A Falcone4, M Di Bartolomeo1, F de Braud7, F Di Nicolantonio2, C Cremolini4, F Pietrantonio8. 1. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 2. Department of Oncology, University of Turin, Candiolo, Turin, Italy; Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Turin, Italy. 3. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 4. Unit of Medical Oncology 2, Department of Translational Research and New Technologies in Medicine and Surgery, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Pisa, Italy. 5. Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 6. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy. 7. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy. 8. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy. Electronic address: filippo.pietrantonio@istitutotumori.mi.it.
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 >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 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 four (16%) patients had ≥ grade 3 (CTCAE 4.0) 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; hazard ratio = 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.
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 >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 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 four (16%) patients had ≥ grade 3 (CTCAE 4.0) 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; hazard ratio = 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.
Authors: Monica Niger; Federico Nichetti; Andrea Casadei-Gardini; Federica Morano; Chiara Pircher; Elena Tamborini; Federica Perrone; Matteo Canale; Daniel B Lipka; Andrea Vingiani; Luca Agnelli; Anna Dobberkau; Jennifer Hüllein; Felix Korell; Christoph E Heilig; Sara Pusceddu; Francesca Corti; Michele Droz; Paola Ulivi; Michele Prisciandaro; Maria Antista; Marta Bini; Laura Cattaneo; Massimo Milione; Hanno Glimm; Bruno C Köhler; Giancarlo Pruneri; Daniel Hübschmann; Stefan Fröhling; Vincenzo Mazzaferro; Filippo Pietrantonio; Maria Di Bartolomeo; Filippo de Braud Journal: Mol Oncol Date: 2022-06-13 Impact factor: 7.449
Authors: Yongjun Cha; Sun Young Kim; Hyun Yang Yeo; Ji Yeon Baek; Moon Ki Choi; Kyung Hae Jung; Seung Myung Dong; Hee Jin Chang Journal: Neoplasia Date: 2018-12-15 Impact factor: 5.715