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

F. Morano, S. Corallo, M. Niger, L. Barault, M. Milione, R. Berenato, R. Moretto, G. Randon, M. Antista, A. Belfiore, A. Raimondi, F. Nichetti, A. Martinetti, L. Battaglia, F. Perrone, G. Pruneri, A. Falcone, M. Di Bartolomeo, F. De Braud, F. Di NicolantonioC. Cremolini, F. Pietrantonio

Research output: Contribution to journalArticle

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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 ¼ 0.29, 95% CI 0.02-0.41; P ¼ 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.

Original languageEnglish
Pages (from-to)1800-1806
Number of pages7
JournalAnnals of Oncology
Volume29
Issue number8
DOIs
Publication statusPublished - Jan 1 2018

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irinotecan
temozolomide
Salvage Therapy
Methyltransferases
DNA Methylation
Colorectal Neoplasms
DNA
Microsatellite Repeats
Methylation
Disease-Free Survival
Immunohistochemistry
Confidence Intervals
Survival

Keywords

  • Colorectal cancer
  • Irinotecan
  • MGMT
  • TEMIRI
  • Temozolomide

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation. / Morano, F.; Corallo, S.; Niger, M.; Barault, L.; Milione, M.; Berenato, R.; Moretto, R.; Randon, G.; Antista, M.; Belfiore, A.; Raimondi, A.; Nichetti, F.; Martinetti, A.; Battaglia, L.; Perrone, F.; Pruneri, G.; Falcone, A.; Di Bartolomeo, M.; De Braud, F.; Di Nicolantonio, F.; Cremolini, C.; Pietrantonio, F.

In: Annals of Oncology, Vol. 29, No. 8, 01.01.2018, p. 1800-1806.

Research output: Contribution to journalArticle

Morano, F, Corallo, S, Niger, M, Barault, L, Milione, M, Berenato, R, Moretto, R, Randon, G, Antista, M, Belfiore, A, Raimondi, A, Nichetti, F, Martinetti, A, Battaglia, L, Perrone, F, Pruneri, G, Falcone, A, Di Bartolomeo, M, De Braud, F, Di Nicolantonio, F, Cremolini, C & Pietrantonio, F 2018, 'Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation', Annals of Oncology, vol. 29, no. 8, pp. 1800-1806. https://doi.org/10.1093/annonc/mdy197
Morano, F. ; Corallo, S. ; Niger, M. ; Barault, L. ; Milione, M. ; Berenato, R. ; Moretto, R. ; Randon, G. ; Antista, M. ; Belfiore, A. ; Raimondi, A. ; Nichetti, F. ; Martinetti, A. ; Battaglia, L. ; Perrone, F. ; Pruneri, G. ; Falcone, A. ; Di Bartolomeo, M. ; De Braud, F. ; Di Nicolantonio, F. ; Cremolini, C. ; Pietrantonio, F. / Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation. In: Annals of Oncology. 2018 ; Vol. 29, No. 8. pp. 1800-1806.
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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 ¼ 0.29, 95{\%} CI 0.02-0.41; P ¼ 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.",
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T1 - Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation

AU - Morano, F.

AU - Corallo, S.

AU - Niger, M.

AU - Barault, L.

AU - Milione, M.

AU - Berenato, R.

AU - Moretto, R.

AU - Randon, G.

AU - Antista, M.

AU - Belfiore, A.

AU - Raimondi, A.

AU - Nichetti, F.

AU - Martinetti, A.

AU - Battaglia, L.

AU - Perrone, F.

AU - Pruneri, G.

AU - Falcone, A.

AU - Di Bartolomeo, M.

AU - De Braud, F.

AU - Di Nicolantonio, F.

AU - Cremolini, C.

AU - Pietrantonio, F.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 ¼ 0.29, 95% CI 0.02-0.41; P ¼ 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.

AB - 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 ¼ 0.29, 95% CI 0.02-0.41; P ¼ 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.

KW - Colorectal cancer

KW - Irinotecan

KW - MGMT

KW - TEMIRI

KW - Temozolomide

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U2 - 10.1093/annonc/mdy197

DO - 10.1093/annonc/mdy197

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AN - SCOPUS:85055211679

VL - 29

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EP - 1806

JO - Annals of Oncology

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