Capecitabine and Temozolomide versus FOLFIRI in RAS-Mutated, MGMT-Methylated Metastatic Colorectal Cancer.

Filippo Pietrantonio, Riccardo Lobefaro, Maria Antista, Sara Lonardi, Alessandra Raimondi, Federica Morano, Stefania Mosconi, Lorenza Rimassa, Sabina Murgioni, Andrea Sartore-Bianchi, Gianluca Tomasello, Raffaella Longarini, Gabriella Farina, Fausto Petrelli, Stefania Gori, Giovanni Randon, Salvatore Corallo, Filippo Pagani, Vincenzo Guarini, Federica PalermoAntonia Martinetti, Marco Macagno, Ludovic Barault, Federica Perrone, Elena Tamborini, Massimo Milione, Federica Di Nicolantonio, Massimo Di Maio, Giovanni Fucà, Maria Di Bartolomeo, Filippo de Braud

Research output: Contribution to journalArticlepeer-review

Abstract

To determine whether second-line therapy with capecitabine and temozolomide was superior to irinotecan, leucovorin, and fluorouracil (FOLFIRI) in patients with -mutated, methyl-guanine methyltransferase ( )-methylated metastatic colorectal cancer (mCRC). In this randomized, phase II trial, we enrolled patients with -mutated, -methylated mCRC after failure of oxaliplatin-based regimen. Patients with centrally confirmed methylation were stratified by first-line progression-free survival (PFS) and prior bevacizumab and randomized to either capecitabine plus temozolomide (arm A, CAPTEM) or FOLFIRI (arm B). The primary endpoint was PFS analyzed on intention-to-treat basis, with 90% power and one-sided significance level of 0.05 to detect an increase of median time from 2 months in arm B to 4 months in arm A. Between November 2014 and May 2019, 86 patients were randomly assigned to arm A ( = 43) or arm B ( = 43). After a median follow-up of 30.5 months (interquartile range, 12.2-36.3), 79 disease progression or death events occurred. Superiority of arm A was not demonstrated (one-sided = 0.223). Progression-free survival and overall survival were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) in arm A versus 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B [HR = 1.19 (0.82-1.72) and HR = 0.97 (0.58-1.61)], respectively. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. Patients with positive MGMT expression by IHC did not benefit from CAPTEM. Temozolomide-based therapy warrants further investigation in molecularly hyperselected subgroups.
Original languageUndefined/Unknown
Pages (from-to)1017-1024
Number of pages8
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume26
DOIs
Publication statusPublished - Mar 1 2020

Keywords

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • therapeutic use
  • Bevacizumab
  • administration & dosage
  • Biomarkers
  • Tumor
  • genetics
  • metabolism
  • Camptothecin
  • Capecitabine
  • Colorectal Neoplasms
  • drug therapy
  • pathology
  • DNA Methylation
  • DNA Modification Methylases
  • DNA Repair Enzymes
  • Female
  • Fluorouracil
  • Humans
  • Irinotecan
  • Leucovorin
  • Male
  • Middle Aged
  • Oxaliplatin
  • Proto-Oncogene Proteins p21(ras)
  • Quality of Life
  • Survival Rate
  • Temozolomide
  • Treatment Outcome
  • Tumor Suppressor Proteins

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