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Randomized phase II study of CAPTEM versus FOLFIRI in RAS mutated, MGMT methylated metastatic colorectal cancer (mCRC): final analysis, tumor biomarkers and methylated ctDNA

Date

29 Sep 2019

Session

Poster Discussion – Gastrointestinal tumours, colorectal

Presenters

Filippo Pietrantonio

Citation

Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394

Authors

F. Pietrantonio1, M. Antista2, R. Lobefaro1, F. Morano3, S. Lonardi4, A. Raimondi5, S. Murgioni6, L. Rimassa7, G. Farina8, R. Longarini9, S. Mosconi10, A. Sartore-Bianchi11, G. Tomasello12, F. Perrone2, L. Barault13, M. Milione14, M. Di Maio15, F. Di Nicolantonio16, M. Di Bartolomeo5, F.G.M. De Braud17

Author affiliations

  • 1 Medical Oncology Dept., Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
  • 2 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 3 Medical Oncology 1, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
  • 4 Medical oncology 1 Unit, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 5 Medical Oncology Department, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
  • 6 Medical Oncology Department, Istituto Oncologico Veneto IRCCS, 35128 - Padova/IT
  • 7 Humanitas Cancer Center, Istituto Clinico Humanitas, 20089 - Rozzano/IT
  • 8 Medical Oncology Department, A.O. Fatebenefratelli e Oftalmico, 20121 - Milan/IT
  • 9 Medical Oncology Department, A.O. S. Gerardo, 20900 - Monza/IT
  • 10 Oncologia Medica, A.O. Papa Giovanni XXIII, 24127 - Bergamo/IT
  • 11 Niguarda Cancer Center And Department Of Oncology And Hemato-oncology, Grande Ospedale Metropolitano Niguarda and University of Milan, Milan/IT
  • 12 Oncology, ASST Grande Ospedale Metropolitano Niguarda, 20162 - Milan/IT
  • 13 Department Of Oncology, Candiolo Cancer Institute - FPO, 10060 - Turin/IT
  • 14 Anatomic Pathology Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 15 Dipartimento Di Oncologia, Università degli Studi di Torino, 10128 - Torino/IT
  • 16 Laboratorio Di Epigenetica Del Cancro, Istituto di Candiolo, FPO -IRCCS, 10060 - Candiolo/IT
  • 17 Medical Oncology & Haemathology Dept., Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
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Background

In non-randomized trials, temozolomide (TMZ) has shown activity in about 10% of pts with chemorefractory mCRC bearing MGMT methylation.

Methods

This multicenter, randomized phase II trial investigated PFS superiority of second-line CAPTEM (Arm A) vs FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts had ECOG PS 0-1, measurable disease, and failed prior oxaliplatin-based therapy. Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28) or B was stratified according to time elapsed from the start of oxaliplatin-based therapy and PD (

Results

A total of 86 pts were randomized (43 per arm). After a median follow-up of 30.5 months (IQR 12.2-36.3), 79 disease PFS events occurred. PFS and OS were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) months in arm A vs 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B (HR = 1.86 [0.82-1.72] and HR = 0.97 [0.58-1.61]), respectively. ORR and DCR were 11.6% and 53.5% in both arms. 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. In the subgroup with negative MGMT IHC expression, there were no significant differences between the two arms in terms of activity and efficacy endpoints, whereas in pts with positive MGMT IHC expression CAPTEM regimen was associated with significantly inferior outcomes in terms of PFS (2.0 vs 3.5 mos; HR = 2.08 [1.02-4.21]), OS (5.7 vs 10.6 mos; OR = 1.07 [0.39-2.93]) and DCR (15.4 vs 56.5%; OR = 0.23 [0.04-0.99]), interaction test p = 0.125, 0.732, 0.028. Predicting outcomes with MB was more accurate when using ctDNA vs tumor DNA.

Conclusions

TMZ-based treatment should be investigated by a phase III trial, ideally conducted in patients with MGMT methylated/MGMT IHC negative tumors.

Clinical trial identification

NCT02414009.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale Tumori di Milano.

Funding

Fondazione IRCCS Istituto Nazionale Tumori di Milano.

Disclosure

F. Pietrantonio: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. F. Morano: Honoraria (self): Servier Italia SpA . S. Lonardi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Bristol-Mayers-Squibb. L. Rimassa: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Italfarmaco; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Baxter; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: ArQule; Honoraria (self), Advisory / Consultancy: Xelixis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai. A. Sartore-Bianchi: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Honoraria (self), Advisory / Consultancy: TizianaLife Sciences; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Pharm Research Associated; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Octimet Oncology; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Teofarma; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini. All other authors have declared no conflicts of interest.

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