Abstract
Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer
(mCRC) patients except those with dMMR/MSI tumors. However, until very recently we
had only non-comparative promising data in this population with anti-programmed cell
death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with
anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies.
This comparative phase II trial (NCT 03186326), conducted in more than 100 centers
in France, will include dMMR/MSI mCRC patients with progression after a first-line
treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety
of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion
criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC
and failure of a standard first-line regimen. Patient will be randomised to receive
Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted
agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is
expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints
include objective response rate, overall survival, quality of life and toxicity. In
addition, circulating tumour DNA and microbiota will be explored to test their potential
prognostic and predictive values. The study was opened in March 2018.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Digestive and Liver DiseaseAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.Cell. 2015; 161: 205-214https://doi.org/10.1016/j.cell.2015.03.030
- Colorectal cancer and immunity: what we know and perspectives.World J Gastroenterol. 2014; 20: 3738-3750https://doi.org/10.3748/wjg.v20.i14.3738
- Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.Science. 2006; 313: 1960-1964https://doi.org/10.1126/science.1129139
- Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations.Mod Pathol. 2009; 22: 1186-1195https://doi.org/10.1038/modpathol.2009.80
- Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability.Immunity. 2016; 44: 698-711https://doi.org/10.1016/j.immuni.2016.02.025
- Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy.Cancer Res. 2015; 75: 3446-3455https://doi.org/10.1158/0008-5472.CAN-14-3051
- Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.Eur J Cancer. 2013; 49: 2233-2242https://doi.org/10.1016/j.ejca.2013.02.015
- Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: a pooled analysis from 2 randomized clinical trials.JAMA Oncol. 2018; 4: 379-383https://doi.org/10.1001/jamaoncol.2017.2899
- Predictors of disease-free survival in colorectal cancer with microsatellite instability: an AGEO multicentre study.Eur J Cancer. 2015; 51: 925-934https://doi.org/10.1016/j.ejca.2015.03.011
- Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.Br J Cancer. 2009; 100: 266-273https://doi.org/10.1038/sj.bjc.6604867
- Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies.Ann Oncol. 2019; 30: 1466-1471https://doi.org/10.1093/annonc/mdz208
- Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: an AGEO retrospective multicenter study.Int J Cancer. 2020; 147: 285-296https://doi.org/10.1002/ijc.32879
- Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.Clin Cancer Res. 2014; 20: 5322-5330https://doi.org/10.1158/1078-0432.CCR-14-0332
- PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520https://doi.org/10.1056/NEJMoa1500596
- A phase II study of Avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer.Cancer Res Treat. 2020; 52: 1135-1144https://doi.org/10.4143/crt.2020.218
- Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study [published correction appears in Lancet Oncol.Lancet Oncol. 2017; 18 (2017 Sep;18(9):e510]): 1182-1191https://doi.org/10.1016/S1470-2045(17)30422-9
- Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.J Clin Oncol. 2018; 36: 773-779https://doi.org/10.1200/JCO.2017.76.9901
- Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.Nat Med. 2020; 26: 566-576https://doi.org/10.1038/s41591-020-0805-8
Andre T., Shiu K.K., Kim T.W., Jense B.V.n., Jensen H.L., Punt C.J., et al.; Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch re-pair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study abstract: LBA4; ASCO 2020
- Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 1374-1385https://doi.org/10.1016/S1470-2045(16)30364-3
- Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status.JAMA Oncol. 2019; 5: 551-555https://doi.org/10.1001/jamaoncol.2018.4942
- Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study).Clin Cancer Res. 2017; 23: 5416-5425https://doi.org/10.1158/1078-0432.CCR-16-3155
- Metastatic colorectal cancer (mCRC): french intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).Dig Liver Dis. 2019; 51: 1357-1363https://doi.org/10.1016/j.dld.2019.05.035
- Anti program death-1/anti program death-ligand 1 in digestive cancers.World J Gastrointest Oncol. 2015; 7: 95-101https://doi.org/10.4251/wjgo.v7.i8.95
- Prognostic and predictive value of the Immunoscore in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France PRODIGE-GERCOR cohort study [published correction appears in Ann Oncol.Ann Oncol. 2020; 31 (2020 Sep;31(9):1276]): 921-929https://doi.org/10.1016/j.annonc.2020.03.310
- International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.Lancet. 2018; 391: 2128-2139https://doi.org/10.1016/S0140-6736(18)30789-X
Article info
Publication history
Published online: December 25, 2020
Accepted:
November 26,
2020
Received:
November 13,
2020
Identification
Copyright
© 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
