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Clinical Trial
. 2020 Feb;5(1):e000638.
doi: 10.1136/esmoopen-2019-000638.

Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study

David Lau  1 , Eleftheria Kalaitzaki  1 , David N Church  2 , Hardev Pandha  3 , Ian Tomlinson  4 , Nicola Annels  3 , Marco Gerlinger  5 , Francesco Sclafani  1 , Gillian Smith  1 , Ruwaida Begum  1 , Richard Crux  1 , Angela Gillbanks  1 , Sarah Wordsworth  6 , Ian Chau  1 , Naureen Starling  1 , David Cunningham  1 , Tony Dhillon  7   8
Affiliations
Clinical Trial

Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study

David Lau et al. ESMO Open. 2020 Feb.

Abstract

Background: 10%-15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or POLE exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show POLE-mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or POLE mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS).

Methods: We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or POLE exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018.

Trial registration number: NCT03827044.

Keywords: POLE mutation; adjuvant therapy; colon cancer; microsatellite instability; mismatch repair.

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Conflict of interest statement

Competing interests: IC has received advisory board fees from AstraZeneca, Bayer, Bristol Meyers Squibb, Eli-Lilly, Five Prime Therapeutics, Merck Serono, MSD, Pierre Fabre, Oncologie International and Roche; received research funding from Eli-Lilly, Janssen-Cilag, Merck Serono and Sanofi Oncology and honoraria from Eli-Lilly outside the submitted work. NS has received research funding from AstraZeneca, Bristol-Myers Squibb, Merck Serono and honoraria from AstraZeneca. DNC has research funding from Amgen, Sanofi, Merrimack, AZ, Celgene, MedImmune, Bayer, 4SC, Clovis, Eli Lilly, Janssen and Merck. TD has research funding from Merck Serono/Pfizer, honorarium/advisory board fees from Bayer, MSD, Sanofi Aventis, Amgen, Servier and Everything Genetic.

Figures

Figure 1
Figure 1
Study design of the POLEM trial. *Capecitabine chemotherapy for 24 weeks or capecitabine/oxaliplatin for 12 weeks. dMMR, deficient mismatch repair; MSI-H, microsatellite instability high; MSS, microsatellite stable; pMMR, proficient mismatch repair.
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