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Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: The ARETHUSA trial
Open accessAbstract
TPS2659 Background: Metastatic colorectal cancer (CRC) harbouring genetic defects in the mismatch-repair pathway (MMRd) presents with a high tumor mutational burden (TMB), and is highly sensitive to anti–programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes, and consequently the increase of TMB and immunogenic neoantigens, thus suggesting that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods: Arethusa (NCT03519412) is a 2-cohorts, phase II trial consisting of three different phases. In the SCREENING, 348 mCRC RAS-mutated patients will be tested for MMR status. MMRd patients will proceed directly to TRIAL for immediate pembrolizumab treatment (expected 14). MMR-proficient (MMRp) patients will be further tested for expression of O 6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. IHC-negative, promoter methylation-positive MMRp patients (expected 67) will enter in the PRIMING phase and will be treated with TMZ until PD. TMB will then be assessed on tumor biopsies at resistance. Those patients that will have > 20 mutations/megabase will proceed to TRIAL (expected 20) and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated., while the MMRd cohort will be used for comparison. Tissue biopsies, longitudinal blood and stool collection will be used for discovery of predictive molecular biomarkers and assessment of tumor evolution. Clinical trial information: NCT03519412.
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The ARETHUSA trial demonstrated that increasing tumor mutational burden with TMZ priming treatment and achieving disease control with pembrolizumab could be shown in a limited number of patients.
“This study demonstrated that increasing the tumor mutational burden (TMB) with TMZ priming treatment and achieving disease control with pembrolizumab could be shown in a limited number of patients.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [89]
All patients in the ARETHUSA study were RAS mutant, and the majority (72%) of patients in the MAYA study were RAS mutant.
“All patients in the ARETHUSA study were RAS mutant patients, and the majority (72%) of the patients in the MAYA study were RAS mutant patients.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [89]
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Metadata
- Authors
- Siena, S., Sartore-Bianchi, A., Personeni, N., Pietrantonio, F., Germano, G., Amatu, A., Bonoldi, E., Valtorta, E., Barault, L., Di Nicolantonio, F., Siravegna, G., Crisafulli, G., Rimassa, L., De Braud, F. G., Santoro, A., Lazzari, L., Luraghi, P., Amirouchene-Angelozzi, N., Bardelli, A., & Marsoni, S.
- Affiliations
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy;
- IRCCS Humanitas Research Hospital (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Candiolo Cancer Institute (IT)
- Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy;
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;
- IFOM (IT)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- TPS2659-TPS2659
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2947553355
- Cited by
- 15
- References
- 0
- Citations by year
- 2025: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3
- Type
- conference abstract
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, temozolomide, mismatch repair deficiency, tumor mutational burden, PD-1 inhibitors, MGMT promoter methylation, O6-methylguanine-DNA methyltransferase, predictive biomarkers
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