Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours
Geurts, Birgit S; Battaglia, Thomas W; van Berge Henegouwen, J Maxime; Zeverijn, Laurien J; de Wit, Gijs F; Hoes, Louisa R; van der Wijngaart, Hanneke; van der Noort, Vincent; Roepman, Paul; de Leng, Wendy W J; Jansen, Anne M L; Opdam, Frans L; de Jonge, Maja J A; Cirkel, Geert A; Labots, Mariette; Hoeben, Ann; Kerver, Emile D; Bins, Adriaan D; Erdkamp, Frans G L; van Rooijen, Johan M; Houtsma, Danny; Hendriks, Mathijs P; de Groot, Jan-Willem B; Verheul, Henk M W; Gelderblom, Hans; Voest, Emile E
(2023) BMC Cancer, volume 23, issue 1
(Article)
Abstract
BACKGROUND: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication,
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based on their tumour molecular profile. PATIENTS AND METHODS: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. RESULTS: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. CONCLUSION: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. TRIAL REGISTRATION: Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
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Keywords: Biomarkers, Brain Neoplasms, Humans, Microsatellite Instability, Mismatch repair deficiency, Precision medicine, Durvalumab, Immunotherapy, Microsatellite instability, Genetics, Oncology, Cancer Research, Journal Article
ISSN: 1471-2407
Publisher: BioMed Central
Note: Funding Information: The Drug Rediscovery Protocol team thanks the Stelvio for Life Foundation and the Dutch Cancer Society for their financial support; AstraZeneca for their in-kind and financial support; the Centre for Personalized Cancer Treatment; Multidisciplinary Expert Board for supporting the central case-review process; the Independent Data Monitoring Committee for their advice on cohort decisions and the monitoring of preliminary safety data; the Netherlands Cancer Institute’s Biobank Facility, Scientific Department and Pharmacy for their facilitating services; the Hartwig Medical Foundation for their in-kind support by providing sequencing on baseline biopsies; and all participating hospitals for supporting and facilitating the conduct of the DRUP trial. Funding Information: The DRUP trial is supported by the Stelvio for Life Foundation, [grant number not applicable]; the Dutch Cancer Society [grant number 10014]; and received equal funding from a number of pharmaceutical companies, among which AstraZeneca. Publisher Copyright: © 2023, The Author(s).
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