Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours

Birgit S. Geurts, Thomas W. Battaglia, J. Maxime van Berge Henegouwen, Laurien J. Zeverijn, Gijs F. de Wit, Louisa R. Hoes, Hanneke van der Wijngaart, Vincent van der Noort, Paul Roepman, Wendy W.J. de Leng, Anne M.L. Jansen, Frans L. Opdam, Maja J.A. de Jonge, Geert A. Cirkel, Mariette Labots, Ann Hoeben, Emile D. Kerver, Adriaan D. Bins, Frans G.L. Erdkamp, Johan M. van RooijenDanny Houtsma, Mathijs P. Hendriks, Jan Willem B. de Groot, Henk M.W. Verheul, Hans Gelderblom, Emile E. Voest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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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, 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.

Original languageEnglish
Article number205
JournalBMC Cancer
Volume23
Issue number1
DOIs
Publication statusPublished - 4 Mar 2023

Bibliographical note

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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