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

B.S. Geurts, T.W. Battaglia, J.M.V. Henegouwen, L.J. Zeverijn, G.F. de Wit, L.R. Hoes, H. van der Wijngaart, V. van der Noort, P. Roepman, W.W.J. de Leng, A.M.L. Jansen, F.L. Opdam, M.J.A. de Jonge, G.A. Cirkel, M. Labots, A. Hoeben, E.D. Kerver, A.D. Bins, F.G.L. Erdkamp, J.M. van RooijenD. Houtsma, M.P. Hendriks, J.W.B. de Groot, H.M.W. Verheul, H. Gelderblom, E.E. Voest*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


BackgroundIn 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 methodsPatients 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.ResultsTwenty-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-gamma expression in patients without CB.ConclusionDurvalumab 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-gamma expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings.
Original languageEnglish
Article number205
Number of pages14
JournalBMC Cancer
Issue number1
Publication statusPublished - 4 Mar 2023


  • Durvalumab
  • Immunotherapy
  • Microsatellite instability
  • Mismatch repair deficiency
  • Precision medicine


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