BMC Cancer (Mar 2023)

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 Rooijen,
  • Danny Houtsma,
  • Mathijs P. Hendriks,
  • Jan-Willem B. de Groot,
  • Henk M. W. Verheul,
  • Hans Gelderblom,
  • Emile E. Voest

DOI
https://doi.org/10.1186/s12885-023-10663-2
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 14

Abstract

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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.

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