Dataset Information

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

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.

SUBMITTER: Geurts BS

PROVIDER: S-EPMC9985217 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Geurts Birgit S BS Battaglia Thomas W TW van Berge Henegouwen J Maxime JM Zeverijn Laurien J LJ de Wit Gijs F GF Hoes Louisa R LR van der Wijngaart Hanneke H van der Noort Vincent V Roepman Paul P de Leng Wendy W J WWJ Jansen Anne M L AML Opdam Frans L FL de Jonge Maja J A MJA Cirkel Geert A GA Labots Mariette M Hoeben Ann A Kerver Emile D ED Bins Adriaan D AD Erdkamp Frans G L FGL van Rooijen Johan M JM Houtsma Danny D Hendriks Mathijs P MP de Groot Jan-Willem B JB Verheul Henk M W HMW Gelderblom Hans H Voest Emile E EE

BMC cancer 20230304 1

<h4>Background</h4>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.<h4>Patients and methods</h4>Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care o ...[more]

PMID: 36870947

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Dataset Information

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

Background

Patients and methods

Results

Conclusion

Trial registration

Publications

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

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