TY - JOUR
T1 - Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours
AU - Geurts, Birgit S.
AU - Battaglia, Thomas W.
AU - van Berge Henegouwen, J. Maxime
AU - Zeverijn, Laurien J.
AU - de Wit, Gijs F.
AU - Hoes, Louisa R.
AU - van der Wijngaart, Hanneke
AU - van der Noort, Vincent
AU - Roepman, Paul
AU - de Leng, Wendy W. J.
AU - Jansen, Anne M. L.
AU - Opdam, Frans L.
AU - de Jonge, Maja J. A.
AU - Cirkel, Geert A.
AU - Labots, Mariette
AU - Hoeben, Ann
AU - Kerver, Emile D.
AU - Bins, Adriaan D.
AU - Erdkamp, Frans G. L.
AU - van Rooijen, Johan M.
AU - Houtsma, Danny
AU - Hendriks, Mathijs P.
AU - de Groot, Jan-Willem B.
AU - Verheul, Henk M. W.
AU - Gelderblom, Hans
AU - Voest, Emile E.
N1 - 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).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
KW - Durvalumab
KW - Immunotherapy
KW - Microsatellite instability
KW - Mismatch repair deficiency
KW - Precision medicine
UR - https://www.scopus.com/pages/publications/85149586789
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85149586789&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/36870947
U2 - 10.1186/s12885-023-10663-2
DO - 10.1186/s12885-023-10663-2
M3 - Article
C2 - 36870947
SN - 1471-2407
VL - 23
JO - BMC cancer
JF - BMC cancer
IS - 1
M1 - 205
ER -
SDG 3 Good Health and Well-being