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:10.1186/s12885-023-10663-2

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

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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 language	English
Article number	205
Journal	BMC Cancer
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12885-023-10663-2
Publication status	Published - Dec 2023

Keywords

Biomarkers
Brain Neoplasms
Humans
Microsatellite Instability
Mismatch repair deficiency
Precision medicine
Durvalumab
Immunotherapy
Microsatellite instability

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Geurts, B. S., Battaglia, T. W., van Berge Henegouwen, J. M., Zeverijn, L. J., de Wit, G. F., Hoes, L. R., van der Wijngaart, H., van der Noort, V., Roepman, P., de Leng, W. W. J., Jansen, A. M. L., Opdam, F. L., de Jonge, M. J. A., Cirkel, G. A., Labots, M., Hoeben, A., Kerver, E. D., Bins, A. D., Erdkamp, F. G. L., ... Voest, E. E. (2023). Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours. BMC Cancer, 23(1), Article 205. https://doi.org/10.1186/s12885-023-10663-2

@article{cd35fd0abe1c4e88b138df1e9f23bd23,

title = "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.",

keywords = "Biomarkers, Brain Neoplasms, Humans, Microsatellite Instability, Mismatch repair deficiency, Precision medicine, Durvalumab, Immunotherapy, Microsatellite instability",

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

note = "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{\textquoteright}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: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1186/s12885-023-10663-2",

language = "English",

volume = "23",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central",

number = "1",

}

Geurts, BS, Battaglia, TW, van Berge Henegouwen, JM, Zeverijn, LJ, de Wit, GF, Hoes, LR, van der Wijngaart, H, van der Noort, V, Roepman, P, de Leng, WWJ, Jansen, AML, Opdam, FL, de Jonge, MJA, Cirkel, GA, Labots, M, Hoeben, A, Kerver, ED, Bins, AD, Erdkamp, FGL, van Rooijen, JM, Houtsma, D, Hendriks, MP, de Groot, J-WB, Verheul, HMW, Gelderblom, H & Voest, EE 2023, 'Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours', BMC Cancer, vol. 23, no. 1, 205. https://doi.org/10.1186/s12885-023-10663-2

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

Y1 - 2023/12

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 - Biomarkers

KW - Brain Neoplasms

KW - Humans

KW - Microsatellite Instability

KW - Mismatch repair deficiency

KW - Precision medicine

KW - Durvalumab

KW - Immunotherapy

KW - Microsatellite instability

UR - http://www.scopus.com/inward/record.url?scp=85149586789&partnerID=8YFLogxK

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 -

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

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