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 Rooijen; D. Houtsma; M.P. Hendriks; J.W.B. de Groot; H.M.W. Verheul; H. Gelderblom; E.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

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 journal › Article › Academic › peer-review

Abstract

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 language	English
Article number	205
Number of pages	14
Journal	BMC Cancer
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s12885-023-10663-2
Publication status	Published - 4 Mar 2023

Keywords

Durvalumab
Immunotherapy
Microsatellite instability
Mismatch repair deficiency
Precision medicine
OPEN-LABEL
RESISTANCE
PEMBROLIZUMAB
BLOCKADE
CRITERIA

Access to Document

10.1186/s12885-023-10663-2Licence: CC BY

Cite this

Geurts, B. S., Battaglia, T. W., Henegouwen, J. M. V., 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{c35b56a5c8b944fb869918f9aab7c2a3,

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

abstract = "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.",

keywords = "Durvalumab, Immunotherapy, Microsatellite instability, Mismatch repair deficiency, Precision medicine, OPEN-LABEL, RESISTANCE, PEMBROLIZUMAB, BLOCKADE, CRITERIA",

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

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 = mar,

day = "4",

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

language = "English",

volume = "23",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central Ltd",

number = "1",

}

Geurts, BS, Battaglia, TW, Henegouwen, JMV, 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, JWB, 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, B.S.

AU - Battaglia, T.W.

AU - Henegouwen, J.M.V.

AU - Zeverijn, L.J.

AU - de Wit, G.F.

AU - Hoes, L.R.

AU - van der Wijngaart, H.

AU - van der Noort, V.

AU - Roepman, P.

AU - de Leng, W.W.J.

AU - Jansen, A.M.L.

AU - Opdam, F.L.

AU - de Jonge, M.J.A.

AU - Cirkel, G.A.

AU - Labots, M.

AU - Hoeben, A.

AU - Kerver, E.D.

AU - Bins, A.D.

AU - Erdkamp, F.G.L.

AU - van Rooijen, J.M.

AU - Houtsma, D.

AU - Hendriks, M.P.

AU - de Groot, J.W.B.

AU - Verheul, H.M.W.

AU - Gelderblom, H.

AU - Voest, E.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 - 2023/3/4

Y1 - 2023/3/4

N2 - 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.

AB - 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.

KW - Durvalumab

KW - Immunotherapy

KW - Microsatellite instability

KW - Mismatch repair deficiency

KW - Precision medicine

KW - OPEN-LABEL

KW - RESISTANCE

KW - PEMBROLIZUMAB

KW - BLOCKADE

KW - CRITERIA

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 -