학술논문
Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours
Document Type
article
Author
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
Source
BMC Cancer, Vol 23, Iss 1, Pp 1-14 (2023)
Subject
Language
English
ISSN
1471-2407
Abstract
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.