Abstract 124P
Background
PD-1 inhibitors have proven effective against mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumors; however, the efficacy of PD-L1 inhibitors, such as durvalumab, remains to be established in these tumors. In the Drug Rediscovery Protocol (DRUP) patients (pts) are treated with drugs outside their labeled indication, based on a specific tumor molecular profile in multiple parallel cohorts (NCT02925234). Here, we report the results of the tumor-agnostic cohort ‘’durvalumab for dMMR/MSI-H solid tumors’’.
Methods
Eligible pts had advanced dMMR/MSI-H solid tumors and exhausted all treatment options. Durvalumab 1500mg every 4 weeks was administered until disease progression or unacceptable toxicity. Primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease (SD) ≥16 weeks) and safety. Pts were enrolled using a Simon like 2-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1/8 pts had CB in stage 1. At baseline, biopsies for biomarker analyses, including whole genome sequencing (WGS), were obtained.
Results
24 evaluable pts with 10 different cancer types were included: colorectal (n=7), bile duct (n=3), breast (n=2), endometrial (n=2), gastric (n=3), small intestine (n=3), glioblastoma (n=1), neuroendocrine (n=1), pancreatic (n=1) and prostate (n=1). CB was observed in 13 pts (54%) with an OR in 7 (29%). Median progression-free survival was 5 months (95% CI 2-not reached) and median overall survival was 26 months (95% CI 9-not reached). No unexpected toxicity was observed. WGS was successfully performed in 17 pts and confirmed MSI-H in 88%. Interestingly, pts without CB had significantly higher structural variant tumor mutation burden (SVTMB) than pts with CB (median SVTMB 300 vs. 138, P 0.026). Additionally, we observed two JAK1 frameshift mutations (K860/P430) in 4 pts, all without CB, suggesting a JAK1-mediated immune checkpoint inhibitor resistance mechanism.
Conclusions
Durvalumab provided durable responses in pts with advanced dMMR/MSI-H solid tumors and was well-tolerated. Higher SVTMB and the presence of JAK1 mutations were associated with a lack of CB; however, larger studies are warranted to validate these findings.
Clinical trial identification
NCT02925234; Release data: 28 August 2016.
Editorial acknowledgement
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
Stelvio for life: funding; Dutch Cancer Society (KWF): funding; Hartwig Medical Foundation (HMF): sequencing; Pharmaceutical partners (Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Janssen, Lilly, Merck, Novartis, Pfizer, Roche): funding and study drugs.
Disclosure
F.L. Opdam: Non-Financial Interests, Principal Investigator: GSK, Int1B3, AstraZeneca, Cytovation, Relay, Taiho, Roche, Merus, Boehringer Ingelheim, Crescendo, Pierre Fabre, Lilly, RevMed. J.W.B. de Groot: Financial Interests, Institutional, Advisory Board: BMS, Pierre Fabre, Servier. E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate, to charity: Biogeneration Ventures; Financial Interests, Institutional, Advisory Board, Hourly rate, no compensation in 2019-2020: InteRNA; Financial Interests, Institutional, Invited Speaker, DRUP trial: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Invited Speaker, DRUP trial DRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Invited Speaker, DRUG Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: Jama Oncology; Non-Financial Interests, Leadership Role, Board of Directors: Cancer Core Europe. All other authors have declared no conflicts of interest.