A phase I trial of LHC165 single agent and in combination with spartalizumab in patients with advanced solid malignancies

LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agen...

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Published in:	ESMO open Vol. 9; no. 8; p. 103643
Main Authors:	Curigliano, G., Jimenez, M.M., Shimizu, T., Keam, B., Meric-Bernstam, F., Rutten, A., Glaspy, J., Schuler, P.J., Parikh, N.S., Ising, M., Hassounah, N., Wu, J., Leyk, M., Chen, X., Burks, H., Chaudhury, A., Otero, J., Cabanas, E.Garralda
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-08-2024 Elsevier
Subjects:	advanced solid tumors LHC165 Original Research PDR001 TLR7 agonist advanced solid tumors PDR001 TLR7 agonist LHC165
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Summary:	LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors. In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion. Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site. LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors. •This is a first-in-human study of LHC165, an IT TLR agonist, in adult patients with advanced malignancies.•LHC165 showed limited antitumor activity and acceptable safety with/without spartalizumab, an IV PD-1 inhibitor.•AEs with LHC165 therapy were generally mild to moderate, manageable with dose reductions and treatment delays.•The recommended dose for expansion was LHC165 600 μg biweekly IT and spartalizumab 400 mg every 4 weeks IV.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Wakayama Medical University Hospital, Wakayama, Japan.
ISSN:	2059-7029 2059-7029
DOI:	10.1016/j.esmoop.2024.103643