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Phase 1b/2 study evaluating safety, efficacy and immune effects of TLR9 agonist cavrotolimod with anti-PD-1 antibodies among patients with advanced solid tumors
Journal article   Open access   Peer reviewed

Phase 1b/2 study evaluating safety, efficacy and immune effects of TLR9 agonist cavrotolimod with anti-PD-1 antibodies among patients with advanced solid tumors

Mohammed M Milhem, Trisha M Wise-Draper, Sunandana Chandra, Glenn J Hanna, Douglas E Laux, Theresa M Medina, George Ansstas, Adil Daud, Ciara M Kelly, Steven J O’Day, …
Journal for immunotherapy of cancer, Vol.13(7), e011651
07/25/2025
DOI: 10.1136/jitc-2025-011651
PMCID: PMC12306225
PMID: 40713179
url
https://doi.org/10.1136/jitc-2025-011651View
Published (Version of record) Open Access

Abstract

BackgroundThere is an unmet need for novel immunotherapies to overcome immune evasion in patients with advanced skin cancers resistant to programmed death (PD)-1 / PD-ligand 1 (PD-L1) blockade. Cavrotolimod is a novel spherical nucleic acid configuration of a toll-like receptor 9 agonist oligonucleotide, designed to trigger innate and adaptive immune responses to tumors.Patients and methodsThe safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod, first dosed alone and then in combination with anti-PD-1 antibodies (pembrolizumab or cemiplimab), were assessed in a combined Phase 1b/2 dose escalation/dose expansion study in patients with advanced skin cancers, including melanoma, Merkel cell carcinoma and cutaneous squamous cell carcinoma (www.clinicaltrials.gov; NCT03684785).ResultsA total of 58 patients (20 in dose-escalation and 38 in expansion cohorts) were enrolled. 55 (95%) of the 58 patients experienced progressive disease on prior anti-PD-(L)1 therapy. Cavrotolimod, in combination with anti-PD-1 therapy, produced objective responses in 6 (12%) and stable disease (SD) in 8 (16%) of 51 evaluable patients on this study, leading to a disease control rate of 27% (14/51). 5 of 6 (83%) patients with an objective response and 13 of 14 (93%) patients with disease control had progressed on prior anti-PD-(L)1 therapy. Disease control was durable, with median duration of 54 (range 24–88+) weeks for responses and 24 (range 11–35+) weeks for SD. Regression of both injected and non-injected tumors was observed. Cavrotolimod, alone and in combination with anti-PD-1 therapy, had a manageable safety profile with mostly transient adverse events (AEs). The most frequent Grade 3/4 cavrotolimod-related AEs were fatigue and injection site reactions. Cavrotolimod dosing was associated with robust chemokine/cytokine induction and lymphocyte activation in peripheral blood. Serial tumor biopsies of injected tumors suggested upregulation of genes associated with the interferon pathway, antiviral proteins, immune checkpoints, chemokines, granzymes and costimulatory proteins, along with increases in certain immune cell populations.ConclusionsCavrotolimod had a manageable safety profile and showed clinical activity in anti-PD-(L)1 refractory cutaneous malignancies, suggesting potential for further development as an antitumor immunotherapy in combination with other agents.Trial registration number NCT03684785.
 Skin Cancer Immune Checkpoint Inhibitor Intratumoral Nanoparticle Oncolytic and local immunotherapy Toll-like receptor - TLR

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