ulevostinag (MK-1454)

Pharmacological activation using cyclic dinucleotides (CDN) STING agonists (ADU-S100 and MK-1454) and non-CDN STING agonists (diABZI and MSA-2), as well as MPS1 inhibitors (CFI-402257, BAY-1217389, and CC-671), has effectively triggered strong type I interferon responses and caused tumour regression in preclinical and clinical trials. When combined with radiotherapy, PARP inhibitors, or immune checkpoint blockers, these agents exhibit enhanced synergy but are constrained by tumour heterogeneity and context-dependent toxicity. Here, we reviewed the complexity of the cGAS-STING and its potential as a double-edged sword in cancer treatment, underscoring the need for strict strategies to harness this pathway while enhancing antitumour immunity and mitigating pro-tumorigenic effects.

In contrast, early-phase clinical trials of STING agonists, including ADU-S100, SYNB1891, IMSA101, and MK-1454, have shown acceptable safety and pathway engagement but generally modest and variable clinical responses, primarily reflected by low objective response rates and limited disease stabilization. We highlight emerging drug delivery platforms, such as nanocarriers, antibody-drug conjugates, and exosome-based systems, as key modulators of efficacy and safety, and emphasize the importance of biomarker-guided approaches for patient stratification and trial optimization. By integrating biological insight with translational feasibility, this review provides a framework for advancing STING-based combination immunotherapy toward more durable and personalized cancer treatment.

Intratumoral ulevostinag (±pembrolizumab) had manageable toxicity, dose-dependent pharmacokinetics, and evidence of STING activation and target engagement. Combination therapy showed antitumor activity in participants with untreated metastatic or unresectable, recurrent HNSCC.

P2, N=18, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed | N=200 --> 18 | Trial completion date: Apr 2023 --> Sep 2022 | Trial primary completion date: Apr 2023 --> Sep 2022

P1, N=157, Completed, Merck Sharp & Dohme Corp. | Active, not recruiting --> Completed | N=235 --> 157

P1, N=235, Active, not recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Oct 2022 --> Apr 2022 | Trial primary completion date: Oct 2022 --> Apr 2022

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

P2, N=200, Active, not recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Sep 2023 --> Apr 2023 | Trial primary completion date: Sep 2023 --> Apr 2023

P1, N=235, Active, not recruiting, Merck Sharp & Dohme Corp. | Recruiting --> Active, not recruiting

P2, N=200, Active, not recruiting, Merck Sharp & Dohme Corp. | Recruiting --> Active, not recruiting

In KEYNOTE-048, which compared pembro ± chemotherapy with cetuximab + chemotherapy in patients with previously untreated metastatic or recurrent head and neck squamous cell carcinoma (HNSCC), pembro significantly prolonged OS as monotherapy in patients with a PD-L1 combined positive score (CPS) ≥1 and ≥20 and in combination with chemotherapy in patients with CPS ≥1 and ≥20 and in the total population. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial identification: 2019-003060-42; NCT04220866.