STX-001 Produces Durable Systemic Responses in PD-1–Resistant Melanoma

Intratumoral STX-001, a lipid nanoparticle (LNP)–encapsulated, interleukin-12 (IL-12)–expressing self-replicating mRNA, produced durable responses with tumor regression in both injected and non-injected lesions in patients with advanced solid tumors, including PD-1–resistant melanoma, according to findings from a first-in-human phase 1/2 trial (NCT06249048) presented at the 2026 SITC Annual Meeting.¹ The 100-µg dose offered the best balance of efficacy and tolerability, and translational analyses tied clinical benefit to interferon-γ (IFN-γ) signaling and T-cell infiltration in both injected and distant lesions.

Among 36 evaluable patients across all dose levels, more than 40% experienced tumor regression, and activity was observed at every dose level tested. Overall, 48.7% (n = 19/39) of patients remained on study for at least 6 months, and the median duration of response was 8.7 months. The data cutoff occurred when the last patient reached 6 months on study, and many responses were ongoing at that time. In the 100-µg expansion cohort of patients with melanoma (n = 15), the confirmed objective response rate (ORR) per RECIST criteria was 33% (n = 5/15), satisfying the trial's predefined Simon two-stage success threshold; more than half of these patients experienced some degree of tumor regression.

"We know that we want to induce enhanced antigen presentation [and] interferon-γ programs in the injected lesion, and then increased T cells that then travel to the non-injected lesions, and that's certainly what we see," lead study author Georgina V. Long, AO, BSc, PhD, MBBS, FRACP, FAHMS, FAA, FASCO, medical director of Melanoma Institute Australia and chair of melanoma medical oncology and translational research at Melanoma Institute Australia and Royal North Shore Hospital, The University of Sydney, in Australia, said in a presentation of the data.

How was the trial designed?

Eligible patients needed to have advanced solid tumors, an ECOG performance status of 0 or 1, adequate organ function, and at least 1 lesion that could be both injected and biopsied. Those with melanoma had to meet SITC criteria for PD-1 resistance, with progression confirmed.

Patients received fixed doses of STX-001 injected into the tumor once every 3 weeks, with the same lesion reinjected whenever possible. Escalation used a Bayesian optimal interval design, starting at 30 µg and moving through 100 µg, 300 µg, and 900 µg, with dose-limiting toxicities assessed over 21 days; investigators later added a 10-µg cohort to optimize dosing. The 100-µg cohort was then expanded using a Simon two-stage design.

The study's primary goals were to characterize safety and tolerability and to choose a dose for further development. Secondary goals were pharmacokinetics, which were reported previously at the 2025 ASCO Annual Meeting,² and early signals of antitumor activity; investigators also performed exploratory biomarker analyses.

A total of 39 patients were enrolled (10 µg, n = 3; 30 µg, n = 8; 100 µg, n = 17; 300 µg, n = 8; 900 µg, n = 3).¹ The median age was 60 years (range, 23-83), 51.3% of patients were female, and 64.1% had an ECOG performance status of 0. Patients had received a median of 3 prior lines of therapy (range, 0-9), including a median of 2 prior lines of immunotherapy (range, 0-7). Most patients had melanoma (84.6%); other tumor types included breast cancer (7.7%), head and neck cancer (5.1%), and breast angiosarcoma (2.6%).

All 15 patients with melanoma in the 100-µg cohort had received prior anti–PD-1 therapy as monotherapy or in combination; 53% had received anti–PD-1 plus anti–CTLA-4 therapy, and 40% had received anti–PD-1 plus anti–LAG-3 therapy.

What did the safety analysis show?

All patients experienced adverse effects (AEs) of any cause, with grade 3 or higher AEs reported in 53.8% of the overall population (n = 39) and 41.2% of the 100-µg cohort (n = 17). Treatment-related AEs (TRAEs) occurred in 97.4% of all patients, including grade 3 or higher TRAEs in 38.5%. In the 100-µg cohort, the respective TRAE rates were 94.1% and 23.5%. Long noted that the grade 3 events were predominantly transient blood count changes consistent with IFN-γ activity.

Three patients (7.7%) in the overall population discontinued treatment because of TRAEs, 1 (2.6%) of which was due to a grade 3 or higher event; no patients in the 100-µg cohort discontinued treatment because of TRAEs.

Cytokine release syndrome (CRS) occurred in 35.9% of all patients, with grade 3 or higher CRS in 1 patient (2.6%), and in 29.4% of patients in the 100-µg cohort, with no grade 3 or higher events. Injection site reactions occurred in 56.4% and 41.2% of patients, respectively. One patient (2.6%) experienced a grade 3 immune-mediated AE, and 1 patient treated at 900 µg experienced immune effector cell–associated neurotoxicity syndrome that was below grade 3.

Did responses extend beyond the injected lesions?

Regression was observed in non-injected as well as injected lesions, which Long characterized as a clear abscopal effect. Patients whose injected lesion did not respond were unlikely to experience a response in non-injected lesions. Investigators noted that the trial's data capture system recorded injected and RECIST target lesions but not non-injected lesions, so the waterfall plots underrepresent non-injected lesion shrinkage. In one case, a 72-year-old woman with melanoma that had progressed on prior PD-1, CTLA-4, and LAG-3 blockade who received STX-001 at 30 µg had apparent progression at week 12 but achieved a complete metabolic response by week 30.

Paired RNA sequencing of injected lesions showed statistically significant upregulation of IFN-γ response programs from baseline to on-treatment in responders (n = 15) but not in nonresponders (n = 13), along with lower oxidative phosphorylation and MYC target signatures in responders.

Multiplex immunofluorescence showed that in injected lesions, patients with a complete or partial response or at least 6 months on trial (n = 16) had median paired fold increases of 3.8x in CD8-positive T cells, 5.4x in Th1 CD4-positive helper cells, 5.6x in Tc1 CD8-positive effector cells, and 6.2x in CD86-positive antigen-presenting cells, vs 1.3x, 0.9x, 1.6x, and 2.1x, respectively, among patients with stable or progressive disease and less than 6 months on trial (n = 13). In non-injected lesions, the corresponding increases in the benefit group were 5.2x, 4.5x, 4.5x, and 1.1x vs 1.1x, 0.8x, 0.3x, and 0.4x, respectively, consistent with T cells primed in the injected lesion trafficking to distant disease.

References

1. Long GV, Davar D, Sankhala KK, et al. Durable, interferon-associated systemic responses with STX-001, a LNP-encapsulated IL-12-expressing self-replicating mRNA, used as monotherapy in advanced solid tumors in a phase I/II study. Paper presented at: 2026 Society for Immunotherapy of Cancer (SITC) Annual Meeting; November 4-8, 2026; Phoenix, AZ. Abstract 823
2. Strand Therapeutics announces initial first-in-human phase 1 data for STX-001 in patients with advanced solid tumors at the 2025 ASCO Annual Meeting. News release. Strand Therapeutics. May 28, 2025. Accessed November 7, 2026. https://www.businesswire.com/news/home/20250528368906/en