PH-762 Demonstrates Safety and Local Efficacy in Skin Cancer

Today, Phio Pharmaceuticals announced updated pathologic results from its ongoing phase 1b dose-escalation trial of PH-762, an investigational small interfering RNA (siRNA) therapeutic targeting programmed cell death protein 1 (PD-1). The therapy utilizes Phio’s proprietary intasyl gene silencing platform, designed to enhance local immune activation against tumor cells through intratumoral modulation of immune checkpoints.¹

Study Overview

The open-label phase 1b trial (NCT06014086) is evaluating the safety, tolerability, and preliminary efficacy of PH-762 administered via intratumoral injection in patients with cutaneous squamous cell carcinoma (cSCC; Stages I, II, and IV), as well as those with stage IV melanoma and stage IV Merkel cell carcinoma (MCC). The investigational protocol includes 4 weekly intratumoral injections, with a pathologic response assessment approximately 5 weeks after the first dose.

The study employs a dose-escalation design across 5 cohorts to determine safety and establish a maximum tolerated dose. As of the most recent update, 18 patients have completed treatment: 16 with cSCC, 1 with metastatic melanoma, and 1 with metastatic MCC.

Efficacy Findings

Among the 16 cSCC patients, cumulative histopathologic outcomes include:

• 6 patients (37.5%) achieving a complete response (100% tumor clearance)
• 2 patients (12.5%) with a near complete response (>90% clearance)
• 2 patients (12.5%) demonstrating a partial response (>50% clearance)
• 6 patients (37.5%) classified as non-responders (<50% clearance)

In addition, 1 patient with metastatic Merkel cell carcinoma exhibited a partial response (>50% clearance), while the patient with metastatic melanoma demonstrated a non-response (<50%). Importantly, no patients across the study have shown clinical disease progression following treatment to date.

Within the fifth and final dose cohort, comprising 3 patients with cSCC, pathologic results demonstrated 100% tumor clearance in 1 patient, >90% clearance in another, and >50% clearance in the third, suggesting a potential dose-response relationship as treatment escalates.

Safety and Tolerability

The Safety Monitoring Committee (SMC) conducted a pre-specified review of safety outcomes for the initial three patients in the fifth cohort and confirmed no dose-limiting toxicities (DLTs) or clinically significant treatment-emergent adverse events at the highest tested dose concentration.

According to Phio, no DLTs or clinically meaningful immune-related or systemic toxicities have been observed at any dose level. The cumulative dose escalation from the first to the fifth cohort represents approximately a 20-fold increase in administered concentration.

Phio’s Acting Chief Medical Officer, Mary Spellman, MD, reported that PH-762 has been well tolerated throughout the trial, with no notable immune-related adverse events. The absence of clinically relevant toxicities, even at high intratumoral concentrations, supports the feasibility of PH-762 as a localized therapeutic option for cutaneous malignancies.

Mechanism of Action and Clinical Context

PH-762 is designed to silence PD-1 mRNA locally within the tumor microenvironment using Phio’s intasyl (Interfering RNA Transfection via Self-Delivering siRNA) platform. Unlike systemically administered checkpoint inhibitors, which act on circulating T cells, intratumoral PH-762 seeks to modulate immune checkpoint signaling directly within the tumor, potentially amplifying anti-tumor immune responses while minimizing systemic immune-related toxicity.²

Given that cutaneous squamous cell carcinoma is one of the most common non-melanoma skin cancers, with rising incidence and increasing treatment complexity in elderly and immunocompromised populations, a well-tolerated, non-surgical, localized therapy could represent a significant therapeutic advance, particularly for patients who are poor surgical candidates or wish to avoid disfiguring procedures.

Next Steps and Outlook

While the phase 1b results remain preliminary, the combination of encouraging pathologic response rates and a favorable safety profile supports further investigation of PH-762. Phio may continue to screen and treat additional patients within the fifth cohort to strengthen the dataset before advancing to later-phase clinical evaluation.

The ongoing study continues to collect data to refine optimal dosing parameters, characterize immune-related pharmacodynamics, and assess durability of response. The company stated future studies will likely explore combination strategies with systemic immunotherapies or expand indications to other accessible solid tumors.

Conclusion

Intratumoral PH-762 demonstrates promising local tumor clearance and an acceptable safety profile in early-phase evaluation for cutaneous carcinomas. Although larger studies are required to confirm efficacy and long-term outcomes, the initial findings provide compelling rationale for continued clinical development of siRNA-based intratumoral checkpoint modulation in oncology.

References

1. Phio Pharmaceuticals announces positive pathology results: Final maximum dose cohort for INTASYL PH-762 skin cancer trial. News release. Phio Pharmaceuticals. Published November 3, 2025. Accessed November 3, 2025. https://www.biospace.com/press-releases/phio-pharmaceuticals-announces-positive-pathology-results-final-maximum-dose-cohort-for-intasyl-ph-762-skin-cancer-trial
2. Phio Pharmaceuticals announces positive safety monitoring committee recommendation to advance INTASYL PH-762 skin cancer clinical trial to fifth dose escalation cohort. News release. Phio Pharmaceuticals. Published June 25, 2025. Accessed November 3, 2025. https://phiopharma.com/phio-pharmaceuticals-announces-positive-safety-monitoring-committee-recommendation-to-advance-intasyl-ph-762-skin-cancer-clinical-trial-to-fifth-dose-escalation-cohort/