PH-762, an intratumoural PD-1-directed immunotherapy shows early potential in cutaneous carcinomas

Could you provide an overview of PH-762 and its proposed mechanism of action in the treatment of cutaneous carcinomas?

The INTASYL® compound, PH-762 (Phio Pharmaceuticals, Inc.; King of Prussia, PA, USA), is a proprietary siRNA compound designed to silence the PDCD1 gene, which encodes the immune checkpoint protein PD-1. By silencing PD-1 mRNA in T cells, and thereby preventing PD-1 protein expression, PH-762 aims to restore and enhance anti-tumor immune responses.

PH-762 is an asymmetric siRNA duplex, with a precise nucleotide sequence that allows selective targeting of PD-1. Targeting PD-1 or its ligand, PD-L1, the compound blocks co-inhibitory receptors which are expressed by anti-tumor T cells. The established clinical use of immune checkpoint antibodies directed at PD-1 or PD-L1 has demonstrated that this is an effective strategy to treat various cancers, including squamous cell carcinoma.¹

Unlike antibodies that block immune inhibitory PD-1 or PD-L1 interactions extracellularly, PH-762’s activity is intracellular in the T cell, silencing PD-1 mRNA and down-regulating protein expression, leading to enhanced T cell activation as assessed by interferon-gamma secretion and inhibition of tumor growth in a mouse model of melanoma.²

What advantages might PH-762’s structural and chemical modifications offer over existing approaches for cutaneous carcinomas?

PH-762 is an asymmetric siRNA duplex engineered with three key components that allow it to function without the need for complex delivery systems. Its precisely designed nucleotide sequence enables selective targeting of the PD-1 gene, PDCD1, while minimizing off-target effects. A cholesterol moiety allows the molecule to cross cell membranes intact in sterile saline solution, while a phosphorothioate backbone improves stability against degradation and enhances binding to the T cell surface. Together, this self-delivering architecture is intended to reduce the toxicities associated with lipid nanoparticles and viral vectors.

Once delivered by direct intratumoral injection, PH-762 enters cells through natural endocytosis (eliminating the need for lipid nanoparticles, viral vectors, or other formulation enhancements) and silences the PD-1 gene at its source within T cells.

Most cancer immunotherapies today use monoclonal antibodies delivered by intravenous infusion to block PD-1 or PD-L1 on the surface of tumor cells. These therapies circulate throughout the entire body and can produce serious immunologic side effects affecting the cardiovascular, gastrointestinal, dermatological, and respiratory systems.³ As PH-762 is injected directly into the tumor, immune function is reactivated at the gene level rather than blocking proteins on the surface of the tumor.

What were the aims, design and eligibility criteria of the phase 1b study?

Then open-label phase 1b clinical study entitled “Dose Escalation Study of Neoadjuvant Intratumoral PH-762 for Cutaneous Squamous Cell Carcinoma, Melanoma, or Merkel Cell Carcinoma” (PHIO-762-2301) was conducted in 22 patients, 20 of whom were diagnosed with cSCC, 1 patient with melanoma and one with Merkel cell carcinoma.

The intratumoral administration of PH-762 was studied for the neoadjuvant treatment of histologically confirmed cSCC (resectable Stage II or lower local tumors; unresectable Stage II or lower local tumors unresponsive to or not a candidate for radiation therapy; metastatic disease that has progressed during or following prior checkpoint inhibitor therapy), melanoma (Stage IV metastatic disease with a cutaneous lesion that has progressed during or following prior checkpoint inhibitor therapy, or antiBRAF + MEK therapy if BRAF-mutation present), or Merkel cell carcinoma (Stage IV metastatic disease with a cutaneous lesion that has progressed during or following prior checkpoint inhibitor therapy). Lesions to be injected were required to be ≥ 1.0 cm and ≤ 3.0 cm (in the longest dimension).

Escalating concentrations of PH-762 were evaluated sequentially across five dose cohorts, each comprising at least three patients: Cohort 1, 1.14 mg/mL; Cohort 2, 2.39 mg/mL; Cohort 3, 5.01 mg/mL; Cohort 4, 10.50 mg/mL; and Cohort 5, 22.00 mg/mL. Patients received intratumoral injections of PH-762 to one study lesion once weekly, four times over a 3-week period, prior to surgical excision at approximately 5 weeks after the initial injection.

Control lesions, if present, were not injected but were eligible for excision at the same time as the study lesion as per standard of care. Post-tumor excision, patients were followed-up for approximately 11 weeks (or 13 weeks after the last dose of PH-762).

The overall aim of the dose-escalation trial was to evaluate the safety and tolerability of intratumoral PH-762 for cutaneous carcinomas, including cSCC, and metastatic melanoma or Merkel cell carcinoma. Additionally, the tumor response was to be categorized, and the pharmacokinetic profile described to determine the dose or dose range, for continued clinical development.

The key efficacy endpoints were pathological response and reduction in the tumor burden (size). Changes in tumor size were assessed using a modification of the Response Criteria for Intratumoral Immunotherapy (RECIST).This modified criterion, iRECIST, is currently used in studies of immune-based therapeutics and measures the longest diameter of extranodal lesions at baseline, or residual tumor at later timepoints, and the short axis of nodal lesions. ⁴

What has been observed in terms of efficacy?

In the phase 1b study, pathologic response in a fully excised lesion was a key efficacy endpoint used to determine clinical benefit.

Pathologic response is the standard measure used to determine partial response or complete clearance of a lesion following surgical excision, as it is based on direct histologic evaluation of excised tissue. This approach is widely regarded as providing a more rigorous assessment of treatment response than modalities such as radiation therapy or local destructive procedures, which are typically assessed through clinical follow-up rather than immediate histologic confirmation.

In patients with cSCC lesions, pathologic response indicated partial or complete tumour resolution in 13 out of 20 patients following four intratumoral injections of PH-762, across all five dose cohorts. Additionally, the single patient with metastatic Merkel cell carcinoma experienced a partial response. Pathologic complete response was reported for 9 of 20 participants with primary cSCC lesions, and major pathologic response or near complete response was reported for an additional two primary lesions, while two more had pathologic partial response and seven had pathologic non-response. Although no patients in cohort 1 achieved pathologic complete response or major/near pathologic complete response, one or more patients in each later cohort were responders.

Modest mean reductions in tumour burden from baseline were also observed. At the time of lesion excision, 2 weeks after the final injection of PH-762, the greatest mean reductions in lesional diameter were seen in Cohorts 2 and 5, corresponding to the cohorts with the highest response rates. In terms of iRECIST response, assessed cumulatively across all cohorts at Day 36, a complete response was reported in 3 patients (13.6%), a partial response in 9 (40.9%), and stable disease in 10 patients (45.5%).

A reduction in lesion size (measured by greatest diameter) indicates potential improvement compared with standard surgical or alternative therapeutic approaches. Decreases in lesion size may allow for less extensive surgical intervention and smaller resection margins, thereby reducing the risk of intraoperative and postoperative complications. However, reliance on iRECIST criteria alone appears insufficient as a clinical endpoint, as these criteria underestimate the extent of the pathological response. This discrepancy may be attributable to local inflammatory changes and tissue remodeling, including healing or scarring, which can be difficult to distinguish from residual tumor on imaging or clinical examination.

What were the key findings in terms of safety and tolerability?

There were no serious adverse events and no deaths reported in the phase 1b study. In addition, no dose-limiting toxicities or adverse events of special interest were reported.

Treatment-emergent adverse events (TEAEs) were reported by 19 of 22 (86.4%) enrolled patients, including 11 (50%) patients with study drug-related TEAEs, and 9 (40.9%) with injection procedure-related TEAEs. Study drug-related TEAEs most commonly included injection site reactions, including (by Preferred Term): Injection site pruritus (5 events, 4 patients), Injection site pain (4 events, 4 patients), Injection site swelling (2 events, 2 patients), Injection site erythema (1 event, 1 patient), and Injection site oedema (1 event, 1 patient). Other treatment-related events included Fatigue (3 events, 2 patients), Headache (1 event, 1 patient), Lymphadenopathy (1 event, 1 patient), and Neutrophilia (1 event, 1 patient). All reported TEAEs were mild-to-moderate (CTCAE Grades 1 or 2) in severity.

What will be the next steps towards realizing the potential of PH-762?

Following these encouraging results, Phio Pharmaceuticals, Inc, intends to continue clinical development of PH-762. To achieve this the company plans to seek initial guidance from the US Food and Drug Administration (FDA) as it designs a pivotal trial. It has also entered into an agreement with a US manufacturer to develop clinical material for the next phase of the study.