At the 2026 ASCO Annual Meeting, Joseph J. Sacco and colleagues presented final safety, efficacy, and biomarker findings from the first-in-human phase 1 study evaluating RP2, an HSV-1–based oncolytic immunotherapy, administered as monotherapy or in combination with nivolumab in patients with advanced solid tumors.
RP2 is a genetically modified herpes simplex virus type 1 (HSV-1) designed to enhance antitumor immunity through multiple mechanisms. The construct expresses a fusogenic glycoprotein (GALV-GP-R−), human GM-CSF, and a human anti–CTLA-4 antibody.
Study Design and Treatment
The study enrolled patients with advanced or metastatic solid tumors who had at least one measurable injectable lesion and had either progressed after available standard therapies or were unable to tolerate them.
In the dose-escalation portion, patients received intratumoral RP2 monotherapy every two weeks. Expansion cohorts evaluated RP2 either as monotherapy or in combination with nivolumab at the recommended phase 2 dose. Patients could receive up to eight RP2 doses, and additional treatment courses were permitted according to protocol. In the combination cohort, nivolumab treatment began during cycle 2 or cycle 4 and continued for approximately 20 to 22 months.
Patient Characteristics
As of December 1, 2025, a total of 85 patients had been enrolled and treated, including 25 patients who received RP2 monotherapy and 60 who received RP2 plus nivolumab.
The median patient age was 59 years. Tumor types included uveal melanoma (n=17), cutaneous melanoma (n=11), colorectal cancer (n=14), head and neck cancer (n=13), pancreatic cancer (n=12), and sarcoma (n=7). Prior immune checkpoint inhibitor therapy had been administered to 42% of patients.
Importantly, most patients (58/85) received injections into deep visceral lesions, primarily within the liver and lungs.
Safety
All enrolled patients completed treatment.
RP2 demonstrated a manageable safety profile. Treatment-related adverse events occurring in more than 10% of patients included pyrexia, chills, fatigue, influenza-like illness, hypotension, pruritus, and nausea.
Grade 3 or higher treatment-related adverse events occurred in 20% of patients, although no individual grade ≥3 toxicity was reported in more than two patients. Investigators also noted that treatment of deep visceral lesions was generally well tolerated.
Efficacy
Among the 75 patients with at least one post-baseline tumor assessment, the objective response rate (ORR) was 17.3% (13/75), including one unconfirmed response. The median duration of response reached 22.1 months, while the disease control rate (DCR) was 44.0% (33/75).
Particularly encouraging activity was observed in uveal melanoma, where responses occurred in 5 of 15 evaluable patients, corresponding to an ORR of 33.3%.
RP2 monotherapy produced confirmed responses in 4 of 21 evaluable patients (19%), including patients with esophagogastric adenocarcinoma, uveal melanoma, chordoma, and mucoepidermoid carcinoma. Among these responders, complete responses were observed and the median duration of response had not yet been reached.
Key Efficacy Results
- ORR: 17.3% (13/75), including 1 unconfirmed response
- Median duration of response: 22.1 months
- DCR: 44.0% (33/75)
- Uveal melanoma ORR: 33.3% (5/15)
Evidence of Systemic Antitumor Immunity
One of the most notable findings of the study was evidence of systemic antitumor activity. Tumor regression was observed not only in injected lesions but also in distant non-injected lesions.
All three patients with monotherapy responses involving non-injected lesions demonstrated tumor reduction at sites that had not received direct RP2 administration, supporting the ability of RP2 to generate systemic immune-mediated antitumor effects.
Biomarker Findings
Biomarker analyses demonstrated robust intratumoral immune activation following treatment.
Investigators observed increased CD8-positive T-cell infiltration, PD-L1 upregulation, and activation of inflammatory immune pathways within tumor tissue. Evidence of epitope spreading was also identified, including the emergence of novel virus-associated and cancer-associated T-cell clones.
Together, these findings support the proposed mechanism of RP2 as an oncolytic immunotherapy capable of stimulating broad antitumor immune responses.
Conclusion
The final results of this first-in-human study demonstrated that RP2, administered either alone or in combination with nivolumab, was well tolerated and produced durable responses in heavily pretreated patients across multiple advanced solid tumor types.
The observation of prolonged responses, activity in uveal melanoma, regression of distant non-injected lesions, and evidence of immune activation provides support for the continued clinical development of RP2.
These findings have led to the ongoing evaluation of RP2 in uveal melanoma and support further investigation across additional solid tumor indications.