RP1 Plus Nivolumab Offers Hope in Anti–PD-1 Refractory Melanoma

An analysis of the phase 2 IGNYTE trial (NCT03767348) found that the combination of RP1 (vusolimogene oderparepvec) and nivolumab (Opdivo) yielded significant clinical efficacy with durable responses and systemic antitumor effect in patients with advanced melanoma who had previously failed anti–PD-1 therapy.¹

In the cohort of 140 patients, the combination achieved a confirmed objective response rate (ORR) of 32.9%, including a complete response (CR) rate of 15.0%, as assessed by independent central review. Responses were highly durable, with a median duration of response (DOR) of 33.7 months. The 2-year overall survival (OS) rate was 63.3%, with the median OS not yet reached.

The treatment induced responses in both directly injected tumors and noninjected distant lesions, including visceral metastases in the lung and liver, demonstrating a powerful systemic immune-mediated effect.

The Clinical Challenge in Post-ICI Melanoma

While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma, a significant portion of patients do not achieve lasting benefit. Primary resistance to anti–PD-1 therapy occurs in 30% to 50% of patients, and an additional 25% develop secondary resistance after an initial response. Prognosis is poor among patients whose disease progresses on anti–PD-1 therapy, with a median overall survival of approximately 1 year in real-world settings.

Subsequent treatment options are limited by significant drawbacks. Lifileucel (Amtagvi), a tumor-infiltrating lymphocyte therapy, is the only FDA-approved option for this patient population, but it is associated with severe toxicity. Nearly all patients experience grade 3/4 adverse events (AEs), and the treatment-related mortality rate is 7.5%.

The combination of nivolumab and ipilimumab (Yervoy) is also an option for this patient population, but it also carries high toxicity, with 57% of patients experiencing grade 3 or greater AEs. For the approximately 50% of patients with BRAF-mutant melanoma, BRAF/MEK inhibitors are available; however, responses may not be durable, and up to 60% of patients experience grade 3 or greater treatment-related AEs (TRAEs).

This landscape highlights a critical unmet need for effective and less toxic therapies that can provide meaningful clinical benefit for patients with melanoma that has progressed on anti-PD-1 treatment.

The IGNYTE trial is a phase 1/2 study evaluating RP1 as a monotherapy or in combination with nivolumab. This report focuses on the registrational phase 2 cohort of 140 patients with advanced melanoma that had progressed on a prior anti–PD-1-containing regimen.

RP1 is a next-generation, intratumorally administered oncolytic immunotherapy based on a clinical strain of herpes simplex virus type 1 selected for enhanced oncolytic activity. It is engineered to express 2 transgenes to maximize its therapeutic effect as follows:

1. Granulocyte-macrophage colony-stimulating factor: To stimulate an immune response
2. GALV-GP-R–: a fusogenic protein that causes tumor cells to fuse, enhancing direct tumor killing and promoting a highly immunogenic form of cell death, which in turn drives a systemic antitumor immune response

A total of 140 patients (age ≥18 years) with unresectable stage IIIB to IV cutaneous melanoma who had confirmed disease progression after at least 8 weeks of their last prior anti–PD-1 therapy were included for analysis. Patients received an initial intratumoral dose of RP1, followed by up to 7 additional doses every 2 weeks. Nivolumab (240 mg) was given every 2 weeks, starting with the second RP1 dose, and continued for up to 2 years.^1,2

The primary end point was ORR; secondary end points included DOR, CR rate, progression-free survival (PFS), and OS.

The study enrolled a patient population with poor prognostic factors, underscoring the high unmet need.¹

Key Findings: Efficacy and Clinical Outcomes

The trial met its primary end point, demonstrating significant and durable clinical activity. The median follow-up was 15.5 months.

The combination of RP1 and nivolumab yielded impressive results. Notably, 69.5% of responses were ongoing at 1 year after response initiation, highlighting the durability of the treatment effect.

A key finding was the treatment's ability to generate a systemic response that affected tumors throughout the body, not just those directly injected with RP1. Among responding patients, 93.6% of injected lesions and 79.0% of noninjected lesions experienced a reduction of at least 30%. Responses in noninjected lesions occurred with similar frequency, depth, and kinetics as those in injected lesions.

Crucially, this systemic effect extended to visceral organs; of the 52 noninjected visceral lesions (including those in the lung and liver) in responders, 96.2% showed a reduction from baseline. Initial tumor increase before response (pseudoprogression) was frequently observed in both injected and noninjected lesions of responding patients.

The combination of RP1 and nivolumab also demonstrated clinically meaningful efficacy across all evaluated subgroups, including those with historically poor prognoses.

Safety and Tolerability Profile

The combination of RP1 with nivolumab demonstrated a favorable and manageable safety profile. A total of 90.0% of patients experienced at least 1 TRAE. The vast majority of TRAEs were low-grade and transient, with 77.1% classified as grade 1 or 2. The incidence of grade 3 TRAEs was 9.3%, and grade 4 TRAEs occurred in 3.6% of patients (5 events total). No treatment-related deaths (grade 5 events) were observed. The safety profile generally overlapped with that of nivolumab monotherapy, with no evidence of additive toxicity.

Conclusion and Future Outlook

The IGNYTE trial demonstrates that the combination of RP1 and nivolumab is a highly promising therapeutic strategy for patients with advanced melanoma that has progressed on prior anti–PD-1 therapy. The treatment provides deep, durable, and systemic responses, even in patients with poor prognostic features, alongside a favorable safety profile that compares well with other available options.

“The IGNYTE clinical trial was a single-arm study, and the results should therefore be contextualized with historical data for patients with melanoma that progressed while being treated with anti–PD-1 therapy. Previous studies have shown that only 6% to 7% of patients are expected to respond to continued anti–PD-1 monotherapy after confirmed progression on an anti–PD-1–containing regimen. An ORR of 32.9% with 69.5% of responses ongoing for at least 1 year demonstrates a clear benefit of RP1 combined with nivolumab compared with expectations for nivolumab alone,” the study authors wrote.

A randomized, phase 3 confirmatory study, IGNYTE-3 (NCT06264180), is currently enrolling patients. This trial will evaluate RP1 plus nivolumab against the physician’s choice of treatment. It will be crucial in establishing this combination as a potential new standard of care for this challenging patient population.

REFERENCES

1. Wong MK, Milhem MM, Sacco JJ, et al. RP1 combined with nivolumab in advanced anti–PD-1–failed melanoma (IGNYTE). J Clin Oncol. 2025;43(33):3589-3599. doi:10.1200/JCO-25-01346

2. Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated January 24, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT03767348