Clinical deep dive 

Melanoma is a type of skin cancer that originates from the melanocytes (cells that produce the pigment [melanin] that gives skin its color). Melanocytes develop changes in their DNA causing cancer cells to grow more rapidly. Melanoma usually starts on sun-exposed skin, typically on the arms, back, face and legs. It can also occur in the eye. Additionally, in rare occurrences, melanoma can form inside the body in areas such as the nose or throat. The exact cause is unknown, but most melanomas are caused by exposure to ultraviolet (UV) light which exists in sunlight or in tanning lamps. The first sign of melanoma can be a change in an existing mole or the development of a new pigmented or unusual-looking growth on the skin. Risk factors include a family history of melanoma, a history of sunburn, exposure to UV light, having high numbers of moles or atypical moles, having skin that is easily sunburned and/or having a weak immune system. Prevention of modifiable risk factors is key to reducing the risk of melanoma.

Melanoma of the skin is a common type of cancer as it is the fifth most common cancer-type based on the annual number of estimated new cases. It is estimated that 104,960 new cases of melanoma will be diagnosed and about 8,430 deaths will occur due to the condition in the U.S. in 2025. In 2021, an estimated 1.5 million people were living with melanoma of the skin in the US. Melanoma is diagnosed at a median age of 66 years. Most cases (77%) are localized at diagnosis and have a 100% 5-year relative survival. When melanoma is metastasized at diagnosis (5%), the 5-year relative survival decreases to 35%. 

Most cutaneous melanoma cases are diagnosed at an early stage when surgical excision is curative. Checkpoint inhibitor immunotherapy, including PD-1 inhibitors (e.g., nivolumab, pembrolizumab), CTLA-4 inhibitors (e.g., ipilimumab) and lymphocyte-activation gene 3 (LAG-3) inhibitors (e.g., relatlimab-rmbw [component of Opdualag]), are the primary systemic treatment for advanced or metastatic disease (Stage III-IV) and in select patients with Stage II disease to reduce the risk of recurrence. Targeted therapy with V-Raf murine sarcoma viral oncogene homolog B1-directed (BRAF) plus mitogen-activated protein kinase (MEK) inhibitors (e.g., dabrafenib [Tafinlar] plus trametinib [Mekinist]) is recommended for advanced or metastatic disease with BRAF V600 mutation-positive disease, which is present in about half of melanoma cases. However, the duration of response to BRAF plus MEK inhibitors is limited due to the development of acquired resistance. 

Treatment options are limited if melanoma progresses on or after immunotherapy. Combinations of nivolumab with ipilimumab or relatlimab-rmbw may be considered but are associated with Grade 3/4 treatment-emergent adverse events (TEAEs). Other second-line or subsequent therapies include IV-administered lifileucel or aldesleukin (Proleukin); however, both carry boxed warnings for severe infection and other adverse events. In addition, intralesional injection of the modified oncolytic HSV-1 therapy, talimogene laherparepvec and systemic chemotherapy are also recommended in select patients but have not demonstrated improvement in overall survival. Chemotherapy via isolated limb perfusion or infusion has reported good response rates, but its use is limited due to the complexity of the procedure. 

Drug and clinical trial overview 

The ongoing, open-label, Phase 2 IGNYTE trial is evaluating safety (primary endpoint) and efficacy (secondary endpoints) of RP1 in adults with advanced and/or refractory solid tumors. The primary analysis included data from 140 patients with cutaneous melanoma that had failed anti-PD-1 therapy. Eligible patients must have at least one measurable tumor (≥ 1 cm) that can be injected and have shown progressive disease confirmed on two assessments at least 28 days apart while on at least eight weeks of anti–PD-1 ± anti–CTLA-4 therapy, with anti-PD-1 as the most recent treatment. Patients receiving prior oncolytic therapy were excluded.  

Enrolled patients received RP1 plus nivolumab. The study revealed that after a median follow-up of 15.4 months, the objective response rate (ORR) was 33.6% by modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and complete response rate (CRR) was 15%. The median duration of response (DOR) was 21.6 months (range, 1.2 to 43.5). In addition, among patients who responded, most (85%) injected and non-injected lesions were reduced in size by at least 30%. The median overall survival (OS) had not been reached. Survival rates at 1-, 2- and 3-years were 75.3%, 63.3% and 54.8%, respectively. RP1 plus nivolumab was generally well tolerated. Most adverse events were Grade 1 or 2 and included fatigue, chills, pyrexia, gastrointestinal (GI) symptoms, injection site pain, headache, rash and pruritus. Grade 4 events consisted of one event each of elevated lipase, cytokine release syndrome (CRS), myocarditis, hepatic cytolysis and splenic rupture. 

In the IGNYTE trial, RP1 is administered by intratumoral injection at a dose of 1 x 10⁶ plaque-forming units (pfu)/mL in Cycle 1 followed by 1 x 10⁷ pfu/mL every two weeks in Cycles 2–8. Multiple tumors may be injected; injections should be made from largest to smallest lesions. Nivolumab 240 mg is administered IV every two weeks during cycles 2–9 and as 480 mg every four weeks during cycles 10–30. Patients were allowed to restart RP1 beyond eight cycles if they met protocol-specific criteria.