Can you please review the literature regarding vusolimogene oderparepvec-wtpg?

Comment by InpharmD Researcher

Tudriqev (vusolimogene oderparepvec; RP1) in combination with nivolumab received FDA accelerated approval for the treatment of adults with unresectable advanced cutaneous melanoma following disease progression on anti–PD-1 therapy. Available evidence primarily consists of the single-arm Phase 2 IGNYTE trial, which demonstrated an objective response rate of approximately 33%. An updated 3-year survival analysis reported a median overall survival of 32.2 months and a 3-year overall survival rate of 45.5%, with no new safety signals identified. However, interpretation of these findings is limited by the lack of a comparator arm. The randomized Phase 3 IGNYTE-3 trial aims to further evaluate the efficacy and safety of RP1 plus nivolumab compared with physician’s choice of therapy, with study completion anticipated in March 2031.

Pubmed, monographs

Background

On August 6, 2026, the FDA granted accelerated approval to vusolimogene oderparepvec-wtpg (Tudriqev), a genetically modified oncolytic viral therapy, in combination with nivolumab for adults with unresectable advanced cutaneous melanoma who experienced disease progression on a PD-1-blocking antibody-based regimen. Approval was based on objective response rate (ORR) and duration of response (DOR) from the phase 2, open-label, single-arm IGNYTE trial involving 140 patients, of whom 91 with at least one noninjected lesion were included in the efficacy-evaluable population. The ORR was 24.2% (95% confidence interval [CI] 15.8%–34.3%), and median DOR was 14.1 months (95% CI 10.7 months to not reached). Common adverse reactions included fatigue, pyrexia, infections, chills, musculoskeletal pain, nausea, diarrhea, and injection-site reactions. The recommended intratumoral dose is 1 mL/cm of the largest tumor dimension, up to 10 mL across all treated lesions per dose, administered every 2 weeks for 8 doses, beginning with 10⁶ PFU/mL at Week 1 followed by 10⁷ PFU/mL for subsequent doses. IV nivolumab is initiated at Week 3. Continued approval may depend on verification of clinical benefit in confirmatory trials. [1]

According to the 2026 National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma, vusolimogene oderparepvec-wtpg in combination with nivolumab is included as an other recommended treatment option for second-line or subsequent therapy in patients with metastatic or unresectable cutaneous melanoma who experience disease progression, intolerance, or projected risk of progression with BRAF-targeted therapy (category 2A, indicating uniform NCCN consensus that the intervention is appropriate based on lower-level evidence). The guidelines note that intratumoral vusolimogene oderparepvec-wtpg plus nivolumab was evaluated in a phase 2 trial involving 140 patients with unresectable cutaneous melanoma whose disease progressed following anti-PD-1–based therapy, with a response rate of 33%. Among 89 patients with at least one non-injected target lesion, the response rate was 24%. Confirmatory randomized studies are ongoing. [2]

Background References: [1] US Food and Drug Administration. FDA grants accelerated approval to vusolimogene oderparepvec-wtpg in combination with nivolumab for melanoma. Published August 6, 2026. Accessed October 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-vusolimogene-oderparepvec-wtpg-combination-nivolumab-melanoma
[2] National Comprehensive Cancer Network (NCCN). Melanoma: Cutaneous. Version 3.2026. Updated September 2, 2026. Accessed October 8, 2026. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Can you please review the literature regarding vusolimogene oderparepvec-wtpg?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

RP1 Combined With Nivolumab in Advanced Anti–PD-1–Failed Melanoma (IGNYTE)
Design

Phase I/II clinical trial

N= 140
Objective To determine the safety and efficacy of RP1 (vusolimogene oderparepvec) in combination with nivolumab in patients with advanced anti–PD-1–failed melanoma
Study Groups All patients (N= 140)
Inclusion Criteria Patients age ≥18 years with unresectable stage IIIB-IV cutaneous melanoma, confirmed progression while being treated for ≥8 weeks with anti–PD-1 alone or combined with another anticancer therapy
Exclusion Criteria Prior oncolytic therapy, current antiviral therapy, or a history of serious complications from immune checkpoint inhibitor therapy (ICI) therapy
Methods Patients received an initial intratumoral RP1 dose of 1 × 10⁶ plaque-forming units (PFU)/mL, followed by up to seven additional doses of 1 × 10⁷ PFU/mL every 2 weeks, with a maximum volume of 10 mL per dose. Nivolumab 240 mg every 2 weeks was initiated with the second RP1 dose for up to eight cycles, followed by 480 mg every 4 weeks for up to 21 additional cycles. Additional RP1 doses could be administered if clinically indicated.
Duration The cutoff date for the primary data analysis was March 8, 2024, with all patients having the potential for at least 12 months of follow-up
Outcome Measures

Primary: Objective response rate (ORR) using RECIST 1.1

Secondary: Duration of response (DOR), complete response (CR) rate, progression-free survival (PFS), 1- and 2-year overall survival (OS)
Baseline Characteristics   All patients (N= 140)
Median age, years (range) 62.0 (21.0-91.0)
Male 95 (67.9%)
White 103 (73.6%)
Stage IIIB/IIIC/IVM1a 72 (51.4%)
Stage IVM1b/c/d 68 (48.6%)
BRAF status - Wild-type BRAF 87 (62.1%)
BRAF status - Mutant BRAF 53 (37.9%)
LDH level - LDH ≤ULN 92 (65.7%)
LDH level - LDH >ULN 47 (33.6%)
PD-L1 tumor expression - Positive (≥1%) 44 (31.4%)
PD-L1 tumor expression - Negative (<1%) 79 (56.4%)
Primary resistance to prior anti–PD-1 therapy was reported in 65.7% of patients, while 34.3% had secondary resistance. The median duration of the most recent anti–PD-1 therapy was 4.6 months (range, 1.0–55.2). Overall, 46.4% had previously received anti–PD-1 therapy in combination with or sequentially after anti–CTLA-4 therapy.
Results   All patients (N= 140) 95% CI
ORR 32.9% 25.2% to 41.3%
CR rate 15.0% 9.5% to 22.0%
DOR, months 33.7 14.1 to not reached
1-year OS rate 75.3% 66.9% to 81.9%
2-year OS rate 63.3% 53.6% to 71.5%

Abbreviations: CI, confidence interval.

The median time to response was 4.5 months, and the median duration of response was 33.7 months, with 69.5% of responses ongoing at 1 year. Median progression-free survival was 3.6 months, while median overall survival was not reached.

Responses were observed in both injected and noninjected lesions, including visceral lesions. Among responders, 93.6% of injected lesions and 79.0% of noninjected lesions demonstrated at least a 30% reduction in size. Subgroup ORRs included 26.2% in patients previously treated with anti–PD-1 and anti–CTLA-4 therapy, 34.8% in patients with primary anti–PD-1 resistance, and 29.2% in those with secondary resistance.
Adverse Events Treatment-related adverse events occurred in 90.0% of patients, including grade 1/2 events in 77.1%, grade 3 events in 9.3%, and grade 4 events in 3.6%. The most common treatment-related adverse events were fatigue (32.9%), chills (32.1%), pyrexia (30.7%), and nausea (22.1%). No grade 5 treatment-related adverse events were reported.
Study Author Conclusions In conclusion, RP1 combined with nivolumab demonstrated clinically meaningful and durable responses with a favorable safety profile in patients with advanced melanoma that progressed while being treated with an anti–PD-1– containing regimen.
Critique The study demonstrated promising efficacy and a favorable safety profile for RP1 combined with nivolumab in a challenging patient population. However, the single-arm design limits the ability to compare directly with other treatments, and further randomized trials are needed to confirm these findings.
Table 1 References:
[3] 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

 

IGNYTE-3 trial (NCT06264180)

Design

Phase 3, randomized, controlled, multicenter, open-label clinical trial (ongoing)

N≈ 400 (planned)

Objective

To evaluate the overall survival and clinical benefit of RP1 (vusolimogene oderparepvec) plus nivolumab versus physician’s choice in patients with advanced cutaneous melanoma whose disease has progressed after anti–PD-1 and anti–CTLA-4 therapy or who are ineligible for anti–CTLA-4 therapy

Study Groups

RP1 plus nivolumab (n≈ 200)

Physician's choice (n≈ 200)

Inclusion Criteria

Age ≥12 years, unresectable or metastatic stage IIIB–IV cutaneous melanoma, confirmed progression on prior anti–PD-1 and anti–CTLA-4 therapy or anti–PD-1 alone if ineligible for anti–CTLA-4, prior anti–PD-1 treatment for ≥8 weeks or ≥12 weeks for pembrolizumab administered every 6 weeks, ≥1 measurable tumor and injectable lesion ≥1 cm, prior BRAF-directed therapy for BRAF-mutant disease unless not clinically indicated, adequate organ function, ECOG performance status 0–1 for adults or Lansky ≥80 for adolescents

Exclusion Criteria

Primary mucosal or uveal melanoma, more than two prior lines of systemic therapy for advanced melanoma with specified exceptions, active CNS metastases unless previously treated and stable, significant herpetic infection or required systemic antiherpetic therapy, prior oncolytic virus or intratumoral therapy, active autoimmune disease requiring systemic treatment, prior life-threatening immune-related toxicity, LDH >2 times the upper limit of normal.

Methods

Patients receive RP1 plus nivolumab or physician’s choice of nivolumab plus relatlimab, anti–PD-1 monotherapy rechallenge with nivolumab or pembrolizumab, or single-agent chemotherapy with dacarbazine, temozolomide, paclitaxel, or albumin-bound paclitaxel.

Duration

Study start: July 11, 2024

Estimated primary completion: September 30, 2030

Estimated study completion: March 31, 2031

Outcome Measures

Primary outcome: Overall survival (OS)
Secondary outcomes: Progression-free survival (PFS) and objective response rate (ORR) per RECIST 1.1.

Baseline Characteristics

 N/A (ongoing trial)

Results

 N/A (ongoing trial)

Adverse Events

 N/A (ongoing trial)

Study Author Conclusions

N/A (ongoing trial)

InpharmD Researcher Critique

IGNYTE-3 is an ongoing phase 3 confirmatory trial with an estimated completion date of March 2031. Results are not yet available to establish the comparative efficacy and safety of RP1 plus nivolumab. The heterogeneous physician’s-choice comparator may complicate interpretation of treatment effects.



Table 2 References:
[4] Luke JJ, Kong G, Gullo G, Robert C. A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physicians choice in patients with advanced melanoma that has progressed on anti-PD-1 and anti-CTLA-4 therapy (IGNYTE-3). Poster presented at: ASCO Annual Meeting; 2024.
[5] Najjar YG, Robert C, Khushalani NI, et al. A randomized, controlled, multicenter, phase 3 study of RP1 (vusolimogene oderparepvec) combined with nivolumab vs physicians choice of therapy in patients with advanced melanoma that has progressed on anti-PD-1 and anti-CTLA-4 therapy (IGNYTE-3). J Clin Oncol. 2026;44(16_suppl):TPS9597. doi:10.1200/JCO.2026.44.16_suppl.TPS9597
[6] ClinicalTrials.gov. VO and Nivolumab vs Physician's Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs (IGNYTE-3). ClinicalTrials.gov identifier NCT06264180. Updated July 15, 2026. Accessed October 8, 2026.

Biodistribution, shedding, and transmissibility of vusolimogene oderparepvec (RP1)
Design

Phase 2 clinical trial

N= 282
Objective To evaluate the biodistribution, shedding, and potential for transmission of RP1 in patients with skin cancers treated in the IGNYTE clinical trial and assess close-contact exposure across all RP1 clinical studies
Study Groups

Initial melanoma cohort (n=30)

Anti-PD-1 failed cutaneous melanoma cohort (n=141)

Anti-PD-1 naïve non-melanoma skin cancer (NMSC) (n=32)

Anti-PD-1 failed non-melanoma skin cancer (NMSC) cohort (n=79)
Inclusion Criteria Patients with skin cancers treated in the IGNYTE clinical trial, including those with melanoma and non-melanoma skin cancers
Exclusion Criteria Not specified
Methods Patients received intratumoral RP1 in combination with nivolumab. Serial collection of blood, urine, injection-site, dressing, and oral mucosal samples during treatment and follow-up. RP1 DNA quantified by polymerase chain reaction (PCR), and swab samples positive for RP1 DNA tested for replication-competent RP1. Reports of herpetic infection in patients and close contacts were also collected.
Duration Not specified
Outcome Measures

Primary: Biodistribution and shedding of RP1

Secondary: Potential for transmission of RP1 to patient contacts
Baseline Characteristics   All patients (N= 282)
Age, years (mean ± SD) 64.3 ± 13.66
Age group, 18-64 years 135 (47.9%)
Age group, 65-74 years 85 (30.1%)
Age group, >=75 years 62 (22.0%)
Male 196 (69.5%)
White 228 (80.9%)
Black or African American 5 (1.8%)
Asian 2 (0.7%)
American Indian or Alaska Native 1 (0.4%)
Not Reported 46 (16.3%)
Eastern Cooperative Oncology Group (ECOG) Performance 0 169 (59.9%)
ECOG Performance 1 111 (39.4%)
ECOG Performance 2 2 (0.7%)
Results   Detection Rate
RP1 DNA in blood 19.3% of patients
RP1 DNA in urine 0.7% of patients
RP1 DNA at injection site 42.1% of patients
RP1 DNA on dressing 20.8% of patients
RP1 DNA in oral mucosa/saliva 5.9% of patients
Adverse Events No systemic herpes simplex virus infections occurred in patients, and no herpetic infections were reported among caregivers or close contacts.
Study Author Conclusions RP1 is largely confined to injection sites, shedding of live RP1 is rare and transient. No evidence of transmission of RP1 was observed. These findings support the favorable biosafety profile of RP1 with only a negligible risk of environmental release or secondary transmission during clinical use
Critique The study provides comprehensive data on the biodistribution and shedding of RP1, supporting its safety profile. However, the study's limitations include the lack of extensive long-term follow-up and potential microbial contamination affecting some analyses. The controlled clinical environment may not fully reflect real-world use, and further studies are needed to confirm these findings.
Table 3 References:
[7] Wise-Draper TM, Robert C, Wong MK, et al. Biodistribution, shedding, and transmissibility of vusolimogene oderparepvec (RP1). Front Oncol. 2026;16:1798502. doi:10.3389/fonc.2026.1798502

A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial
Design

Clinical trial analysis

N= 140
Objective To evaluate the 3-year overall survival of patients with anti–PD-1–failed melanoma treated with RP1 plus nivolumab
Study Groups

Overall population (N= 140)

Responders (n= 47)

Non-responders (n= 93)
Inclusion Criteria Patients ≥18 years with advanced melanoma and confirmed progression while being treated for ≥8 weeks with anti–PD-1 ± anti–CTLA-4 as the last prior therapy
Exclusion Criteria Not specified
Methods Patients received an initial dose of RP1 intratumorally (1 x 10^6 PFU/mL), followed by up to 7 doses every 2 weeks (1 x 10^7 PFU/mL) in combination with intravenous nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks for up to 2 years. Additional RP1 was allowed if protocol-specified criteria were met. Overall survival was evaluated using the Kaplan-Meier method.
Duration Data cutoff: June 11, 2025
Outcome Measures Primary: Overall survival (OS) rates at 1, 2, and 3 years
Baseline Characteristics   Overall population (N= 140)
Stage IVM1b–d disease 49.3%
PD-L1–negative tumors 55.7%
Prior anti–PD-1 + anti–CTLA-4 therapy 46.4%
Primary resistance to prior anti–PD-1 65.0%
Results  

Overall population

(N= 140)

Responders

(n= 47)

Non-responders

(n= 93)
3-year OS rate 45.5% 81.8% 22.5%
OS rate in stage IVM1b–d 41.8%  - -
OS rate in PD-L1–negative tumors 37.2% - -
OS rate with prior anti–PD-1 + anti–CTLA-4 therapy 37.4% - -
OS rate with primary resistance to anti–PD-1 44.8% - -
Adverse Events The safety profile for RP1 + nivolumab remained consistent with prior reports; no new safety signals were seen.
Study Author Conclusions The 3-year landmark OS rate of 45.5% in the overall population and 81.8% among responders provides further evidence that the deep and durable responses provided by RP1 + nivolumab translate into long-term clinical benefit, including extended OS in patients with melanoma post-confirmed progression on prior anti–PD-1–based therapy.
Critique The study provides valuable insights into the long-term survival benefits of RP1 plus nivolumab in a difficult-to-treat population. However, the lack of a control group and the potential for selection bias due to the specific inclusion criteria may limit the generalizability of the findings. Furthermore, these findings were only available as a published abstract, limiting the ability to verify the full procedures and outcomes assessed. 
Table 4 References:
[8] Wong MKK, Sacco JJ, In GK, et al. A 3-year landmark overall survival analysis of RP1 plus nivolumab in patients with anti-PD-1-failed melanoma from the IGNYTE clinical trial. J Clin Oncol. 2026;44(16_suppl):9518. doi:10.1200/JCO.2026.44.16_suppl.9518