As RP1 Heads to Melanoma Clinics, Experts Look to Streamline Rollout and Rethink Response Criteria

After a nearly 2-year regulatory saga that included 2 complete response letters (CRLs), a contentious advisory committee meeting, and an outpouring of support from the melanoma community, the oncolytic therapy vusolimogene oderparepvec-wtpg (Tudriqev)—known as RP1—received accelerated FDA approval on August 6, 2026, in combination with nivolumab (Opdivo) for patients with advanced melanoma who have progressed on anti–PD-1 therapy.¹ As of August 14, 2026, the drug’s manufacturer, Replimune Group, Inc, anticipated making RP1 commercially available within 60 days.²

The decision followed the July 30, 2026, meeting of the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC), which voted 10 to 3 that the phase 2 IGNYTE trial (NCT03767348) provided clinically meaningful and evaluable evidence for the regimen.³ Physicians who spoke with Targeted Oncology described a drug that, however contested its path to approval, fills a genuine gap for patients who have run out of options after checkpoint inhibitor failure.

“It’s an important and welcome approval because it expands our treatment options in a setting where there remains an unmet need,” Vincent T. Ma, MD, a melanoma and skin cancer specialist and associate professor at the University of Wisconsin School of Medicine and Public Health, said in an interview with Targeted Oncology.

The Long Road to Approval

The registrational IGNYTE cohort enrolled 140 patients with unresectable stage IIIB to IV cutaneous melanoma with disease progression on or after anti–PD-1 therapy to receive the herpes simplex virus (HSV)–derived RP1 in combination with nivolumab. The trial reported a confirmed overall response rate (ORR) of 33.6%, including a 15.0% complete response rate, and a median duration of response of 24.8 months, with responses seen at similar rates in patients with injected and uninjected lesions.⁴ An exploratory 3-year overall survival (OS) analysis, presented at the 2026 American Society of Clinical Oncology Annual Meeting, showed a 47.8% OS rate, with roughly 80% to 85% of responders alive at 3 years.⁵

In an interview, Michael Wong, MD, PhD, the trial’s principal investigator and former physician in chief at Roswell Park Comprehensive Cancer Center, characterized the safety profile as favorable, pointing to published data showing grade 3 or 4 treatment-related toxicities in roughly 13% of patients combined, including a grade 4 rate of just 3.6%, low enough that he has treated patients older than 80 years without excess toxicity.⁴

Despite the reported efficacy and tolerability, the FDA issued a first CRL in July 2025, questioning whether the IGNYTE trial was adequate and well controlled and raising concerns about population heterogeneity. A second CRL followed in April 2026, reiterating many of the same concerns, before the agency convened the CTGTAC meeting.

Wong called the interval between the first denial and eventual approval “difficult to reconcile” from a patient-care standpoint. The melanoma community mobilized after each rejection, including a letter signed by more than 2500 melanoma specialists worldwide and editorials in outlets such as the Wall Street Journal, contributing to the FDA’s decision to convene an outside panel of clinicians, statisticians, and patient advocates for the July meeting.

Wong, who presented data at the meeting from IGNYTE on behalf of the trial sponsor, recounted that the most striking part of the hearing was the public comment period, which included emotional testimony from patients with advanced melanoma and their families about the desperate need for this regimen. “It was compelling. It was heart-wrenching,” he said.

Daniel Wang, MD, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center’s Harold C. Simmons Comprehensive Cancer Center, said in an interview that the process ultimately proved valuable to him and others who treat melanoma. “I thought the FDA and the sponsor brought up really great points,” he said, noting that the discussion clarified both the agency’s concerns about interpretability and the clinical community’s rationale for why many in the field felt the drug should move forward despite its methodological limitations.

Hearing directly from patients highlighted “how much hope this treatment had brought to a lot of people,” which Wang said could never be conveyed with numbers and statistics alone. Ma concurred that the CTGTAC meeting was a “very important and constructive” element of the FDA review process.

Wong said he was gratified by the depth with which the panel members explored the data and clinical implications of IGNYTE and felt this contributed to the positive outcome of the meeting. “Once you get into the details of what’s going on, you understand this is not a trial that was poorly done,” he said.

Rethinking RECIST for Intratumoral Therapies

The FDA raised multiple issues with the IGNYTE trial design, patient population, and outcomes.³ One was distinguishing the contribution of RP1 and nivolumab in the single-arm trial, but this point was countered by the rationale that retreatment with a PD-1 inhibitor is known to be far less effective and would not be considered an ethical comparator arm. In the ongoing confirmatory phase 3 IGNYTE-3 trial (NCT06264180), virtually no patients have received nivolumab monotherapy as physician’s choice of comparator. “Practicing oncologists would never put someone back on a drug that failed,” Wong pointed out.

A more challenging issue the FDA raised was the difficulty of evaluating systemic response to the intratumorally injected RP1. Members of the CTGTAC acknowledged that this was a long-standing issue that the RECIST v1.1 criteria employed in the IGNYTE study readout do not fully address. The FDA’s key objection was that focal injection generally renders treated lesions nonevaluable by RECIST and that although some uninjected target lesions showed tumor regression, more than half of patients in IGNYTE lacked uninjected target lesions to independently confirm a systemic effect.³

Because some patients had all target lesions injected, “it was hard to tell whether there was actually systemic response there,” said Wang. This fed broader questions about how much of the benefit could be attributed to RP1 and nivolumab’s combined systemic effect. He said the trial’s use of treatment beyond progression (TBP)—under which injected lesions could disappear and new ones would be treated in turn—further complicated applying a framework built around traditional systemic therapy, even though TBP might be an effective treatment strategy for RP1. “There needs to be a new standard to better interpret these results,” Wang suggested for intratumoral approaches.

Wong said he didn’t blame the FDA for judging by the criteria that had been selected but contested the FDA’s late reevaluation of the response criteria and even described a patient in his own practice whose biopsy-negative residual lesion was deemed nonevaluable rather than counted as a complete response. “It wasn’t the task at the point of evaluation for people to start redefining or changing the goalposts,” he said.

However, the controversy put a spotlight on the need for new standards, especially as the promise of RP1 may move intratumoral therapies forward. Wong said that we are now at “an inflection point of oncology,” which he compared to the transition from chemotherapy to checkpoint inhibitors, hormonal therapy, and targeted therapies that required researchers to develop new methods and measurements. “The current ruler used to measure efficacy for intratumoral trials doesn’t do these paradigms justice,” he said.

An expert panel convened in 2024 by the Society for Immunotherapy of Cancer identified key considerations for the implementation of clinical trials for intratumoral immunotherapies, such as the use of durable clinical benefit or progression-free survival rather than ORR as phase 2 end points, biomarker-based enrollment to demonstrate systemic effect, and clear requirements for target lesions to include noninjected lesions.⁶

Wong said he is organizing a workshop with clinicians, trial design experts, and the FDA to propose new response criteria for intratumoral and oncolytic virus trials, calling it a “call to arms” ahead of OS data expected from the confirmatory trial.

Ma noted that panelists were split on how to weigh RECIST-based data against clinical plausibility, an assessment reflected across the CTGTAC discussion, with some members viewing durable responses in distant lesions as evidence of a systemic effect and others cautioning that, historically, intratumoral approaches have rarely demonstrated a true systemic effect.³ Still, Ma said he felt the committee “appropriately considered” the depth and durability of responses, including complete responses, alongside feasibility and safety data.

Wong pushed back strongly against the claim that IGNYTE’s data were simply hard to interpret, pointing to the trial’s independent, blinded lesion-by-lesion analysis—in which reviewers assessed injected and noninjected lesions without knowing which had been treated—as, in his experience, among the most rigorous analyses conducted in any oncology trial.

An Unmet Need Beyond Tumor-Infiltrating Lymphocyte Therapy

The undisputed theme surrounding the RP1 approval is that patients who already received anti–PD-1 therapy and BRAF-targeted therapy have very few remaining options. Wang estimated response rates to alternative immunotherapy combinations in this setting at around 10% for otherwise healthy patients, whereas tumor-infiltrating lymphocyte (TIL) therapy, although more effective for some, “comes at a cost of toxicity,” including a meaningful risk of serious adverse events and mortality.

Ma explained how lifileucel (Amtagvi), the only FDA-approved TIL therapy for melanoma refractory to anti–PD-1 therapy, falls short for many patients. Some patients lack sufficient tumor tissue for successful cell procurement, have active or rapidly progressing brain metastases, cannot tolerate the lymphodepleting chemotherapy and interleukin-2 that lifileucel is paired with, or have melanoma subtypes such as uveal melanoma for which TILs are not approved. “That leaves a significant group of patients with few effective standard treatment options,” he said, describing RP1 plus nivolumab as filling a need for therapies that are effective after anti–PD-1 failure but more broadly accessible than cellular therapy. “Having another active therapy available is very meaningful.”

However, Ma cautioned against overextending the new approval’s scope to RP1 as monotherapy. Evidence for its use without a checkpoint inhibitor, drawn largely from the ARTACUS trial (NCT04349436) in transplant recipients with nonmelanoma skin cancers, is not yet sufficient to extrapolate to patients who cannot tolerate checkpoint inhibition.

David Savage, MD, PhD, an assistant professor at the University of New Mexico Comprehensive Cancer Center (UNMCCC) who treats skin cancers and sarcoma, said his center has long anticipated this approval. “For a year now, I have been on pins and needles hoping that this drug would get approved,” he said, adding that he already has several eligible patients in mind and that RP1 was presented to his institution’s pharmacy committee within days of the decision. Even with access to lifileucel, Savage noted that treatment requires surgery, lymphodepleting chemotherapy, and time away from family. Wong likewise said that TIL therapy is “only doable for a very select patient population,” whereas RP1 can be given “ubiquitously” in patients with immunotherapy-refractory disease.

Still, Savage cautioned against overstating RP1’s potential in this population and suggested the unmet need remains. “I think RP1 will help to some degree, but there [are] still going to be [patients] who don’t get a good response despite all those things,” he said.

Bringing RP1 Into Clinical Practice

Unlike a standard systemic therapy, RP1 requires multiple intratumoral injections, particularly during the first several months of treatment, requiring coordination across practices and specialties. “The real-world challenge overall is going to be less about toxicity and more about patient selection, injectable disease, procedural expertise, [and] coordination of care for patients,” said Ma, noting that implementation will “require coordinated workflows among medical oncologists, interventional radiologists, surgeons, and other proceduralists to identify appropriate lesions and deliver treatment efficiently.”

Savage described his center’s approach to this key logistical question: UNMCCC dermatologists with experience injecting talimogene laherparepvec (Imlygic) for superficial skin lesions plan to handle RP1 similarly, whereas deeper lesions, such as lung or nodal metastases, will likely be referred to interventional radiology for ultrasound or CT guidance. In Savage’s practice area, the interventional radiology suite is geographically separate from UNMCCC’s location—adding pharmacy logistics complexity—but an interventional radiologist he approached “expressed complete willingness to work with us to try to get these patients treated.”

According to Ma, the need for multiple intratumoral injections brings procedural and logistical components to treatment selection, and it may not always be easy to determine which lesions are accessible. Scheduling RP1 injections and nivolumab during induction may not suit patients with limited availability or rapidly progressive visceral disease. Additionally, smaller community practices without established multidisciplinary infrastructure may need to refer patients to centers experienced in intratumoral therapy.

Wang, whose institution is treating patients in the confirmatory IGNYTE-3 trial, said early engagement with interventional teams has been essential even for centers with prior oncolytic virus experience. “Every drug and design is a little bit different,” he said, noting that his team’s conversations with interventional radiology and pulmonology helped anticipate logistical hurdles before they affected patient care, and he urged other medical oncologists to develop these relationships early. He added that most toxicities observed in practice so far have been mild and local, although patients should be counseled about how this treatment differs from their previous therapies.

Wong offered guidance from an ad hoc subgroup analysis of IGNYTE: Response rates were higher among patients who had both superficial and deeper visceral lesions injected than among those injected only superficially. “If you just hit the easy-to-get ones on [the] skin and [lymph] nodes…you statistically are not going to get the response rate you desire,” he said. He added that he is working with the drug manufacturer on a practical injection guide for oncologists using RP1. Finally, Wong flagged biosafety considerations for RP1 as a live, engineered HSV. Although it has been modified to prevent propagation and no human-to-human transmission has been observed in clinical trials, severely immunosuppressed patients should still not be placed near others receiving injections in clinic.

Awaiting Confirmatory Phase 3 Data and Beyond

Because accelerated approval rests on response and durability data from a single-arm trial, the ongoing phase 3 IGNYTE-3 trial, randomly assigning patients to RP1 plus nivolumab or physician’s choice of therapy with OS as the primary end point, will be critical to confirming the regimen’s benefit.⁷ Primary completion is expected in 2030.

For now, melanoma physicians are excited to see a new treatment option that they can offer to patients in need but are anticipating the IGNYTE-3 results to evaluate the long-term efficacy of the oncolytic therapy. Ma said the confirmatory data will be important for determining whether the benefit seen from IGNYTE is confirmed in a randomized trial setting and whether RP1 plus nivolumab “ultimately becomes an established part of the melanoma treatment landscape.”

“We still need to cautiously continue to monitor these patients while we have this current accelerated approval,” Ma said.

Wong emphasized the “breakthrough” that RP1’s proposed systemic mechanism represents, saying “the ceiling has been broken” for intratumoral agents and now the “floodgates are open” for exploring new approaches to treatment, including optimization of the viral delivery mechanism, delivery of mRNA via electroporation, or finding other immunogenic triggers. Although intratumoral therapies have had mixed results in the metastatic setting, their favorable tolerability profile and potential for combination with efficacious systemic therapies have led to a great deal of interest across solid tumors.⁷

“I’m just happy that there is [an approval], and we will be moving forward to make it available to our patients with melanoma,” said Savage.

DISCLOSURES: Wong reported being compensated for his time by the drug sponsor when presenting at the CTGTAC meeting.

REFERENCES

1. FDA grants accelerated approval to vusolimogene oderparepvec-wtpg in combination with nivolumab for melanoma. FDA. Updated August 6, 2026. Accessed August 6, 2026. https://tinyurl.com/34v89fmz

2. Replimune reports fiscal first quarter 2027 financial results and provides corporate update. Replimune Group Inc. News release. August 14, 2026. Accessed August 17, 2026. https://tinyurl.com/4thwj4hw

3. Cellular, Tissue, and Gene Therapies Advisory Committee July 30, 2026 meeting announcement — updated information (as of 7/16/2026). FDA. July 30, 2026. Accessed July 30, 2026. https://tinyurl.com/2yjnd7r3

4. 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

5. 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(suppl 16):9518. doi:10.1200/JCO.2026.44.16_suppl.9518

6. Luke JJ, Davar D, Andtbacka RH, et al. Society for Immunotherapy of Cancer (SITC) recommendations on intratumoral immunotherapy clinical trials (IICT): from premalignant to metastatic disease. J Immunother Cancer. 2024;12(4):e008378. doi:10.1136/jitc-2023-008378

7. Ma VT, Steimle AK, Patel JD, et al. Updates on intratumoral therapies in melanoma. Cancer. 2026;132(13):e70400. doi:10.1002/cncr.70400