PRAME-Directed Therapies Advance Melanoma Treatment Across Clinical Settings

PRAME has emerged as one of the most compelling intracellular immunotherapy targets in advanced melanoma, offering a potential new avenue for patients whose disease has progressed after immune checkpoint inhibition, according to Diwakar Davar, MBBS, MSc, and Daniel Olson, MD.

“PRAME is a cancer testis antigen [that] is widely expressed in more than 50 cancers,” Davar said in an interview with OncLive®. “It's a novel target for immunotherapy in multiple cancers. The important thing to understand is that PRAME is actually subcellular, so it's not a [target on the] cell surface target; it's an intracellular target, which means that it cannot conventionally be targeted by things like CAR T-cell therapy. It can be targeted by monoclonal antibodies or CD3 bispecific [antibodies], but it cannot be targeted by a cell surface moiety.”

Davar is an associate professor of medicine, the clinical director of the Melanoma and Skin Cancer Program, and the vice-chief of academic affairs in the Division of Hematology-Oncology and Department of Medicine at University of Pittsburgh in Pennsylvania.

What are the most recent data with PRAME-directed agents in melanoma?

During the 2026 ASCO Annual Meeting, Davar presented data from the phase 1 IMA203-101 study (NCT06743126), which evaluated the autologous PRAME-directed T-cell receptor (TCR) T-cell therapy anzutresgene autoleucel (anzu-cel; IMA203) in patients with PRAME-positive advanced solid tumors, including melanoma, with no available standard of care treatment options.¹ The primary end points were tolerability and determining the recommended phase 2 dose (RP2D). Secondary end points included anzu-cel T-cell engraftment and persistence, as well as efficacy.

“These were all relatively heavily pretreated patients,” Davar noted. “The patients with cutaneous melanoma had a median of 2.5 prior lines of therapy [range, 1-5]. They were almost all heavily checkpoint inhibitor–refractory. All of them had prior checkpoint inhibitor exposure, and the degree of refractoriness could be seen in of the amount of cancer they had.”

Findings from the study revealed that the confirmed overall response rate (ORR) among all patients with melanoma who received anzu-cel (n = 33) was 56%. The unconfirmed ORR was 64%, and the disease control rate was 91%.

Notably, most responders experienced shrinkage of at least 1 lesion by the first scan, and responses were observed in target and non-target lesions. The median time to best overall response was 1.4 months (range, 1.2-2.8), and the median duration of response was 14.6 months (range, 4.2-38.2+). The median progression-free survival (PFS) and overall survival (OS) values were 6.1 months (range, 1.4-39.6+) and 16.2 months (range, 2.4-39.6+). The 6- and 12-month PFS rates were 55% and 37%, respectively; the 12- and 24-month OS rates were 70% and 46%, respectively.

In terms of safety, the tolerability profile of anzu-cel was deemed to be predictable and manageable. The most frequent treatment-emergent adverse effects (TEAEs) were anticipated cytopenias associated with lymphodepletion. Any-grade cytopenia (100%), neutropenia (100%), anemia (100%), leukopenia (100%), lymphopenia (100%), and thrombocytopenia (94%) were reported in significant numbers of patients. Other common any-grade TEAEs included nausea (67%), increased alanine aminotransferase/aspartate aminotransferase levels (52%), and rash (42%).

“Most patients had very rapid, durable shrinkage of the lesions, [which] was quite remarkable,” Davar said. “The 1- and 2-year OS estimates tell you that almost half of everybody you treat were alive at the 2-year mark, which is really remarkable when you think of the fact that these are patients who are heavily pretreated [with an estimated] limited survival.”

Another PRAME-directed TCR product that has shown promise in patients with advanced melanoma is brenetafusp.² The TCR bispecific ImmTAC molecule targeting PRAME and CD3 is being examined in the phase 1/2 IMC-F106C-101 trial (NCT04262466) in patients with unresectable/metastatic melanoma of all subtypes who previously received anti–PD-(L)1 agents and/or BRAF/MEK inhibitors, if applicable. The primary end points are safety and determining the maximum tolerated/expansion dose. Efficacy, pharmacokinetics, molecular response, and predictive biomarkers were also assessed as additional end points.

“The area of interest that we're focused on [in the development of PRAME-directed agents] is PD-1–refractory melanoma,” Olson, an assistant professor of medicine at UChicago Medicine in Illinois, said in an interview with OncLive. “This is certainly an area of unmet need, [although] there are some emerging therapies in the space. We have seen the emergence of tumor-infiltrating lymphocyte therapy, which is a good option for some patients, but it is a relatively intense therapy and has some requirements around tumor size and procurement areas, so it is not an option for everyone. By adding additional options and different ways of targeting melanoma from immune checkpoint inhibitors, we hope to see these longer-term responses.”

Findings from IMC-F106C-101 showed that among all patients who received brenetafusp monotherapy (n = 66) achieved an ORR of 12% and a DCR of 52%. The 6-month OS rate was 87%. Moreover, patients who received brenetafusp in combination with pembrolizumab (Keytruda; n = 10) experienced an ORR of 20% with a DCR of 70%. The 6-month OS rate in this group was 80%. Notably, circulating tumor DNA response was higher among patients with PD-1 primary resistance (53%; n = 8 of 15) compared with the overall group (38%; n = 19 of 50).

At a median follow-up of 22.4 months, the median OS in the monotherapy group was 14.3 (95% CI, 11.3-20.4) months, and the 12-month OS rate was 57%. At a median follow-up of 25.6 months, the median OS was 14.7 months (95% CI, 5.8-not calculable), and the 12-month OS rate was 64% among patients with PD-1 primary resistant disease (n = 20).

Brenetafusp was found to have a predictable, mechanism-driven, and well-tolerated safety profile in both the monotherapy and combination arms. The most frequent treatment-related adverse effects (TRAEs) in the monotherapy and combination arms were cytokine release syndrome and rash; most instances were grade 1 and decreased in intensity over time. TRAEs led to treatment discontinuation in 2 patients in the monotherapy arm and 1 patient in the combination arm.

“The takeaway is the survival [figures] and the DCR; these intermediate end points [often] don't reflect the overall benefit of these therapies,” Olsen said. “[This] update shows that in some of these patients who are PRAME-positive derive this benefit, they can be stabilized for a good period of time. [This gave us the] impetus for a randomized phase 3 study in [the] frontline [setting].”

What are the next steps for targeting PRAME in melanoma?

The ongoing phase 3 PRISM-MEL-301 trial (NCT06112314) is evaluating brenetafusp in combination with nivolumab (Opdivo) in patients with previously untreated advanced melanoma.³ The study is enrolling patients with HLA-A*02:01–positive disease with measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.

Approximately 90 patients will be randomly assigned 1:1:1 to receive brenetafusp at 2 dose levels in combination with nivolumab; or nivolumab or nivolumab plus relatlimab (Opdualag). Additional patients (n = 590) will be randomly assigned to receive brenetafusp plus nivolumab or nivolumab or nivolumab/relatlimab after dose selection.

The primary end point is PFS per blinded independent central review; OS, ORR, and safety are being evaluated as secondary end points.

“The big question is: how does [brenetafusp] perform in the first-line setting?” Olsen said. “It's always interesting when you have a checkpoint [inhibitor] combination, especially in treatment-naive patients, [where] the partner drug can drive a lot of the benefit. This is a randomized study, so it's going to account for that.”

In light of the encouraging data from IMA203-101, anzu-cel is also set for further study in the phase 3 SUPRAME trial (NCT06743126).⁴ SUPRAME is comparing anzu-cel with investigator’s choice of therapy in patients with previously treated advanced cutaneous melanoma. The prospective, multicenter, open-label trial is enrolling adult patients with unresectable/metastatic disease with an ECOG performance status of 0 to 1, measurable disease per RECIST 1.1 criteria, and HLA-A*02:01–positive disease.

Patients will be randomly assigned 1:1 to receive a one-time infusion of anzu-cel after lymphodepletion or investigator’s choice of therapy with nivolumab/relatlimab, nivolumab, ipilimumab (Yervoy), pembrolizumab, lifileucel (Amtagvi), or chemotherapy.

The primary end point is PFS; OS is the key secondary end point. Other secondary end points include ORR, safety, and quality of life. SUPRAME is being conducted across approximately 50 sites in the US and Europe. Approximately 180 patients will be enrolled onto each arm.

“[SUPRAME] is active and heavily enrolling at the current time,” Davar noted. “The response analysis supports the idea that the drug has a broad systemic reach, including into organs that are historically considered hard to treat, such as the liver. The survival and efficacy of the drug at the durable landmark end point of 2 years suggests that this [agent] really does alter the trajectory of these patients.”

References

1. Davar D, Patel SP, Hernandez-Aya LF, et al. Patient-level clinical response dynamics in advanced melanoma with anzutresgene autoleucel (anzu-cel), a PRAME-directed T-cell receptor (TCR) T-cell therapy. J Clin Oncol. 2026;44(suppl 16):9508. doi:10.1200/JCO.2026.44.16_suppl.9508
2. Long GV, Davar D, Hamid O, et al. Phase 1 evaluation of the PRAME-targeted ImmTAC brenetafusp in advanced melanoma (Mel). J Clin Oncol. 2026;44(suppl 16):9527. doi:10.1200/JCO.2026.44.16_suppl.9527
3. Long GV, Atkinson V, Ascierto PA, et al. A phase 3 trial of IMC-F106C (PRAME x CD3) plus nivolumab versus standard nivolumab regimens in HLA-A*02:01+ patients with previously untreated advanced melanoma (PRISM-MEL-301). J Clin Oncol. 2024;42(suppl 16):TPS9602. doi:10.1200/JCO.2024.42.16_suppl.TPS9602
4. Luke JJ, Warner AB, Chmielowski B, et al. SUPRAME: a phase 3 trial comparing IMA203, an engineered T-cell receptor expressing T cell therapy (TCR-T) vs investigator’s choice in patients with previously treated advanced cutaneous melanoma. J Clin Oncol. 2025;43(suppl 16):TPS2673. doi:10.1200/JCO.2025.43.16_suppl.TPS2673