Positive safety and efficacy findings with the PRAME-directed T-cell receptor (TCR) T-cell therapy IMA203 in patients with PD-1 inhibitor–refractory metastatic melanoma from the phase 1 ACTengine trial (NCT03686124) have propelled the launch of the phase 3 SUPRAME trial (NCT06743126), which is comparing IMA203 with investigator’s choice of treatment in patients with previously treated unresectable or metastatic cutaneous melanoma.1
“IMA203 is a novel treatment for melanoma…. It’s the first engineered cell therapy that we have for the potential [management] of melanoma,” Justin Moser, MD, said in an interview with OncLive. “Many [standard melanoma therapies] have 10%, 20%, maybe up to 25% response rates in the refractory setting. [IMA203] looks like it has much higher potential for patients with refractory melanoma.”
Moser is an associate clinical investigator, a melanoma and cutaneous oncology specialist, and a phase 1 trialist at HonorHealth Research Institute in Scottsdale, Arizona. He is also a research associate professor at Arizona State University School of Medicine and Advanced Medical Engineering and a clinical assistant professor at the University of Arizona, both in Phoenix.
IMA203 is engineered to recognize an intracellular PRAME-derived peptide presented by human leukocyte antigen (HLA)-A*02:01 on the cell surface and subsequently initiate an antitumor response.2
“[IMA203] is being studied in [patients with] melanoma because the expression pattern of PRAME in melanoma…is somewhere between 90% and 100%,” Jason J. Luke, MD, FACP, said in an interview with OncLive. “[It’s] important to understand that this is a new kind of cell therapy that’s easier…and faster to make, [which] seems to work better and is less toxic for patients.”
Luke is an associate professor of medicine in the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh in Pennsylvania. He is also the associate director for clinical research and director of the Immunotherapy and Drug Development Center (Phase I) at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center.
ACTengine Data Act as a Catalyst for Further IMA203 Research in Melanoma
Safety data from ACTengine, which were related to the trial’s primary end point and presented during the 2025 American Society of Clinical Oncology Annual Meeting, showed that the most common treatment-emergent adverse effects (TEAEs) were cytopenias associated with lymphodepleting chemotherapy; mild-to-moderate cytokine release syndrome (94.6%); and infrequent, mild, and manageable immune effector cell–associated neurotoxicity syndrome (13.5%). Investigators observed no grade 5 IMA203-related AEs.1 The recommended phase 2 dose (RP2D) was identified as 1 x 109 to 10 x 109 TCR T cells.
The confirmed objective response rate (ORR) with IMA203 was 56% (n = 18/32) among response-evaluable patients with melanoma. Additionally, the unconfirmed ORR was 64% (n = 21/33), and the disease control rate (DCR) was 91% (n = 30/33). At a median follow-up of 13.4 months (n = 33), the median duration of response (DOR) was 12.1 months (range, 1.8+ to 32.6+). Furthermore, at a median follow-up of 14.4 months, the median progression-free survival (PFS) was 6.1 months (range, 1.4 to 34.0+), and the median overall survival (OS) was 15.9 months (range, 2.4 to 34.2+).
In the population of patients with cutaneous melanoma (n = 14), the confirmed ORR was 50%, the unconfirmed ORR was 57%, and the DCR was 93%. At a median follow-up of 16.7 months, the median DOR was not reached (range, 4.2 to 32.6+). Moreover, at a median follow-up of 14.4 months, the median PFS was 6.0 months (range, 1.4 to 34.0+), and the median OS was 13.9 months (range, 2.4 to 34.0+).
SUPRAME Plans to Provide an In-Depth Look at IMA203 vs Standard Therapies in Cutaneous Disease
SUPRAME is an ongoing, prospective, multicenter, open-label, parallel-group trial that is enrolling patients with pathologically confirmed and documented unresectable or metastatic cutaneous melanoma, including acral melanoma.3,4 Patients need to have HLA-A*02:01–positive disease, adequate per-protocol selected organ function, an ECOG performance status of 0 or 1, a life expectancy of more than 6 months, measurable disease per RECIST 1.1 criteria, and disease progression on or after 1 or more PD-1 inhibitors either as monotherapy or in combination with other therapies for the management of unresectable or metastatic cutaneous melanoma. Notably, patients with BRAF-mutated disease should have received 1 prior line of BRAF-directed therapy (with or without a MEK inhibitor) before their initial eligibility assessment for SUPRAME. Exclusion criteria include primary mucosal or uveal melanoma and melanoma of unknown primary, as well as a history of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within the past 3 years.
“This is a TCR-based therapy, and for that reason…we need to know if the patient is [positive for] HLA-A*02:01,” said Luke. “This is a new biomarker that will be necessary in our field.”
“The main limitation for recruiting for this study is the restriction for…HLA-A*02:01, which is found in approximately 30% to 50% of Caucasians, and much less so in patients of other ethnicities,” Moser noted.
Patients eligible for enrollment in SUPRAME who are also eligible for leukapheresis may undergo leukapheresis for the potential manufacturing of IMA203. Patients will be randomly assigned to receive either IMA203 or investigator’s choice of active comparator approved by their respective competent authority.
Patients in the experimental arm will undergo nonmyeloablative chemotherapy for lymphodepletion over 4 days using fludarabine and cyclophosphamide, followed by a onetime administration of IMA203 at the RP2D and adjunctive therapy with low-dose IL-2 for a maximum of 10 days beginning approximately 24 hours after IMA203 infusion. Patients in the control arm may receive nivolumab (Opdivo) as monotherapy or in combination with relatlimab (Opdualag), lifileucel (Amtagvi), pembrolizumab (Keytruda), ipilimumab (Yervoy), dacarbazine, temozolomide (Temodar), paclitaxel as monotherapy or in combination with carboplatin, or albumin-bound paclitaxel. Patients in both arms may receive optional bridging therapy.
“Currently, the only…available option [for patients with refractory melanoma] outside of checkpoint inhibitors is lifileucel, [a] TIL [tumor-infiltrating lymphocyte] therapy, which has roughly a 30% response rate but has logistical [hurdles] in the fact that [patients] have to have disease that can be collected, [and they] have to be a candidate to undergo high-dose chemotherapy and high-dose IL-2,” Moser explained. “IMA203 is unique in the fact that [patients] would not need surgery for collection, and [they] are treated with lower doses of chemotherapy and lower doses of IL-2, meaning patients who may not be candidates for lifileucel may be candidates for IMA203 in the future, if they have the right HLA type and [IMA203] receives FDA approval.”
The primary end point of SUPRAME is PFS, centrally assessed by blinded independent central review per RECIST 1.1 criteria. Secondary end points comprise OS; ORR; PFS locally assessed using RECIST 1.1 criteria; TEAEs; AEs of special interest; serious TEAEs; the frequency and duration of dose interruptions, reductions, and discontinuations; and quality-of-life measures.
SUPRAME was initiated in January 2025 and is enrolling patients at 24 centers in the US and Germany. The estimated primary completion date for the trial is January 2028, and the study is anticipated to run through October 2031.
“[An important contribution from SUPRAME] will be identifying patients at the right period in their care,” Luke emphasized. “What we observed in [ACTengine] was that you can get responses to this agent even in heavily refractory patients, but the risk of toxicity goes up the [longer] you wait. There’s a lot going on in the immune system as cancer is progressing, and now we’re harnessing and administering a powerful immune treatment. Some of the worst AEs we’ve seen have been in patients who have been in the furthest lines of therapy. We want to try to move [IMA203] into the earlier lines of therapy as much as possible. [SUPRAME] requires progression on a frontline therapy, but I would heavily advocate that we should be looking quickly for patients who are refractory to immune checkpoint blockade and quickly moving them to this type of approach. [This is important] for [patients with] melanoma. In the patients [in whom] we identify [that checkpoint inhibition] isn’t working, transitioning to a fundamentally different mechanism—cell-based therapy—is going to be a huge priority. This is going to require a major shift in the way oncologists think. Cellular therapy is going to become a standard [treatment we consider] in solid tumors.”
References
- Wermke M, Alsdorf W, Araujo DM, et al. Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma. J Clin Oncol. 2025;43(suppl 16):2508. doi:10.1200/JCO.2025.43.16_suppl.2508
- Immatics IMA203 PRAME cell therapy data presented at 2025 ASCO Annual Meeting continues to show strong anti-tumor activity and durability in patients with metastatic melanoma. News release. Immatics. May 31, 2025. Accessed June 26, 2025. bit.ly/3ZOIcNg
- SUPRAME-ACTengine IMA203 vs investigator’s choice of treatment in previously treated, unresectable or metastatic cutaneous melanoma (SUPRAME). ClinicalTrials.gov. Updated July 2, 2025. Accessed June 25, 2025. https://www.clinicaltrials.gov/study/NCT06743126
- 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