Phase 1 Data Pave the Way for Further Investigation of IMA203 in Advanced Melanoma

Jason J. Luke, MD, FACP

Following promising data regarding treatment with the PRAME-targeted T-cell receptor [TCR] T-cell therapy IMA203in patients with advanced or metastatic melanoma in the phase 1 ACTengine trial (NCT03686124), the phase 3 SUPRAME trial (NCT06743126) could help further define a potential role for the agent in this previously treated patient population, according to Jason J. Luke, MD, FACP.

During the 2025 ASCO Annual Meeting, updated data from ACTengine revealed that IMA203 produced a confirmed overall response rate (ORR) of 56% (n = 18/32) among all response-evaluable patients with melanoma. The confirmed ORRs in patients with cutaneous (n = 14) or uveal (n = 16) melanoma were 50% and 67%, respectively.

In terms of safety, no grade 5 adverse effects (AEs) related to IMA203 were reported. Instances of cytokine release syndrome (CRS) were manageable; the median time to onset of CRS was 1 day (range, 0-3), the median duration of CRS was 9 days (range, 2-27), and most instances of CRS resolved within 14 days. Notably, no instances of long-term CRS were reported.

“[SUPRAME] is a promising trial based on the phase 1 data for IMA203, wherein heavily pretreated patients with advanced melanoma [achieved a confirmed] ORR at the recommended phase 2 dose of 56% with a [median] duration of response of 12.1 months [range, 1.8+ to 32.6+],” Luke said in an interview with OncLive®. “In this population of patients with no available standard therapy, we saw more than 50% of them [achieve] a long-term response, which is very promising.”

Luke is the associate director for clinical research and the director of the Immunotherapy and Drug Development Center at the University of Pittsburgh Hillman Cancer Center in Pennsylvania.

In the interview, Luke discussed the unique mechanism of action of IMA203, the design of SUPRAME, and the future role of cellular therapies for the treatment of patients with melanoma.

OncLive: What are some notable design characteristics of SUPRAME?

Luke: SUPRAME is [enrolling patients with] previously treated melanoma. Patients will be randomly assigned to receive IMA203 or investigator’s choice of standard-of-care [treatment]. This is the first clinical trial in [patients with] a solid tumor in which be patients will be randomly assigned to receive a cellular therapy vs a standard therapy.

What differentiates IMA203 from other cellular therapies?

IMA203 is a TCR T-cell product that targets PRAME. PRAME is not a tumor-specific antigen; it’s a cancer-testis antigen that’s abnormally expressed in several kinds of cancers. [IMA203] is being studied in [patients with] melanoma because the expression pattern of PRAME is between 90% and 100% of these patients.

Because it is a cellular therapy, there are complexities around how to develop and administer this drug. We’ve seen the integration of tumor-infiltrating lymphocyte [TIL] therapy in the melanoma [treatment landscape]. The advantage of TCR-based therapy is that it’s easier [to administer] and potentially works even better.

With TIL-[based] therapy, we surgically remove the cancer, [harvest] T cells in the tumor, and leverage them into a new drug. Here, we [perform] leukapheresis to isolate T cells from the blood, use lentivirus transfection to insert the TCR into the cells, and then administer them to the patient.

Both of those approaches require lymphodepleting chemotherapy; however, the TCR product does not require IL-2 [therapy], and that’s a differentiator from lifileucel [Amtagvi] or TIL therapy. It’s important to understand that this is a new kind of cellular therapy that’s easier and faster to make, which seems to work better and is less toxic for patients.

Will patients be screened for PRAME expression in SUPRAME?

In ACTengine, we had to screen patients for PRAME expression; in SUPRAME—and hopefully with the subsequent approval of the drug—that will not be required because the expression pattern is so high that it’s unnecessary. [However], it is important to point out that since this is a TCR-based therapy, we must match HLA status. It’s similar to a bone marrow transplant in that we need to know if the patient is positive for HLA-A*02:01. The first step with a therapy [such as] IMA203 is to do a blood test or a buccal swab to check germline HLA status. This is a new biomarker that will be necessary in our field. We need to have all of our patients tested for HLA to identify those who are positive for HLA-A*02:01. If they are positive, then we can proceed with leukapheresis and to make the drug.

What effect could positive data for IMA203 from SUPRAME have on the treatment landscape for patients with melanoma?

[An important contribution from SUPRAME] will be identifying patients at the right period in their care. In ACTengine, we saw that you can get responses to this agent even in patients with heavily refractory disease, 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 we’re harnessing a very powerful immune treatment. Some of the worst AEs that 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 disease progression on a frontline therapy, but I would heavily advocate that we should be looking for those patients who are refractory to immune checkpoint blockade and quickly moving them to this type of approach. In my clinic, we’re performing circulating tumor DNA testing per standard of care. In patients who are receiving an immune checkpoint inhibitor as their first line of therapy for melanoma and show any signs of disease progression, we quickly start pivoting because we want to get the patients to cellular therapy as quickly as possible.

[This is important] for [patients with] melanoma, but I believe more broadly in all of [cancer care], over the next couple of years, we’re going to see checkpoint inhibitors remain as a frontline standard of care that benefits a lot of patients. However, in the patients for whom we identify [that this approach] isn’t working, transitioning to a fundamentally different mechanism is going to be a huge priority and is going to require a major shift in the way we think because we’ve often thought of cellular therapy as something that [is in the realm of] bone marrow transplant. Cellular therapy is going to become something that is standard for patients with solid tumors, initially [only] in [patients with] melanoma, but not for very long. It’s going to be used in [patients with] lung cancer, gynecologic tumors, and more.

Reference

Wermke M, Alsdorf W, Araujo D, 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