IMA203 Demonstrates Early Promise in PD-1–Refractory Metastatic Melanoma

Metastatic Melanoma |
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The PRAME-directed TCR T-cell therapy IMA203 displayed acceptable tolerability and showcased early clinical activity in patients with PD-1–refractory metastatic melanoma, according to data from a phase 1 study (NCT03686124) presented during the 2025 ASCO Annual Meeting.1

With regard to safety, the trial’s primary end point, the most common treatment-emergent adverse effects (TEAEs) were anticipated cytopenias linked with lymphodepleting chemotherapy. Patients also experienced mild-to-moderate cytokine release syndrome (CRS), as well as infrequent immune effector cell–associated neurotoxicity syndrome (ICANS), with cases found to be mostly mild and manageable. Notably, no grade 5 AEs related to IMA203 were observed.

In evaluable patients with melanoma, IMA203 elicited a confirmed overall response (ORR) of 56% (n = 18/32), an unconfirmed ORR of 64% (n = 21/33), and a disease control rate (DCR) of 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+). 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 subset of patients with cutaneous melanoma, the confirmed ORR was 50% (n = 7/14), the unconfirmed ORR was 57% (n = 8/14), and the DCR was 93% (n = 13/14). At a median follow-up of 16.7 months, the median DOR was not reached (NR; range, 4.2 to 32.6+). At a median follow-up of 14.4 months, the median PFS and OS in this group were 6.0 months (range, 1.4 to 34.0+) and 13.9 months (range, 2.4 to 34.0+), respectively. In those with uveal melanoma, the confirmed ORR was higher at 67% (n = 10/15). The unconfirmed ORR was 69% (n = 11/16), and the DCR was 88% (n = 14/16). At a median follow-up of 13.4 months, the median DOR was 11.0 months (range, 1.8+ to 31.6). In this group, the median PFS was 8.5 months (range, 1.4-32.9) at a median follow-up of 8.7 months, and the median OS was 16.2 months (range, 3.2+ to 34.2+) at a median follow-up of 14.5 months.

“Inspired by these encouraging results, a phase 3 registration-directed trial, the SUPRAME trial [NCT06743126] in [patients with] second-plus-line cutaneous melanoma, has just been started,” Martin Wermke, MD, of University Hospital Dresden, in Germany, said in a presentation of the data. “[SUPRAME] will compare IMA203 against investigator’s choice of standard-of-care [SOC] therapy.”

About IM203 and the Phase 1 Study

PRAME is a tumor-associated antigen that is expressed in a wide variety of solid tumors, including melanoma, where it has particularly high expression prevalence, Wermke said. This antigen is not expressed in healthy tissue, which makes it a favorable target for cancer immunotherapy, he added. “IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize an intracellular PRAME-derived peptide presented by HLA-A*02:01 on the cell surface [to] initiate a potent and specific antitumor response,” he said.

The phase 1 study enrolled patients with confirmed advanced and/or metastatic solid tumors who were at least 18 years of age, had an ECOG performance status of 0 or 1, and were positive for HLA-A*02:01 and PRAME. Patients needed to have acceptable organ function but could not have active brain metastases. They were required to have exhausted all SOC treatment options known to confer clinical benefit.

First, patients were tested for HLA-A*02:01, which has a prevalence of 41% in the US population and 48% in the European population. After, they used archived or freshly obtained tissue to assess for PRAME expression. Those who tested positive for both underwent leukapheresis.

The product was manufactured with an approximate 2-week turnaround time, and a 95% success rate was needed to reach the recommended phase 2 dose (RP2D). Patients then underwent lymphodepleting chemotherapy comprised of 30 mg/m2 of fludarabine and 500 mg/m2 of cyclophosphamide on days –6 to –3. “After 2 days of rest,” IMA203 was given as a single infusion, and this was followed by low-dose IL-2 for up to 10 days.

The primary objectives of the trial were tolerability and determination of RP2D in phase 1a of the trial. Secondary objectives included IMA203 T-cell engraftment and persistence, as well as efficacy.

As of the data cutoff date of April 7, 2025, a total of 74 were included in the total safety population; this includes 1 patient who began lymphodepletion chemotherapy but never went on to receive IMA203. A total of 27 patients were treated in the phase 1a dose-escalation portion of the trial across 4 dose levels. A further 46 patients have been treated at the RP2D of 1 to 10 x 109 TCR T cells as part of the phase 1b dose-expansion portion. Of these patients, 33 had melanoma and constitute the melanoma efficacy population; 14 of these patients have cutaneous melanoma, 16 have uveal melanoma, and 3 have another subtype.

The population of patients included in the study was heavily pretreated, Wermke noted. The median prior lines of systemic treatment received ranged from 2 to 3 across the groups. “Please note that all [patients with] melanoma had also been treated with tebentafusp [Kimmtrak],” he said. He added that they included a population with heavy disease burden, with elevated lactate dehydrogenase at baseline, ranging from 56.3% to 64.3% of patients across the groups.

“We also included a lot of patients with difficult-to-treat metastatic sites, including liver metastases, which were found in almost two-thirds of the patients with cutaneous melanoma and 94% of the patients with uveal melanoma,” he added. Moreover, patients received a median of 2.34 x 109 TCR T cells in the total safety population, whereas the median cell dose ranged between 3.94 and 4.58 x 109 TCR T cells in the melanoma cohorts.

Additional Safety Insights

In the total safety population, the most common TEAEs reported in at least 20% of patients included neutropenia (any grade, 91.9%; grade ≥3, 90.5%), anemia (77.0%; 51.4%), thrombocytopenia (67.6%; 36.5%), nausea (60.8%; 0%), leukopenia (52.7%; 51.4%), lymphopenia (52.7%; 52.7%), fatigue (39.2%; 1.4%), increased aspartate aminotransferase levels (39.2%; 6.8%), diarrhea (37.8%; 1.4%), increased alanine aminotransferase levels (37.8%; 9.5%), vomiting (33.8%; 1.4%), constipation (31.1%; 0%), pyrexia (29.7%; 1.4%), hyponatremia (29.7%; 4.1%), hypokalemia (28.4%; 4.1%), rash (24.3%; 0%), maculopapular rash (24.3%; 8.1%), peripheral edema (23.0%; 0%), and increased blood creatinine levels (20.3%; 2.7%).

AEs of special interest included CRS, ICANS, and hemophagocytic lymphohistiocytosis (HLH). CRS occurred at grade 1 in 36.5% of patients, grade 2 in 47.3% of patients, and grade 3 in 10.8% of patients. The median time to onset was 1 day (range, 0-3), and the median duration was 9 days (range, 2-27). Most of these effects resolved by day 14, and no long-term CRS was observed. Interventions for this effect was tocilizumab (Actemra) for 69.7% of patients and steroids for 33.3% of patients.

ICANS was reported at grade 1 in 5.4% of patients, grade 2 in 4.1% of patients, and grade 3 in 4.1% of patients. HLH was observed at grade 2 in 1.4% of patients and grade 3 in 1.4% of patients.

“There was no obvious restriction in terms of responses with respect to metastatic sites,” Wermke added. “We’ve seen responses in liver, lung, lymph node, and other lesions. The median tumor shrinkage ranged from 22.1% to 62.6%, and some lesions showed complete resolution.”

Disclosures: Wermke disclosed having received honoraria from Amgen, BMS GmbH & Co. KG, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Novartis, Pfizer, and SYNLAB. He serves in a consulting or advisory role for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, IMCheck therapeutics, immatics, ISA Pharmaceuticals, Lilly, Novartis, PharmaMar, Regeneron, Tacalyx, and Zymeworks. Research funding was provided by Roche (Inst). Travel, accomodations, and expenses were provided by Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo Europe GmbH, GEMoaB, immatics, Iovance Biotherapeutics, Janssen Oncology, Merck Serono, Pfizer, and Sanofi/Aventis.

Reference

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