Immatics’ TCR-T Therapy Shows Good Phase 1 Safety and Survival Data, Phase 3 Plans Confirmed

Treatment with the investigational TCR-based autologous cell therapy, ACTengine IMA203 (Immatics), has been shown to demonstrate a response rate exceeding 50% while maintaining a favorable tolerability profile across all dose levels tested, according to newly presented data.^1,2 Additionally, the company reported progression-free survival (PFS) and overall survival (OS) data for the first time among patients with melanoma in the trial.

The median PFS in the dose-escalation phase for patients with melanoma (n = 11) in the trial was 2.6 months, increasing to 6.0 months in the dose-expansion phase (n = 28; P <.0001). Likewise, the median OS value in the dose-escalation phase was 6.3 months, and was not reached in the dose-expansion phase (n = 28; P = .0003).Among those with deep responses (n = 12), defined as a 50% or greater tumor reduction, the median PFS was 13.4 months (P = .0033). Those with a less than 50% tumor reduction (n = 14), including tumor size increase, still observed a mPFS more than twice as long as those treated in dose-escalation who had suboptimal doses, at 5.7 months.²

Responses were considered durable as well, with both the total phase 1b melanoma (n = 28) and the phase 1b cutaneous melanoma (n = 13) populations reporting a confirmed objective response rate of 54% (total, n = 14; cutaneous, n = 7) and objective response rate of 62% (total, n = 16; cutaneous, n = 8). Tumor shrinkage was reported by 88% of the total melanoma population (n = 23) and 85% of the cutaneous population (n = 11), with duration of response being 12.1 months for both groups. Median OS was 15.9 months for the cutaneous population, and median PFS was 6.1 months.²

“Observing significant tumor shrinkage and durable responses combined with meaningful progression-free survival and overall survival outcomes after a single treatment with ACTengine IMA203 in this patient population that have all exhausted multiple lines of systemic treatments illustrates the impact IMA203 can have on metastatic melanoma patients. These results now affirm the therapeutic potential of IMA203 and provide a strong rationale for the expedited late-stage clinical development of this product candidate,” Martin Wermke, MD, coordinating investigator of the ACTengine IMA203 TCR-T trial, and the head of the Early Clinical Trial Unit at the National Center for Tumor Diseases Dresden of the University Hospital Carl Gustav Carus Dresden and Technical University of Dresden, said in a statement.¹

Wermke presented the data on October 11, 2024, in an oral presentation at the Society of Melanoma Research Congress, held in New Orleans, Louisiana. The data cut off for this presentation was August 23, 2024.

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Overall, among patients who were heavily pretreated (n = 28) in the phase 1b portion, the median duration of response (DOR) after 2 years was 12.1 months (minimum, 4.2; maximum, 25.5+ months) with a median follow-up of 9.3 months. The disease control rate at week 6 was 92% (24 of 26).

Additionally, a trio of associations and correlations were observed that showed highly consistent dose exposure, biological data, and clinical outcomes in all patients treated with IMA203 with available samples (n = 65). Those were that:

• IMA203 T-cell dose is significantly associated with confirmed clinical responses (P = .02).
• IMA203 T-cell dose is correlated with T cell peak level (C_max, r = 0.84; P = 1.6 × 10^-18).
• IMA203 T-cell peak level (C_max, P = .05) and T cell exposure (AUC_0-28d, P = .05) are associated with confirmed clinical responses.

As for safety, the most frequent adverse events (AEs) were expected cytopenias (Grade 1-4) associated with lymphodepletion in all patients, mild to moderate cytokine release syndrome (Grade 1, 37% [26 of 70]; Grade 2, 46% [32 of 70]; Grade 3, 11% [8 of 70]), and infrequent immune effector cell-associated neurotoxicity syndrome (Grade 1, 6%; Grade 2, 4%; Grade 3, 4%). There were no deaths related to treatment, and the overall melanoma subset’s tolerability was considered consistent with the full IMA203 monotherapy tolerability profile.

The trial consisted of a 70-patient total safety population who participated in phase 1a’s dose escalation (n = 28; dose levels 1-4) and phase 1b’s dose expansion (n = 42; dose level 4/5). Ultimately, the melanoma efficacy population (n = 28) included those patients with melanoma who were included in the phase 1b dose expansion. The recommended phase 2 dose was defined as 1-10 × 10⁹ TCR-T cells (dose level 4/5).

The total safety population (melanoma, n = 41; other, n = 29) consisted of all comers from both the phase 1a (n = 11; cutaneous melanoma, n = 8; uveal melanoma, n = 2; mucosal melanoma, n = 1) and phase 1b (n = 28; cutaneous melanoma, n = 13; uveal melanoma, n = 12; mucosal melanoma, n = 2; melanoma of unknown primary cause, n = 1) populations.

Of note, Immatics applied some manufacturing improvements before the phase 1b portion of the trial kicked off with an aim of boosting “key features” of the treatment, the company stated. As such, 100% of the patients in the dose expansion were treated with an updated version of IMA203 that included a T-cell enrichment process using monocyte depletion or CD8/CD4 positive selection.

The therapy is directed against an HLA-A*02-presented (human leukocyte antigen) peptide derived from preferentially expressed antigen in melanoma (PRAME), a protein frequently expressed in a large variety of solid cancers. Based on the phase 1b data, Immatics announced that it will proceed directly to a registration-enabling phase 3 trial, SUPRAME, and that it has confirmed the regulatory pathway and clinical trial design for IMA203 following FDA Type D meetings.

The SUPRAME phase 3 trial is expected to be a global effort, with sites in the United States and Europe. Immatics is anticipating seeking a biologics license application (BLA) approval in early 2027 the United States. The TCR-T therapy is also being evaluated in phase 1 IMA203CD8 (GEN2) monotherapy, where IMA203 engineered T cells are cotransduced with a CD8αβ coreceptor.

“We are enthusiastic about the clinical data as they confirm our conviction in the durability and long-term efficacy of ACTengine® IMA203, demonstrated by the favorable median progression-free survival for patients in the dose expansion cohort. I would like to highlight that a subgroup of 12 out of 26 patients showed more than 50% reduction of tumor lesions and a median PFS of 13.4 months,” Cedrik Britten, MD, the chief medical officer at Immatics, said in a statement.¹ “We believe the presentation of this data set in conjunction with our recent meeting with the FDA, which has resulted in a pivotal trial design with progression-free survival as the primary endpoint for full approval, positions us to advance the development of IMA203 in the second-line or later metastatic melanoma setting.”

REFERENCES
1. Immatics Announces Updated Phase 1b Clinical Data on ACTengine® IMA203 TCR-T Targeting PRAME in Melanoma Patients and Provides Update on Upcoming SUPRAME Phase 3 Trial. News release. October 10, 2024. Accessed October 28, 2024. https://www.globenewswire.com/news-release/2024/10/10/2961129/0/en/Immatics-Announces-Updated-Phase-1b-Clinical-Data-on-ACTengine-IMA203-TCR-T-Targeting-PRAME-in-Melanoma-Patients-and-Provides-Update-on-Upcoming-SUPRAME-Phase-3-Trial.html
2. Wermke M. ACTengine® IMA203 TCR-T Targeting PRAME in PD1 Refractory Metastatic Melanoma- Phase 1b Dose Expansion Clinical Data Update. Presented at: Society of Melanoma Research Congress; October 11, 2024; New Orleans, LA. https://investors.immatics.com/static-files/fd5cb9de-503e-48b3-8bc6-d9813fab72fb