Updated Phase 1 Data for IMA401 MAGEA4/8 TCR Bispecific: Clinical Activity and Tolerability in Solid Tumors and Rationale for Combination with IMA402

Immunotherapy is changing – revolutionizing – cancer treatment. Immatics Biotechnologies has announced updated results from its ongoing IMA401-101 Phase 1 study (NCT05359445) of its IMA401 MAGEA4/8* T cell receptor (TCR) bispecific (TCER®) at the annual meeting of the American Society of Clinical Oncology (ASCO), being held  May 29 – June 2, 2026, in Chicago, Illinois, with simultaneous publication in Nature Medicine [1].

TCR bispecifics are a highly potent class of targeted immunotherapy, also known as T-cell engagers (TCEs) or bispecific T-cell engagers (BiTEs). They act as a bridge that physically connects T cells to cancer cells, thereby forcing the immune system to destroy the tumor. Unlike ‘traditional bispecifics’, which are limited to targeting cell-surface proteins, TCR bispecifics use an engineered T cell receptor (TCR) domain, enabling recognition of intracellular proteins presented on the cell surface by MHC complexes. This approach significantly broadens the repertoire of potential cancer targets, including many ‘hidden’ antigens which are inaccessible to ‘standard’ antibody therapies.

IMA401, the first-in-class TCR bispecific targeting melanoma-associated antigen A4 (MAGEA4) and melanoma-associated antigen 8 (MAGEA8), demonstrated encouraging clinical activity and favorable tolerability in heavily pretreated patients with advanced solid tumors. Notable responses were observed in head and neck cancer, melanoma, and an initial clinical signal in squamous non-small cell lung cancer (sqNSCLC). Preclinical data and target prevalence analysis support the company’s strategy to combine IMA401 with IMA402 (PRAME bispecific**) to broaden patient reach and enhance anti-tumor activity in lung cancer and additional indications. [1][2]

Bispecific T cell engagers (TCEs) have transformed the landscape of cancer immunotherapy, particularly for hematologic malignancies [3][4], but their application in solid tumors has been constrained by target specificity, safety, and pharmacokinetic challenges [4][5]. TCR-based bispecifics, such as IMA401, aim to overcome these barriers by redirecting T cells to intracellular cancer-associated antigens presented on HLA molecules [5][6]. IMA401 targets a high-density HLA-A*02:01-restricted peptide derived from MAGEA4 and MAGEA8, providing a rationale for broad activity across multiple tumor types. [1][7]

Study design
The IMA401-101 Phase 1 trial is a multicenter, open-label, basket study evaluating the safety, tolerability, pharmacokinetics, and anti-tumor activity of IMA401 as monotherapy and in combination with pembrolizumab in HLA-A*02:01 and MAGEA4/8-positive patients with advanced solid tumors. Dose escalation and expansion were performed using step-dosing and premedication strategies to enhance safety.

The trial enrolled 61 patients (median age 62 years; range 19–82) with >15 different (advanced) solid tumor types. The most common indications included head and neck cancer (the largest subgroup, n=14 at RP2D), melanoma, and Squamous Non-Small Cell Lung Cancer (sqNSCLC). All patients were heavily pretreated (median of three prior lines of therapy).

Safety and Tolerability
In line with the Nature Medicine report, the maximum tolerated dose (MTD) was not reached at doses up to 2.5 mg, but the RP2D was established at 1–2 mg based on the overall risk–benefit profile, particularly due to increased neutropenia at higher doses [1]. Five patients experienced dose-limiting toxicities (DLTs) primarily related to neutropenia, but none occurred at the RP2D with dexamethasone (Decadron®; Merck & Co/MSD) premedication. Notably, no cases of ICANS were observed at any dose level.

• Recommended Phase 2 Dose (RP2D): 1–2 mg IMA401 biweekly, with or without pembrolizumab
• Most common treatment-related adverse events (TRAEs):
  • Low-grade cytokine release syndrome (CRS) (38%, all Grade 1–2)
  • Transient lymphopenia (33%)
  • Reversible neutropenia (31%)
• The study results did not show grade ≥3 CRS or immune effector cell-associated neurotoxicity syndrome (ICANS)
• Tolerability was consistent across monotherapy and combination cohorts, with no additive toxicities observed when combined with pembrolizumab

Clinical Activity
In the overall efficacy-evaluable population across all dose levels (n=56), including low starting doses, the confirmed ORR was 14%, and the DCR was 50%. In the RP2D cohort (n=41), the ORR was 20%, and DCR was 51% [1].

• Head and neck cancer (n=14 at RP2D):
  • Confirmed objective response rate (ORR): 29%
  • Disease control rate (DCR): 64%
  • Median duration of response (mDOR): 8.8 months
  • 12-month overall survival (OS) rate: 63%
  • 6-month progression-free survival (PFS) rate: 43%
  • Three of four responders were ongoing at data cutoff.
  • All responders had 60–100% tumor reduction
  • Responses observed in both monotherapy and pembrolizumab combination arms

• Melanoma (n=6 at RP2D):
  • Both confirmed responses lasted beyond 6 months post-treatment, with one lasting >2.5 years.
  • Confirmed ORR: 33%
  • DCR: 67%
  • Durable responses lasting beyond 6 months, with one ongoing at >2.5 years

• sqNSCLC:
  • A highlighted case involved a patient with ICI-resistant sqNSCLC who received IMA401 plus pembrolizumab as fifth-line therapy and achieved a partial response with shrinkage of all target lesions, despite prior best response being stable disease.
  • An initial clinical signal was observed in a patient with ICI-resistant disease who achieved a partial response with all target lesions shrinking after IMA401 plus pembrolizumab

Pharmacokinetics
Pharmacokinetic analysis showed a median serum half-life close to steady-state of 15.4 days across all dose levels and 17.5 days in patients receiving ≥1 mg biweekly, supporting the feasibility of biweekly dosing. Dose proportionality was observed for C_max, while half-life remained consistent across doses (Serum half-life: Antibody-like, median 15.4–17.5 days, enabling biweekly dosing).

Preclinical and Translational Data
Mass spectrometry-based immunopeptidomics demonstrated that the MAGEA4/8 peptide is presented at least five-fold higher than previously reported HLA-A*02:01-restricted MAGEA4 peptides, and is virtually absent from normal tissues [1][7]. IFNγ exposure in vitro increased target peptide presentation by ~70-fold. Preclinical studies confirmed potent cytotoxic activity of IMA401 against tumor cells at physiologically relevant antigen densities, with minimal off-target effects [7].

• Target prevalence: >90% of patients with sqNSCLC express PRAME and/or MAGEA4/8; ~60% are double-positive
• Combination rationale: Preclinical models demonstrated synergistic anti-tumor activity with IMA401/IMA402 in MAGEA4/8 and PRAME double-positive tumor cell lines

Ongoing and Future Directions

• IMA401/IMA402 combination cohort in sqNSCLC: Now enrolling at multiple sites; first data anticipated in 2027
• Potential for broad application: Dual targeting approach may enhance anti-tumor efficacy and coverage across additional solid tumors

Study limitations
In the Nature Medicine article, the authors emphasized that, despite the small sample size for individual tumor types, the activity observed in head and neck cancer, melanoma, and initial signals in sqNSCLC provide proof of concept for TCR-based TCE therapies that work agnostically of tumor type, depending on antigen presence and density. The study design and protocol were reviewed and approved by independent ethical boards, with extensive patient screening for HLA and target expression. Limitations include the phase 1 design, a limited sample size, and a lack of systematic biomarker analysis of resistance mechanisms.