Marengo Therapeutics announced promising initial Phase 1 clinical data for invikafusp alfa (STAR0602), a first-in-class TCR Vβ6/Vβ10 selective dual T cell agonist, at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting. The STARt-001 Phase 1/2 trial (NCT05592626) evaluated invikafusp alfa as a monotherapy in patients with advanced anti-PD-1 resistant or refractory solid tumors, enriched for biomarkers like high tumor mutation burden (TMB-H). The data suggests potential clinical benefits in heavily pre-treated patients with limited options.
Early Clinical Activity and Safety
Phase 1 data from the STARt-001 trial demonstrated early anti-tumor activity and a manageable safety profile. The study included patients with TMB-H, MSI-H/dMMR, or virally associated tumors who had previously failed anti-PD-1 therapies. Clinical activity of invikafusp alfa was observed in cancers with high tumor mutation burden (TMB-H), including confirmed responses in microsatellite stable (MSS) colorectal cancer, a particularly challenging tumor type to treat.
Zhen Su, M.D., MBA, Chief Executive Officer of Marengo Therapeutics, stated, "The single agent activity observed in Phase 1, especially in PD-1 resistant cold tumors such as colorectal cancer is a critical milestone."
Key Phase 1 Findings
Key highlights from the Phase 1 findings include:
- T Cell Expansion: Sustained and selective in vivo expansion of TCRVβ6/Vβ10 T cells was achieved across all 6 dose levels, with up to ~500% peak increase post invikafusp alfa treatment.
- Disease Control: A Disease Control Rate (PR + SD) was reported in 50% of 28 patients from all dose escalation cohorts, with 32% of patients experiencing tumor shrinkage across six tumor types.
- Optimal Dose Activity: At the optimal biological dose range (0.08 mg/kg and 0.12 mg/kg), invikafusp alfa showed single-agent clinical activity with a 63% Disease control rate, 50% of patients experiencing tumor shrinkage, and a 25% ORR reported in TMB-H, anti-PD-1 resistant patients.
- Safety Profile: The safety profile was consistent with the T cell activation/expansion mechanism of action (MOA) without corticosteroid or tocilizumab pretreatment. The most common treatment-related adverse events (TRAEs) were mainly transient grade 1 & 2 CRS during the first and second infusion without any grade 4 adverse events (AEs) or immune effector cell-associated neurotoxicity syndrome (ICANS).
- Recommended Phase 2 Dose: A Recommended Phase 2 dose (RP2D) of 0.08 mg/kg was selected for Phase 2 dose expansion studies based on safety, PK/PD data, and preliminary anti-tumor activity.
Expert Commentary
"The first-in-human data suggest that this novel approach to selectively activate and expand Vβ T cell subsets may hold promise for treating patients with advanced solid tumors," said Dr. James L. Gulley, Co-Director of the Center for Immuno-Oncology and Clinical Director of the National Cancer Institute. He further noted the encouraging signs of unique Vβ T cell biology in humans and selective expansion of Vβ6/Vβ10 across a range of solid tumors, combined with initial anti-tumor activity, particularly in heavily pre-treated anti-PD-1 resistant cancer patients with TMB-H colorectal cancer.
Ongoing and Future Development
The Phase 2 dose expansion of the STARt-001 study is underway, and Marengo expects to share initial results in the second half of 2025. This trial aims to further evaluate the efficacy and safety of invikafusp alfa in a larger patient cohort. Invikafusp alfa represents a novel approach to cancer immunotherapy, potentially offering a new treatment option for patients with advanced solid tumors resistant to anti-PD-1 therapies. The selective activation and expansion of Vβ T cell subsets could overcome resistance mechanisms and improve outcomes in these challenging-to-treat cancers.
