FDA Grants Fast Track Designation to Invikafusp Alfa for Advanced Colorectal Cancer

The FDA has granted Fast Track designation to invikafusp alfa (STAR0602), a first-in-class selective dual T cell agonist developed by Marengo Therapeutics, for the treatment of unresectable, locally advanced, or metastatic colorectal cancer (CRC) with high tumor mutational burden (TMB-H). This designation aims to expedite the development and review of drugs addressing serious conditions with unmet medical needs.

The FDA's decision was influenced by promising results from the Phase 1/2 STARt-001 trial, a first-in-human study evaluating the safety, tolerability, and preliminary clinical activity of invikafusp alfa monotherapy in heavily pretreated patients with advanced solid tumors. The Phase 1 data, presented at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting, demonstrated encouraging anti-tumor activity and a favorable safety profile.

Clinical Trial Data

The Phase 1 data showed that invikafusp alfa induced sustained and selective in vivo expansion of TCRVβ6/Vβ10 T cells across all six dose levels, with an approximate 500% maximum peak increase following treatment. Among 28 evaluable patients in the dose-escalation cohorts, the disease control rate (DCR) was 50%, and 32% experienced tumor shrinkage across six different tumor types. Notably, at the optimal biological dose range of 0.08 mg/kg to 0.12 mg/kg, invikafusp alfa demonstrated single-agent clinical activity, with a DCR of 63%, tumor shrinkage in 50% of patients, and an overall response rate (ORR) of 25% in patients with TMB-H and anti-PD-1 resistance.

The safety profile of invikafusp alfa was consistent with its T-cell activation and expansion mechanism of action, without the need for pretreatment with corticosteroids or tocilizumab. The most common treatment-related adverse events (TRAEs) were primarily grade 1 and 2 cytokine release syndrome, observed during the first and second infusions. No grade 4 AEs or immune effector cell-associated neurotoxicity syndrome were reported.

Ongoing Phase 2 Trial

Based on the Phase 1 results, Marengo Therapeutics has initiated a Phase 2 clinical trial, enrolling patients at sites in France and Spain. This trial will further evaluate invikafusp alfa at the recommended Phase 2 dose of 0.08 mg/kg in patients with PD-1 resistant tumors.

Ke Liu, MD, PhD, Chief Development Officer of Marengo Therapeutics, stated, "The single-agent anti-tumor activity observed in Phase 1, particularly in PD-1-resistant 'cold' tumors like colorectal cancer, gives us confidence in our approach and fuels our hope to reach as many patients as possible."

The company anticipates reporting additional efficacy data later in 2025.

Mechanism of Action

Invikafusp alfa is designed to selectively target a common Vβ T cell subset present in all cancers. By combining a novel non-clonal mode of TCR activation with a T cell co-stimulator in the same molecule, it promotes the expansion of a new population of clonally enriched, effector memory Vβ T cells, enhancing tumor immune responses and promoting durable tumor clearance.

Bruce Chabner, MD, Clinical Director Emeritus for the Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School, commented, "Marengo's selective Vβ T cell activation approach targeting specific T cell subsets enriched in tumor-infiltrating lymphocytes to enhance anti-tumor activity is unique and highly promising. This novel treatment could lead to a new class of therapeutics for tumor types that are PD-1 insensitive or resistant, especially in colorectal cancer where current treatment options remain limited."