Invikafusp alfa, a first-in-class, selective, dual T-cell agonist, has shown promising single-agent activity in patients with heavily pretreated anti–PD-(L)1–resistant solid tumors. The findings from the phase 1/2 STARt-001 trial, presented at the 2024 SITC Annual Meeting, indicate a potential new approach for patients with limited treatment options.
The study's lead author, Dr. James L. Gulley from the National Cancer Institute, highlighted that the data validates a new class of selective T-cell receptor (TCR) Vβ dual T-cell agonists for precision cancer immunotherapy. The most significant efficacy was observed in the tumor mutational burden–high (TMB-H) population, particularly in patients with microsatellite stable (MSS) colorectal cancer (CRC).
Mechanism of Action
Invikafusp alfa works by binding to a selective set of T cells that express Vβ6 or Vβ10, and it also brings interleukin 2 (IL-2) on the other arm of the antibody. This IL-2 will only bind to the same T cells, activating them specifically. According to Dr. Gulley, these Vβ6 or Vβ10 T cells are among the highest-expressed T cells in tumor-infiltrating lymphocytes across a wide range of different tumors.
STARt-001 Trial Design and Patient Population
The phase 1/2 STARt-001 trial enrolled patients with unresectable, locally advanced, or metastatic solid tumors that were TMB-H, microsatellite instability–high (MSI-H)/mismatch repair-deficient (dMMR), or virally associated cancers. Prior treatment with anti–PD-(L)1 therapy was allowed. The phase 1 portion of the trial used a standard 3+3 dose-escalation schema, with patients receiving invikafusp alfa intravenously every 2 weeks at doses ranging from 0.01 mg/kg to 0.16 mg/kg.
The primary objectives of phase 1 were to establish the recommended phase 2 dose (RP2D) and evaluate safety and tolerability. Secondary objectives included evaluating preliminary antitumor efficacy and pharmacokinetics. The phase 2 dose expansion employed an optimal Simon’s 2-stage design, enrolling patients into cohorts based on TMB-H, MSI-H, or TMB-H/MSI-H/dMMR CRC status.
The primary cohort included 28 patients with a median age of 57.9 years. Most patients were female (53.6%), White (78.6%), and had an ECOG performance status of 1 (64.3%). A significant proportion had received at least 4 prior lines of therapy (57.1%), including prior anti–PD-(L)1 therapy (89.3%).
Efficacy and Safety Results
The disease control rate (DCR) across all dose-escalation cohorts was 50%. Notably, in the optimal biological dose range of 0.08 mg/kg to 0.12 mg/kg, invikafusp alfa achieved a 63% DCR. A total of 50% of patients saw tumor shrinkage, and a 25% objective response rate (ORR) was reported in patients with TMB-H and those resistant to anti–PD-1 therapies.
The treatment's safety profile was consistent with its mechanism of action, reflecting T-cell activation and expansion in vivo. The most common treatment-related adverse events (TRAEs) were primarily transient grade 1 and 2 cytokine release syndrome observed after the first and second infusions. No grade 4 AEs or immune effector cell–associated neurotoxicity syndrome were reported. The maximum tolerated dose was not reached, and 0.08 mg/kg was selected as the RP2D.
Clinical Significance
These early findings suggest that invikafusp alfa may offer a new therapeutic option for patients with advanced solid tumors that are resistant or refractory to PD-1 inhibitors. The single-agent activity observed, particularly in PD-1 resistant cold tumors such as colorectal cancer, is a critical milestone. Phase 2 dose expansion cohorts are currently enrolling to further explore the potential of invikafusp alfa across a range of tumor types.
Ongoing Development
Invikafusp alfa (STAR0602) is the first T-cell activator developed using Marengo Therapeutics' STAR platform. It selectively targets a common subset of T cells present in all cancers and activates the TCR with a T-cell co-stimulator, allowing for the expansion of clonally enriched effector memory Vβ T cells that boost tumor immune responses to target tumors.
