Invikafusp Alfa Earns FDA Fast Track Designation in Locally Advanced CRC

The FDA based its decision on findings from the first-in-human phase 1/2 STARt-001 trial (NCT05592626) assessing the safety, tolerability, and preliminary clinical activity of invikafusp alfa monotherapy for patients with advanced antigen-rich solid tumors.

The investigational selective dual T-cell agonist invikafusp alfa (STAR0602) has earned fast track designation from the FDA for the treatment of those with unresectable, locally advanced, or metastatic colorectal cancer (CRC) harboring high tumor mutational burden (TMB-H), according to a press release from the developer, Marengo Therapeutics, Inc.¹

The FDA based its decision on findings from the first-in-human phase 1/2 STARt-001 trial (NCT05592626) assessing the safety, tolerability, and preliminary clinical activity of invikafusp alfa monotherapy for patients with advanced antigen-rich solid tumors. Investigators previously presented phase 1 findings at the 2024 Society for Immunotherapy of Cancer Annual Meeting (SITC).²

Phase 1 data showed that invikafusp alfa yielded sustained and selective in vivo expansion of TCRVβ6/Vβ10 T cells across all 6 dose levels with an approximately 500% maximum peak increase following treatment. Among 28 evaluable patients in the dose-escalation cohorts, the disease control rate (DCR) was 50%, and 32% achieved tumor shrinkage across 6 types of disease. At an optimal biological dose range of 0.08 mg/kg to 0.12 mg/kg, the experimental agent demonstrated a DCR of 63%, tumor shrinkage in 50% of patients, and an overall response rate (ORR) of 25% among those with cancers with TMB-H and anti–PD-1 resistance.

The safety profile of invikafusp alfa was consistent with T-cell activation or expansion mechanism of action without pretreating patients with tocilizumab (Actemra) or corticosteroids. Regarding common treatment-related adverse effects (TRAEs), investigators primarily observed grade 1/2 cytokine release syndrome without grade 4 toxicity or immune effector cell-associated neurotoxicity syndrome. Investigators determined a recommended phase 2 dose of 0.08 mg/kg based on phase 1 findings.

“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,” Bruce Chabner, MD, clinical director Emeritus for the Massachusetts General Hospital Cancer Center and a professor of Medicine at Harvard Medical School, said in the press release.¹ “The phase 2 clinical investigation of invikafusp alfa is ongoing, and this novel treatment could lead to a new class of therapeutics for tumor types that are PD-1–insensitive or resistant, especially in [CRC] where current treatment options remain limited.”

Developers generated invikafusp alfa using a library of antibodies directed toward non-clonal variable Vβ regions of the T-cell receptor joined to different co-stimulatory moieties. The agent was designed to selectively target a common Vβ T cell subset expressed in all cancers and facilitate expansion of new clonally enriched effector memory Vβ T cells that aid tumor immune responses and boost enduring tumor clearance.

Investigators of the phase 1/2 STARt-001 trial are evaluating treatment with invikafusp alfa across 2 parts: a dose-escalation portion in phase 1 and a dose-expansion portion in phase 2.

The trial’s primary end points include dose-limiting toxicities in phase 1, AEs and serious AEs in phase 1 and 2, and ORR in phase 2.³ Secondary end points include duration of response, DCR, progression-free survival, overall survival, and maximum observed plasma concentration.

Patients 18 years and older with histologically confirmed unresectable, locally advanced, or metastatic solid tumors for which standard curative therapies do not exist or are ineffective may enroll on the trial. Specifically, patients were required to have TMB-H, microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) disease, and virally associated tumors to enroll on the phase 1 portion of the trial. Eligibility criteria for phase 2 include having TMB-H, MSI-H or dMMR disease, CRC, virally associated tumors, metastatic triple-negative breast cancer, platinum-resistant epithelial ovarian cancer, metastatic castration-resistant prostate cancer, primary stage IV or recurrent non–small cell lung cancer, and immunogenic solid tumors.

References

1. Marengo’s first-in-class invikafusp alfa (STAR0602) receives U.S. FDA fast track designation for treatment of unresectable, locally advanced, or metastatic colorectal cancers with high tumor mutational burden (TMB-H). News release. Marengo Therapeutics, Inc. January 8, 2025. Accessed January 9, 2025. https://tinyurl.com/3xt2m2td
2. Marengo presents promising first-in-human safety, tolerability and clinical activity data for its lead program, invikafusp alfa (STAR0602), at the 2024 SITC Annual Meeting. News release. Marengo Therapeutics, Inc. November 9, 2024. Accessed January 9, 2025. https://tinyurl.com/2etcjzem
3. A Study of a selective T cell receptor (TCR) targeting, bifunctional antibody-fusion molecule STAR0602 in participants with advanced solid tumors (START-001). ClinicalTrials.gov. Updated October 24, 2024. Accessed January 9, 2025. https://tinyurl.com/5e7tcvjj