Abstract CT205: Updated clinical results, recommended phase 2 dose (RP2D) determination and translational study results for START-001: A phase 1/2 trial of invikafusp alfa, a first-in-class TCR b chain-targeted bispecific antibody in patients with anti-PD(L)1-resistant, antigen-rich solid tumors
Authors: Ryan J. Sullivan, Claire F. Friedman, Nick Tschernia, Mercedes Herrera Juarez, Jeffrey Schlom, Yo-Ting Tsai, Renee N. Donahue, Guru P. Sonpavde, Aparna Parikh, Aurelien Marabelle, Shannon McCue, Karunya Srinivasan, Jacques Moisan, Madan Katragadda, Raj Chopra, Kevin Chin, Andrew Bayliffe, Zhen Su, Ke Liu, James L. Gulley, Lillian L. Siu
Journal: Cancer Research (2025)

Abstract Background: Invikafusp alfa (STAR0602), a selective, dual T cell agonist targeting Vβ6/Vβ10 T cells, is being evaluated in START-001: a multicenter Phase 1/2 monotherapy trial in patients with anti-PD(L)1-resistant, antigen-rich solid tumors (TMB-H, MSI-H/dMMR, or virally associated). Methods: Reported here are: 1) updated clinical results of the completed dose escalation of intravenous invikafusp, Q2W, per 3+3 design with backfill at optimal biological dose (OBD) levels; 2) first report on RP2D determination based on PK, PD, safety and anti-tumor activity; 3) new results of translational immunology studies. Results: As of 7 Jan 2025, 41 patients (18 with TMB-H tumors) with a median of 4 prior lines of therapies across 18 different types of antigen-rich tumors were enrolled. Updated clinical results: No new safety signals were seen since previously reported and the most common TEAE was CRS (mostly grades 1 and 2), consistent with invikafusp’s MoA. Of 12 patients with TMB-H tumors who received the OBD (either 0.08 or 0.12 mg/kg) monotherapy, 9 had ≥ 1 tumor assessment at the time of submission. Overall, 6 (66.6%) of these 9 patients had disease control [confirmed partial response (cPR) + stable disease (SD)]. Four (44.4%) of these 6 had measurable tumor shrinkage per RECIST: 2 (22.2%) MSS CRC patients experienced cPR with one response lasting ∼12 months; 2 (22.2%) (1 with melanoma and 1 with pancreatic cancer) had tumor shrinkage with overall SD. Another 2 (22.2%) of 6 (1 with esophageal cancer and the other with MSS CRC) had SD. RP2D: Invikafusp peak serum concentrations (Cmax) increased proportionally with doses ≥ 0.08 mg/kg resulting in Cmax at or above the pharmacological EC90. Dose-dependent, selective expansion of peripheral Vβ6 and Vβ10 T cells was observed in all patients by flow cytometry and gene expression analyses, with maximal peak expansion at 0.08 and 0.12 mg/kg doses and decreasing expansion at 0.16 mg/kg. At the RP2D (0.08 mg/kg), CD8+ Vβ6/ Vβ10 T cells reached an average peak expansion of ∼600% on Day 8. Translational studies (n=7 patients): Consistent with preclinical studies, expanded peripheral Vβ6/Vβ10 T cells exhibited an atypical central memory (TCM) phenotype with expression of cytotoxic effector molecules. Selected patients had ctDNA decrease and expansion of antigen-specific Vβ6/Vβ10 T cells with one patient with ctDNA decrease who experienced stable disease and was on trial for ∼15 months. Increase in soluble markers of T cell activation (e.g., IFN-γ, sCD25) within hours after dosing were observed, with less pro-inflammatory cytokine (e.g., TNF-α and IL-6) release up to the RP2D. Conclusions: Invikafusp, a selective, dual T cell agonist, as monotherapy, led to clinically meaningful anti-tumor activity in anti-PD(L)-1 resistant tumors. It promoted potent and selective expansion of mainly CD8+ Vβ6/ Vβ10 T cells with a novel TCM phenotype, and led to ctDNA decrease and expansion of antigen-specific T cells. Based on these initial clinical results, US FDA granted Fast track Designation for invikafusp in TMB-H CRC and a Phase 2 trial is ongoing in antigen-rich (e.g., TMB-H &amp; MSI-H/dMMR) tumors. Citation Format: Ryan J. Sullivan, Claire F. Friedman, Nick Tschernia, Mercedes Herrera Juarez, Jeffrey Schlom, Yo-Ting Tsai, Renee N. Donahue, Guru P. Sonpavde, Aparna Parikh, Aurelien Marabelle, Shannon McCue, Karunya Srinivasan, Jacques Moisan, Madan Katragadda, Raj Chopra, Kevin Chin, Andrew Bayliffe, Zhen Su, Ke Liu, James L. Gulley, Lillian L. Siu. Updated clinical results, recommended phase 2 dose (RP2D) determination and translational study results for START-001: A phase 1/2 trial of invikafusp alfa, a first-in-class TCR b chain-targeted bispecific antibody in patients with anti-PD(L)1-resistant, antigen-rich solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT205.