Bispecific dual T cell agonist invikafusp alfa in solid tumors: the phase 1/2 START-001 trial

Invikafusp alfa (invika), a first-in-class, bispecific, dual T cell agonistic antibody selectively targeting Vβ6/Vβ10 T cell subsets, is being evaluated in START-001, a multicenter phase 1/2 monotherapy trial in participants with mostly immune checkpoint blockade (ICB)-resistant, antigen-rich solid tumors. Primary outcomes were safety/tolerability and recommended phase 2 dose (RP2D) in phase 1 and anti-tumor activity in phase 2. As of 12 March 2025, phase 1 completed dose escalation (n = 34) through dose levels of 0.01, 0.02, 0.04, 0.08, 0.12 and 0.16 mg kg^-1 without reaching maximum tolerated dose, and initial phase 2 enrolled 18 participants. Two participants experienced reversible dose-limiting toxicities, one at each of the 0.08 mg kg^-1 and 0.16 mg kg^-1 dose levels. The most common treatment-related adverse event was cytokine release syndrome, mainly grades 1 and 2. No treatment-related deaths or non-laboratory grade 4 adverse events were reported. At the optimal biological doses (OBDs; 0.08 mg kg^-1 and 0.12 mg kg^-1) in combined phase 1 and phase 2 cohorts, the overall objective response rate was 14.8% (4/27), including confirmed partial responses in immunologically cold tumors, such as microsatellite stable colorectal cancer and programmed death-ligand 1 (PD-L1)-negative non-small cell lung cancer. No objective responses were seen at doses lower than 0.08 mg kg^-1. Invika selectively and potently expanded peripheral and intratumoral Vβ6/Vβ10 T cells, of a predominantly memory-like phenotype, dose-dependently, peaking at the OBDs. Pharmacodynamic increases in interferon-γ and soluble CD25 followed a similar pattern. Integrated analyses from safety, pharmacokinetic, pharmacodynamic and preliminary anti-tumor data supported the selection of 0.08 mg kg^-1 as the RP2D. In conclusion, phase 1 of START-001 met its primary outcomes by demonstrating the acceptable safety profile of invika consistent with its mechanism of action and selecting an RP2D. Initial phase 2 results further corroborated the safety of invika and expanded its preliminary evidence of clinically meaningful anti-tumor activity in ICB-resistant solid tumors, supporting further evaluation in the ongoing phase 2. ClinicalTrials.gov identifier: NCT05592626 .