Abstract CT041: Initial results from a first in human phase 1 study of KVA12123, an anti-VISTA antibody, alone and in combination with pembrolizumab in patients with advanced solid tumors

Abstract Background: VISTA is an immune checkpoint highly expressed on myeloid cells that suppresses T cell activation. Its expression is associated with poor prognosis in cancer patients and may contribute to resistance to anti-CTLA-4 and anti-PD(L)1 therapies. KVA12123 binds to VISTA at neutral and acidic pHs and blocks VISTA interactions with its different potential ligands. This fully human IgG1 monoclonal antibody has a unique epitope and was engineered to improve its pharmacokinetic and to reduce the risk of CRS observed with prior anti-VISTA antibodies. Methods: VISTA-101 (NCT05708950) is a Phase 1/2 dose escalation and expansion clinical trial of KVA12123 as monotherapy and in combination with pembrolizumab, in adult patients with advanced solid tumors. The primary objectives evaluate safety and tolerability to define a maximum tolerated dose and a recommended phase 2 dose (RP2D). The secondary objectives address the pharmacokinetic (PK) and receptor occupancy (RO), as well as patient tumor response using iRECIST. VISTA-101 is also assessing predictive biomarkers of response. Phase 1 is an accelerated BOIN design consisting of two arms: Part A) KVA12123 monotherapy dose escalation from 3 mg to 1000 mg (Q2W) including 6 cohorts and, Part B) KVA12123 dose escalation from 30 mg to 1000 mg (Q2W) in combination with 400 mg of pembrolizumab (Q6W) including 4 cohorts. Results: In January 9th 2025, 36 patients were dosed including 24 patients in Part A and 12 in Part B. Enrollment in all monotherapy cohorts (3 to 1000mg) has been completed as well as 3 of the 4 combination cohorts (30 to 300mg KVA + Pembro 400mg). Treatments have been well tolerated and no dose limiting toxicities observed. The most common adverse events are grade 1 and 2 chills, fatigue and infusion related reactions with no evidence of CRS. In the monotherapy arm, the best overall response (BOR) is stable disease (SD) in 13 of 19 patients who received at least one follow-up scan. One NSCLC patient with prior CPI-exposure experienced SD lasting 62 weeks. In the combination arm, BOR to date is 1 of 9 with a sustained confirmed partial response with 54% tumor reduction of mucoepidermoid carcinoma histology. This patient has been on-study for 60 weeks. Additionally, there is SD in 3 of 9 evaluable patients, with one RCC previously exposed to CPI with a 24% tumor reduction. PK in part A showed an extended profile with saturation at 1000 mg dose associated with RO demonstrating full target engagement at higher concentrations. These data will define our RP2D. We also observed a dose-dependent induction of pro-inflammatory cytokines and increases of activated immune cell populations. Enrollment in the last combination cohort (1000mg KVA + 400mg Pembro) is ongoing. Final safety, tolerability, PK and clinical response in the mono and combination arms will be presented, as well as PK and biomarker data. Citation Format: Jason T. Henry, Manish R. Patel, Paul Swiecicki, Ida Micaily, Benjamin Garmezy, Kalyan Banda, Marya Chaney, Julia Cohen, Vinny Hayreh, Evan Y. Yu, Shawn P. Iadonato, Thierry Guillaudeux, Lee Rosen. Initial results from a first in human phase 1 study of KVA12123, an anti-VISTA antibody, alone and in combination with pembrolizumab in patients with advanced 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 CT041.