Anti-VISTA therapy may be the therapy type to be used with PD-1/PD-L1 inhibitors to treat patients with advanced solid tumors, expert say. One agent, KVA12123, has just entered phase 1 clinical research.
KVA12123, a VISTA binding fully human engineered IgG1 monoclonal antibody, is a novel agent under exploration for the treatment of advanced solid tumors.1
Immunotherapy is one of the standard treatments for advanced solid tumors, according to Michael A. Curran, PhD. With PD-1/PD-L1 inhibitors, in particular, cold cancers have an overall response rate (ORR) of between 5%-20%, whereas hot cancers have a 40%-50% ORR. This leaves 45% of cancers ineligible for treatment with PD-1/PD-L1 inhibitors.
“We can look at existing checkpoints such as PD-1 and CTLA-4 as T-cell focused immune modulators although PD-1 has some effects on the myeloid department as well. But VISTA is truly multimodal, and its effects across the tumor microenvironment and therefore, is an attractive target to behave synergistically with existing the existing T-cell focused therapies,” explained Curran, associate professor, Department of Immunology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX during the Kineta KOL Event on KVA12123: VISTA as an Immuno-Oncology Target hosted by Kineta, Inc.
VISTA blockade has demonstrated the ability to improve T cell fitness and perform synergistically with anti-PD-1 therapies in preclinical models, according to Curran. VISTA blockade could also mediate pro-inflammatory conditioning of TME. These characteristics set KVA12123 from other IgG1 agents on the market including CI-8993, SNS-101, and PMC309, according to Shawn P. Iadonato, PhD, chief executive officer, Kineta, Inc, who was also a presenter during the KOL call.
KVA12123 monotherapy achieved 75% tumor growth inhibition in bladder cancer models. In T-cell lymphoma models, the tumor growth inhibition was 66%.1
In other preclinical studies in which anti-VISTA therapy was combined with anti-PD-1 therapy, the tumor growth inhibition rate was 68% compared with 35%-42% in colon cancer subjects treated with anti-VISTA alone, and 42%-60% in those treated with anti-PD-1 alone. In a bladder cancer model, KVA12123 plus anti-PD-1 therapy achieved 85% tumor growth inhibition compared with 40% with anti-VISTA alone, and 67% with anti-PD-1 alone.
KVA12123 was well-tolerated in non-human studies. The subject treated had no mortality, no change in cytokine release syndrome (CRS) cytokine levels, and no treatment-related adverse events.
Curran stated, “we see an important role of VISTA as monotherapy. In combination with PD-1, this kind of data has been very predictive of subsequent efficacy in cancer. I think it is a cautionary tale that we have to monitor these patients for immune-related adverse events. Unlike CTLA-4 blockade, VISTA knockouts are not lethal. That also says that you're at a good spot where this is a very important immune-regulatory molecule that tumors lean on quite heavily to maintain their immunosuppressive environment, but it's blockade should be quite tolerable. It will be investigated alone or in combination with pembrolizumab for the treatment of patients with advanced solid tumors,” Curran said.
In a phase 1/2 study (NCT05708950), KVA12123 will be evaluated alone and in combination with pembrolizumab (Keytruda), announced Iadonato during the event. In phase 1, up to 60 patients with advanced solid tumors will be evaluated, and in the phase 2 portion of the study, most patients will have either non–small cell lung cancer, head and neck squamous cell carcinoma, ovarian cancer, or renal cell carcinoma.1,2
The primary end points to be explored in the study include safety/tolerability, the recommended phase 2 dose (RP2D) of KVA12123, and the maximum-tolerated dose of KVA12123. The secondary end points of the study are pharmacokinetics, immunogenicity, and tumor response defined by ORR per RECIST v1.1 criteria. As an exploratory end point, the study will also investigate biomarker and receptor occupancy. The exploratory biomarkers to be investigated include chemokine and cytokine receptor in the blood, immune cell population in the blood, and VISTA expression before and after treatment.
During part A of the phase 1 dose-escalation portion of the study, KVA12123 will be administered at either 3 mg, 10 mg, 30 mg, 300 mg, or 1000 mg twice daily. Up to 6 patients will be included in each dose cohort. In part B of the phase 1 study, patients will also be administered pembrolizumab 400 mg, every 6 weeks.
Patients treated during part Z of the phase 1 study will go on to phase 2, part C cohort. This cohort will include patients with NSCLC or HNSCC who will be treated with KVA12123 at the RP2D.
Patients who were treated in the part B cohort of the phase 1 study will move on to the part D cohort of the phase 2 study. Patients in this cohort will receive the RP2D of KVA12123 plus pembrolizumab 400 mg.
“In terms of key catalysts over the remainder of 2023, the major catalysts are the initial patients that are being recruited into the monotherapy, part A in combination therapy, part B of the clinical trial, and then initial data safety readouts in the third quarter, and initial efficacy readouts in the fourth quarter of 2023, said Iadonato.
Part A and B of the study will be conducted at 10 sites across the United States. Three of the study sites have already begun the recruitment of patients in Colorado, Florida, and Tennessee.
1. Kineta KOL Event on KVA12123: VISTA as an Immuno-Oncology Target. Kineta, Inc website. March 20, 2023. Accessed March 20, 2023. https://lifescievents.com/event/kineta-kol-event/
2. A clinical trial of KVA12123 treatment alone and in combination with pembrolizumab in advanced solid tumors (VISTA-101). ClinicalTrials.gov. Updated March 9, 2023. Accessed March 20, 2023. https://clinicaltrials.gov/ct2/show/NCT05708950