KVA12123 Appears Well-Tolerated in Advanced Solid Tumors Across 3 Doses


In the first 3 cleared monotherapy cohorts of the VISTA-101 trial, KVA12123 showed promising safety and pharmacokinetics with a sign of efficacy across patients with advanced solid tumors.

T-Cell cancer cell © catalin - stock.adobe.com.jpg

T-Cell cancer cell © catalin - stock.adobe.com.jpg

KVA12123 has demonstrated safety and is well tolerated at doses of 3, 10, and 30 mg in patients with advanced solid tumors, according to new data from the phase 1/2 VISTA-101 trial (NCT05708950).1

Across the first 3 cleared monotherapy cohorts, KVA12123 was well-tolerated with no dose-limiting toxicities observed. There was also no evidence of cytokine release syndrome (CRS)-associated toxicities detected.

At the 30 mg dose level, administration of KVA12123 achieved >90% VISTA receptor occupancy (RO), and there was a greater than dose-proportional increase in drug exposure across all the doses evaluated in the trial.

“KVA12123 in our clinical trial, VISTA-101, and the first 3 [cleared] monotherapy cohorts, is very welltolerated [with] no dose-limiting toxicities, no sign of CRS, [and] the pharmacokinetics achieved complete coverage, almost 90% of receptor occupancy at the 30 mg dose. The [pharmacokinetic] profile demonstrates a great exposure at higher doses, and we see a sign of efficacy using our biomarkers,” said Thierry Guillaudeux, PhD, chief scientific officer of Kineta, during a live virtual event hosted by Kineta.

During the virtual event, Michael A. Curran, PhD, associate professor at MD Anderson Cancer Center Department of Immunology, and Evan Y. Yu, MD, professor and medical oncology section head at Fred Hutchinson Cancer Center, discussed data from the VISTA-101 trial and KVA12123 for the treatment of patients with advanced solid tumors.

During Curran’s presentation highlighting new data of KVA12123, he discussed the key challenges with current cancer therapies, shining a light on the potential for VISTA blocking immunotherapy to reverse immunosuppression in the tumor microenvironment (TME) and drive antitumor activity.


“VISTA is multifunctional within the tumor microenvironment. VISTA functions bidirectionally and at the level of engaging T cells, which is classically what we think of in terms of checkpoint inhibition. VISTA can engage the PSGL-1 molecule, which is an interaction that occurs most efficiently and low pH tumor microenvironments,” said Curran.

VISTA, or V-domain immunoglobulin suppressor of T-cell activation, is an immunoregulatory molecule involved in maintaining T-cell and myeloid quiescence.2

“By hitting VISTA, we can not only affect the polarity of the myeloid stroma, [but] we can also at the same time release T cells from targeted inhibition and maybe also at the level of tumor-induced inhibition as well. That's a unique feature when we think about other targets in the tumor microenvironment that regulate T-cell function, things like LAG-3 or TIM-3. This ability to co-regulate the myeloid stroma as well as T cells at the same time is a unique feature of VISTA,” added Curran.

VISTA stands out from other immune checkpoint inhibitors in that it is expressed on naive T cells while other inhibitors like CTLA-4 and PD-1 are expressed on activated T cells. This distinction sets VISTA apart and could lead to novel therapeutic approaches.

The role VISTA plays is in enforcing tolerance to self-antigen. It is expressed on many different cells in the TME, including myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. VISTA upregulation in higher-grade gliomas vs lower-grade gliomas has been associated with worse prognosis in several types of cancer. Further, VISTA has been found to be upregulated in higher grades of oral squamous cell carcinomas, gastrointestinal cancers, and prostate cancers compared with lower grades of the diseases.

Overall, anti-VISTA antibodies have shown promise in preclinical studies as a potential therapeutic approach for cancer.

“We see this ability for VISTA and PD-L1 blockade together to act as a nonredundant lead to release T cells from immune inhibition,” said Curran.

Several VISTA-targeting inhibitors are in development. These inhibitors have shown promise in preclinical studies, and some are already in clinical trials. One VISTA-targeting inhibitor, CA-170, showed a clinical benefit rate of 75% and progression-free survival of 19.5 weeks in patients with nonsquamous non-small cell lung cancer (NSCLC) in a phase 2 trial. Another VISTA-targeting inhibitor, HMBD-002, is being investigated in phase 1 trials for the treatment of triple-negative breast cancer and NSCLC.

These results suggest that VISTA-targeting inhibitors have the potential to be effective treatments for cancer. More research is needed to confirm these findings, but VISTA-targeting inhibitors are a promising new approach to cancer therapy.

“The unique potential value of VISTA…is its multimodal functioning within the tumor microenvironment, the ability to co-modulate myeloid and T-cell function at the same time, as well as its potential to have both monotherapeutic and potentially synergistic combination efforts,” added Curran.

In preclinical models, KVA12123 has shown single-agent tumor growth inhibition in preclinical models, as well as when given in combination with PD-1. The use of KVA12123 drives an integrated innate and adaptive antitumor response in the MB49 preclinical model.

KVA12123 was also well-tolerated. No CRS-associated signals were observed in preclinical models and no treatment-related adverse events were seen. Additionally, there was no mortality and no overt clinical signs of weight loss.

Cancer Cell Image: © sipgus - stock.adobe.com

Cancer Cell Image: © sipgus - stock.adobe.com

VISTA-101 Trial

KVA12123, a VISTA-blocking immunotherapy, is currently in development as a twice-weekly infusion. KVA12123 has unique epitope binding and an optimized IgG1 Fc region and previously has demonstrated a strong monotherapy tumor growth inhibition in preclinical models. Additionally, the agent has not shown any evidence of CRS in patients.2,3

The VISTA-101 trial is evaluating the safety, tolerability, pharmacokinetics (PK), immunogenicity, and tumor response of KVA12123 as a monotherapy and in combination with pembrolizumab (Keytruda).3

In the open-label, multicenter, dose-escalation and dose-expansion phase 1/2 study, patients with advanced solid tumors are included who are 18 years of age and older with a histologically or cytologically confirmed, locally advanced or metastatic solid tumor that has progressed or was not responsive to standard-of-care therapy.2 Further, patients must have an expected survival of ≥16 weeks, measurable disease, an ECOG performance status score of 0 or 1, adequate organ function, and normal thyroid function or hypothyroid with stable supplementation.

Phase 1, the dose-escalation portion, is a masked trial in up to 60 patients with advanced solid tumors. Phase 2, the dose-expansion, will include patients with non–small cell lung cancer, head and neck cancer, ovarian cancer, colorectal cancer, and renal cell carcinoma, among others.

The drug is infused in patients every 2 weeks, and the first 3 cohorts of the study have been cleared with 3 mg, 10 mg, and 30 mg.

“The phase 1 dose-escalation portion is divided into a monotherapy, which is a KVA12123 dose-escalation, which has 6 cohorts. Then, the combination, which is the KV12123, in combination with pembrolizumab, has 4 cohorts,” said Vinny Hayreh, MD, vice president of Kineta clinical research, during the live event. “In general, we're enrolling 36 patients, but in the lower doses of the monotherapy, we did enroll fewer patients. After we have completed the first 3 cohorts, and now we are at 100 mg of the monotherapy, and we're ready to initiate the combination therapy with pembrolizumab.”

The primary end points of the study are type and frequency of adverse events and determining the maximum-tolerated dose. Secondary end points include PK and investigator assessment of radiographic imaging according to iRECIST, including patients with progressive disease, stable disease, partial response, and complete response.

Baseline characteristics for the first 3 cohorts of the study showed that there are more male patients in the study compared with females (64% v 36%), and the majority of patients are White (64%).1 The mean age of patients is 60.8 years (range, 47-72). Regarding disease stage, 55% of patients have stage IV disease, 18% have stage II disease, 9% have stage I disease, and 18% were not reported. Further, all patients had received prior treatment with antineoplastic medication and surgery, 82% of patients were treated with prior radiation, 82% of patients had an ECOG performance status of 1 at baseline, and 18% had an ECOG performance status of 0.

For safety, all treatment-emergent adverse events (TEAEs) were grade 1-2. A total of 45% of patients had TEAEs, including 3 (27%) patients with an infusion-related reaction, and 1 (9%) patient each had constipation, diarrhea, dyspepsia, arthralgia, myalgia, tachycardia, blood potassium decreased, decreased appetite, cough, and rash maculo-papular.

“Overall, when we look at our tolerability and our safety, the safety is actually very good. These are the related adverse events to date for the 3 cohorts. We have had no dose-limiting toxicities and all of these events were grade 1 and 2,” said Hayreh.

Notably, there were no elevations in TNFa, IL-6, or IL-10, and no evidence of CRS-associated cytokine induction following treatment with KVA12123.

In the 30 mg cohort, the agent showed a greater than dose-proportional PK profile. A greater than 90% VISTA RO was reached across patients included in the 30 mg cohort. Additionally, the agent showed a dose-proportional induction of pro-inflammatory biomarkers that are needed for strong antitumor activity.

“​​The PK profile demonstrates a graded exposure at higher dose, and we have some efficacy, sign of efficacy using our biomarker chemokine immune cell population,” added Guillaudeux.

Overall, these data on KVA12123 are encouraging, and the VISTA-101 trial remains ongoing.

  1. Kineta KOL event to review new data from VISTA-101 clinical trial of KVA12123 in patients with advanced solid tumors. Kineta, Inc. December 5, 2023.
  2. ElTanbouly MA, Zhao Y, Nowak E, et al. VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance. Science. 2020;367(6475):eaay0524. doi:10.1126/science.aay0524
  3. A clinical trial of KVA12123 treatment alone and in combination with pembrolizumab on advanced solid tumors (VISTA-101). ClinicalTrials.gov. Updated July 13, 2023. Accessed December 5, 2023. https://tinyurl.com/2wd9u9b9
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