KVA12123 Showcases Early Tolerability in Advanced Solid Tumors

KVA12123 monotherapy and in combination with pembrolizumab (Keytruda) demonstrated early signals of on-target activity and tolerability at all dose levels examined to date in patients with advanced solid tumors enrolled in the phase 1/2 VISTA-101 trial (NCT05708950).¹

In the first 4 monotherapy dose-escalation cohorts, which evaluated KVA12123 at 3 mg, 10 mg, 30 mg, or 100 mg every 2 weeks, and the initial cohort in combination with pembrolizumab (n = 3), which examined the agent at 30 mg plus pembrolizumab at 400 mg, treatment was found to be well tolerated with no dose-limiting toxicities (DLTs) observed at any dose level. Moreover, investigators have not found any evidence of cytokine release syndrome (CRS)–associated cytokine induction at any dose evaluated in these initial cohorts.

Biomarker analysis indicated that KVA12123 had dose-proportional induction of CXCL10, CCL2, CCL4, and CCL4, which are proinflammatory biomarkers that are needed to produce potent antitumor activity. In the blood, consistent increases in nonclassical monocytes, natural killer cells, CD4-positive, and CD8-positive T cells were also observed.

A proprietary assay was utilized to examine VISTA RO on immune cells in study participants and it was found that when the agent was administered at 30-mg and 100-mg doses, it achieved a VISTA RO that was higher than 90%. Pharmacokinetic findings also revealed a greater than dose-proportional increase in drug exposure across all dose levels examined.

“We are encouraged with the efficacy-related biomarker data that demonstrate on-target activity of KVA12123 in our phase 1/2 clinical trial. Additionally, the safety profile supports advancing to higher doses in the monotherapy and combination cohorts of the study,” said Shawn Iadonato, PhD, chief executive officer of Kineta, Inc. “We believe KVA12123 continues to show its potential as a next-generation immunotherapy that may overcome immunosuppression in the tumor microenvironment. The clinical study is progressing on time, and we anticipate fully enrolling the phase 1 portion of the trial by April 2024.”

The first-in-human, open-label, multicenter, dose-escalation and -expansion study enrolled patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors that have progressed or were not responsive to standard treatment, or who had no curative approaches available to them.² Patients needed to be at least 18 years of age, have measurable disease by iRECIST criteria, have an ECOG performance status of 0 or 1, and have an expected survival of at least 16 weeks. They needed to have acceptable organ function in the 10 days before KVA12123 initiation and normal thyroid function.

Those with untreated central nervous system metastasis, leptomeningeal disease, or cord compression were excluded, as were those who had concurrent malignancies other than the disease under study and that needed systemic therapy. Patients could not be immunodeficient, could not have a history of pneumonitis or interstitial lung disease requiring steroids, and could not have previously received VISTA-targeted therapy or undergone allogeneic, solid organ, stem cell, or adoptive T-cell transplant.

Part A of the trial includes 6 dose-escalation cohorts of 1 to 6 patients who will receive treatment with single-agent KVA12123. Part B is comprised of 4 dose-escalation cohorts consisting of 1 to 6 participants who will receive KVA12123 paired with pembrolizumab. The key objective of these 2 parts is to identify the recommended phase 2 dose for examination in parts C and D. Part C will include 2 disease-specific dose-expansion cohorts that will receive KVA12123 monotherapy. Part D includes 5 disease-specific dose-expansion cohorts who will be given the combination.

The other key objectives of the research are to evaluate the type and frequency of adverse effects (AEs) and the type and frequency of treatment-related AEs. Secondary objectives include examining the pharmacokinetic profile of KVA12123, the concentration of antidrug antibodies, and more.

The agent cleared the first 4 monotherapy dose levels and the first combination cohort.¹ Notably, patients enrolled on VISTA-101 were heavily pretreated in that they had previously received several lines of therapy, including radiation, chemotherapy, and immunotherapy. About half of patients experienced failure with prior checkpoint inhibition.

Dosing for the 300-mg monotherapy cohort and the 100-mg combination cohorts have been initiated, according to Kineta.

“We are pleased to see the compelling safety data of KVA12123 and the lack of CRS-associated cytokine induction. The drug has been very well tolerated in patients,” Thierry Guillaudeux, PhD, chief scientific officer of Kineta, added in the press release. “These data are encouraging and consistent with the results from our preclinical models.”

References

1. Kineta provides update on its ongoing phase 1/2 VISTA-101 clinical trial of KVA12123 in patients with advanced solid tumors. News release. Kineta, Inc. January 17, 2024. Accessed January 24, 2024. https://kinetabio.com/2024/01/17/kineta-provides-update-on-its-ongoing-phase-1-2-vista-101-clinical-trial-of-kva12123-in-patients-with-advanced-solid-tumors/
2. A clinical trial of KVA12123 treatment alone and in combination with pembrolizumab in advanced solid tumors (VISTA-101). ClinicalTrials.gov. Updated July 13, 2023. Accessed January 24, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05708950