NKX019 Showcases Manageable Safety, Early Activity in R/R B-cell Non-Hodgkin Lymphoma

The allogeneic natural killer (NK) cell therapy NKX019 was found to have an acceptable toxicity profile and to induce deep and durable responses in patients with relapsed or refractory B-cell non-Hodgkin lymphomas, according to preliminary data from a phase 1 trial (NCT05020678).¹

Data presented at the 2023 EHA Congress showed that as of the data cutoff date of November 22, 2022, no dose-limiting toxicities (DLTs) were reported with the product, nor were there any cases of immune effector cell–associated neurotoxicity syndrome, graft-vs-host disease, or greater than grade 3 cytokine release syndrome.

When given at the highest dose levels, the therapy induced an overall response rate of 80% in evaluable patients (n = 10), which included a complete response (CR) rate of 70%; in those with large B-cell lymphoma (LBCL), the CR rate was 50%.

When broken down by histology, 4 of the patients with follicular lymphoma (n = 5), achieved a CR as their best response to treatment and 1 patient experienced a partial response (PR). The patient with follicular lymphoma grade 3b achieved a PR as their best response to treatment. Of the 6 patients with LBCL, 2 patients achieved a CR as their best response, 2 patients had stable disease (SD), and 2 patients had progressive disease (PD). Moreover, the patients with mantle cell lymphoma (MCL; n = 1) and marginal zone lymphoma (MZL; n = 1) both achieved CR as their best response.

“Deep responses with durability of greater than 6 months [was observed] in multiple patients with potential for retreatment should the tumor recur,” Michael Dickinson, MBBS, DMedSc, FRACP, FRCPA, lead study author and an associate professor at Peter MacCallum Cancer Centre, in Melbourne, Austrailia, stated in a presentation of the data. “The on-demand availability and the manageable safety profile make outpatient administration [of NKX019] possible.”

Although the emergence of autologous CAR T-cell therapies have transformed the treatment landscape for patients with hematologic malignancies, the custom manufacturing required to make these products impedes prompt treatment. Other challenges include the incidence of potentially severe T-cell–mediated adverse effects (AEs) and patient accessibility.

NKX019 is a cryopreserved, allogeneic CAR NK cell therapy that targets CD19 and is derived from healthy donors. The product is comprised of an OX40 costimulatory domain and mbIL-15 for activation. NK cells are known to offer antigen-independent tumor surveillance and to be able to eliminate cancer cells through activating and inhibitory signals.

The multicenter, open-label, phase 1 study enrolled patients with relapsed or refractory CD19-positive B-cell malignancies who previously received at least 2 lines of treatment. Patients were required to have an ECOG performance status of 0 or 1. For the dose-finding phase of the research, they also needed to be naïve to CAR T-cell therapies.

First, patients underwent lymphodepletion comprised of cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for days -5 to -3. On day 0, they received their first dose of NKX019; they received 2 more doses of the product on days 7 and 14, respectively. The investigative product was given for a total of 3 doses per each 28-day cycle.

“Multiple cycles allowed [for the] deepening [of] responses for subjects tolerating and benefitting from the treatment,” Dickinson said. “Subjects in CR may receive an additional cycle as consolidation.”

The end points of the trial include safety and tolerability, antitumor activity, and pharmacokinetics.

In the 19 patients enrolled in the trial, the median age was 59 years (range, 21-82). Thirteen patients had an ECOG performance status of 1. Most patients (n = 13) were from Australia and the remainder (n = 6) were from the United States. Diagnoses included LBCL (n = 7), follicular lymphoma (n = 5), MZL (n = 1), MCL (n = 1), chronic lymphocytic leukemia (n = 2), and B-cell acute lymphoblastic leukemia (n = 3). Notably, 43% of those with LBCL had an International Prognostic Index of 3+ and 60% of those with follicular lymphoma were high risk. The median number of prior lines of therapy received was 4 (range, 2-10).

Additional data showed that those who achieved a CR as their best response experienced tumor reductions that ranged from approximately 57% to 100%. Those who experienced PRs experienced approximate reductions that ranged from 74% to 79%.

Investigators measured interleukin (IL)-6, interferon-γ, IL-10, and IL-8 levels at baseline and at many time points during the treatment cycle. They reported that there were minimal elevations above baseline, and there was no link between elevated serum cytokines and clinical response to NKX019.

Moreover, when the product was given at higher doses, it was found to correlate with a higher Cmax. Specifically, when given at a dose level of 300 M cells (n = 5), the median Cmax was less than 6.7 (range, <6.7-393). When given at 1 B/1.5 B cells (n = 14), the median Cmax was 156.9 (range, <6.7-567.0).

Peak concentration trended higher in those who achieved a CR. Specifically, the Cmax in the patient who received NKX019 at 300 M cells and achieved a CR was 393. In the 7 patients who received the product at 1 B/1.5 B cells, the median Cmax was 298 (range, <6.7-567.0). In contrast, in the 4 patients who received the product at 300 M cells and the 7 patients who received it at 1 B/1.5 B cells and did not achieve a CR, the median Cmax was less than 6.7.

Of the 19 patients evaluable for safety, 84% experienced grade 3 or higher AEs; these effects included decreased neutrophil count (63%), decreased platelet count (42%), febrile neutropenia (26%), anemia (21%), decreased white blood cell count (16%), and decreased lymphocyte count (11%).

Twenty-six percent of patients developed a fever within 8 hours of treatment, and this toxicity was found to resolve within 1 day.

Enrollment into the expansion cohorts of those with LBCL who are naïve or previously exposed to CAR T-cell therapy is ongoing, and the product will be evaluated at the recommended phase 2 dose. The antitumor activity of the agent will also be evaluated in combination with rituximab (Rituxan).

Reference

Dickinson M, Hamad N, Bryant C, et al. First in human data of NKX019, an allogeneic CAR NK for the treatment of relapsed/refractory (R/R) B-cell malignancies. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S261.