TAK-007 Shows Favorable Safety, Early Efficacy Data in R/R B-Cell Non-Hodgkin Lymphoma

Treatment with TAK-007, an off-the-shelf allogeneic CD19 CAR-NK cell therapy demonstrated initial responses and a favorable safety profile in heavily pretreated patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to data from a phase 2 study (NCT05020015) presented at the 2024 ASH Annual Meeting.

The overall response rate (ORR) in the overall study population (n = 26) was 53.8%, 30.8% of which were complete responses (CRs) and 23.1% of which were partial responses (PRs). Among patients who received TAK-007 at a dose of 800 x 106 cells (800M; n = 23), the response rate was 61%.

Within the 800M escalation and expansion cohorts, patients with large B-cell lymphoma (LBCL; n = 14) had an ORR of 50.0%, CR rate of 21.4% and PR rate of 28.6%. For those with indolent NHL (n = 9), these respective rates were 77.8%, 55.6%, and 22.2%. Of note, ORRs were 42.9% and 68.8% in patients from the 800M cohorts who were and were not previously exposed to CD19-targeted CAR T-cell therapy, respectively. The median duration of response was 2.6 months in the LBCL cohorts and 4.9 months in the indolent NHL cohorts.

“We did see responses that seemed to be independent of baseline CD19 expression, and unfortunately, long-term remission seemed to be limited,” lead study author Justin M. Darrah, MD, codirector of the Lymphoma Program and director of the CAR T-cell program at Cedars-Sinai in Los Angeles, California, said during an oral presentation of the data. “We think it's possible that administration of more than 1 dose of TAK-007 at the [800M] dose may result in higher efficacy and better durability response and may be an area for future exploration.”

Regarding safety, treatment-emergent adverse effects (TEAEs) occurred in all patients in the study and were generally manageable. No dose-limiting toxicities were reported. At baseline, 81% of patients experienced grade 2 or greater cytopenias. The most common nonhematologic TEAEs included nausea (58%) and fatigue (54%); 77% of nonhematologic TEAEs were grades 1 and 2. Infusion-related reactions only occurred in 1 patient following treatment with TAK-007. Cytokine release syndrome (CRS) was observed in 3 patients (grade 1, n =2; grade 2, n = 1). TAK-007-related immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed and there were no reports of graft-vs-host-disease (GVHD).

Trial Design

The open-label, multicenter phase 2 trial evaluated TAK-007 in patients with relapsed/refractory LBCL and indolent NHL. Eligibility criteria included CD19-positive disease; measurable disease per Lugano classification; and prior receipt of at least 2 lines of systemic therapy.

Twenty-six patients were enrolled onto the study across 9 sites in the United States. In the dose escalation portion of the trial, 3 patients with LBCL received TAK-007 at a dose of 200 x 106 cells (200M). The 800M dose was administered to 4 patients with LBCL and 2 with indolent NHL.

The dose expansion phase of the study included 17 patients (LBCL, n = 10; indolent NHL, n = 7); all patients received the 800M dose.

Patients in both portions of the study first received lymphodepleting chemotherapy on days –5 to –3. TAK-007 infusion occurred on day 0, primary follow-ups occurred after no more than 6 months, and secondary follow-up was conducted between months 7 to 24.

The primary end points of the study were safety and tolerability; secondary end points included efficacy, cellular kinetics, and immunogenicity.

Patient Baseline Demographics

In the overall patient cohort, the median age was 64 years (range, 38-83); the majority were male (69%), White (88%), and not Hispanic or Latino (92%). Regarding disease subtypes at study entry in the overall patient cohort included LBCL not otherwise specified (31%), LBCL arising from indolent NHL that is either follicular lymphoma or marginal zone lymphoma (27%), high-grade B-cell lymphoma with MYC/BCL2/BLC6 rearrangement (8%), follicular lymphoma (31%), and splenic marginal zone lymphoma (4%).

Of note, the median number of prior lines of therapy in the 200M escalation cohort and 800M escalation and expansion cohorts were 6 (range, 5-6), 4.5 (range, 2-11), and 5 (2-9), respectively. Prior exposure to anti-CD19 therapy was reported in 67%, 50%, and 22% of patients in these respective groups; 67%, 43%, and 11% of those patients received prior CAR T-cell therapy. Patients in these cohorts were either refractory (33%; 57%; 22%), relapsed (33%; 36%;67%), or had an unknown response (33%; 7%; 11%) to their last line of therapy.

Additional Safety and Pharmacokinetic Data

In the overall patient cohort, 92% of patients had grade 3 or greater TEAEs. The most common TEAEs were neutropenia (73%) and leukopenia (50%). Serious TEAEs were reported in 77% of patients but were not attributed to TAK-007 or lymphodepleting chemotherapy in 54% of patients. These included 7 patients who died because of underlying lymphoma.

The cellular kinetics exhibited a multiphasic disposition, which represented an initial cellular contraction and subsequent cellular expansion. Peak serum levels were observed post-TAK-007 infusion on days 7-10, in which a terminal elimination phase was followed by decreasing levels on days 10-28. The exposure-response analysis indicated a positive correlation between higher exposure to TAK-007 and response to treatment. There were no reports of treatment-emergent humoral immunogenicity specific to donor HLA or the extracellular domain of CAR molecules on TAK-007.

“CAR T-cell therapies have shown sustainable and curative benefits for leukemia and B-cell lymphoma, but have limitations, [such as a] lengthy and complex production process due to autologous, customized nature,” Darrah concluded. “CAR-NK cells have the potential to overcome these limitations, and early clinical trial data have shown that their administration is not associated with the development of CRS, ICANS, or GVHD.”

Reference

Darrah J, Varadarajan I, Mehta A, et al. Efficacy and safety of TAK-007, cord blood-derived CD19 CAR-NK cells, in adult patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). Blood. 2024;144(suppl 1): 95. doi:10.1182/blood-2024-194807