medwireNews: KITE-363 and KITE-753, which use the same bicistronic chimeric antigen receptor (CAR) construct with dual co-stimulation, show potential for clinical benefit in patients with large B-cell lymphoma (LBCL), say researchers.
The phase 1 findings, presented at the 67th ASH Annual Meeting and Exposition in Orlando, Florida, USA, give an update on previously reported safety and efficacy data for KITE-363, demonstrating high and durable response rates, as well as novel findings on the safety profile for KITE-753, which unlike KITE-363 uses a “rapid-manufacturing process to preserve naïve and stem cell memory T cells,” said the presenter.
The therapies independently target CD-19 and CD-20 CAR in a synergistic approach “designed to prevent antigen escape,” with each having costimulatory domains of CD28 and 4-1BB, respectively, which “boosts CAR T-cell performance,” Saurabh Dahiya (Stanford University School of Medicine, California, USA) explained.
For the open-label study, patients who had relapsed or refractory B-cell lymphoma despite receiving at least two prior lines of therapy were treated with one of three doses of KITE-363 (0.5 x 106, 1.0 x 106, or 2.0 x 106 CAR-T cells/kg) or KITE-753 (3.0 x 104, 1.0 x 105, or 2.0 x 105 CAR-T cells/kg). Dahiya highlighted the lower doses of KITE-753 compared with KITE-363.
Only steroids with or without radiotherapy were permitted as bridging therapy, and measurable disease had to be present prior to infusion. Systemic chemo-immunotherapy was not permitted. During dose escalation, there were no dose-limiting toxicities with either product.
Durable response to KITE-363
At a median follow-up of 17.5 months, the objective response rate (ORR) was 87% among the 22 CAR-naïve patients receiving KITE-363 at the highest dose, all of whom had LBCL. They were considered “particularly high risk,” noted the investigator, due to 68% being primary refractory and 73% having elevated lactase dehydrogenase (LDH) at baseline. Yet, 78% achieved a complete response (CR), with the median duration not reached. It appeared to plateau at around 6 months, he acknowledged, with a 12-month rate of 71%.
There was no change in the safety findings previously reported, with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events being primarily grade 1 or 2, with none of grade 4 or 5.
Sustained safety and efficacy with rapid manufacturing
Dahiya and team were able to confirm the preservation of naïve T cells with rapid manufacturing, with higher percentages of both stem cell memory CD4 and CD8 cells seen with KITE-753 compared with KITE-363, “irrespective of dose or prior CAR-T exposure.”
The 30 patients in the KITE-753 group had a median age of 59 years and 67% were men. Most (87%) had LBCL while the remainder had indolent non-Hodgkin’s lymphoma. The proportion of patients with stage III/IV disease was 73%, 17% had bulky disease (≥7.5 cm), 27% were primary refractory, and 53% had elevated pre-treatment LDH. A total of 10 patients received bridging therapy, to which 10% had a partial response.
The time between leukapheresis and infusion was a median of just 13.5 days, “reflecting the rapid manufacturing process,” Dahiya observed.
Over a median follow-up of 4 months for all patients, and 2.9 months for the 19 patients receiving the highest dose of KITE-753, CRS developed in 14 (47%) patients overall, at a median 9.5 days, all of which were grade 1 or 2, with only one grade 1 event in a patient receiving the middle dose.
Similarly, there were no grade 3 or worse cases of ICANS. Grade 1–2 events occurred in four (13%) patients overall, at a median of 12.5 days, with only two events occurring in patients receiving the highest dose, both of which resolved within 48 hours.
The ORR among the 20 patients who were CAR-naïve was “high” at 80%, said Dahiya, with a CR rate of 70%, and a median time to first response of 29 days. The corresponding rates among patients taking the highest dose were 86% and 79%. And Dahiya pointed out that nine of the 11 CAR-naive patients with CRs in the highest dose group achieved this within 1 month and the remaining two within 3 months.
Among the 10 patients who had received prior CAR-T cell therapy, 50% had an ORR, with CR in 30%.
These findings “indicate strong depth of response, supporting the potential for durable remissions with KITE-753,” said Dahiya.
He also reported that, while the highest dose of CAR-T was 10 times lower with KITE-753 than KITE 363, there was still “strong” CAR-T cell expansion, at a median of 19,602 copies by day 15, compared with a median of 44,064 by day 8, “highlighting its robust CAR-T proliferative capacity, with high peak expansion that appears to be decoupled from the toxicity.”
Dahiya concludes that the data “support the advancement of KITE-753 into pivotal development, with trials planned for early 2026, including a third line plus LBCL trial, and a randomized phase 3 trial in second line LBCL.”
