KTE-X19 Continues to Show Durable Efficacy in Relapsed/Refractory MCL

After a minimum of 1 year of follow-up, patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated substantial and durable clinical benefit and a manageable safety profile when receiving KTE-X19 chimeric antigen receptor (CAR) T cell therapy, according to a poster from the 2021 Transplantation & Cellular Therapies Meetings.¹

“Within this patient population, which lacks curative treatment options, most patients achieved durable CR [complete response], and no new safety signals were reported,” the investigators wrote for their abstract published in Blood.² “Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL.”

Patients received 2×106 cells/kg of KTE‑X19, an autologous anti-CD19 CAR T-cell therapy, after progressing on 1 or more prior therapies to evaluate the long-term efficacy, safety, and pharmacology of the drug in the ZUMA-2 trial (NCT02601313).¹ Before getting KTE-X29, patients could receive optional bridging therapy of dexamethasone, ibrutinib (Imbruvica), or acalabrutinib (Calquence), then conditioning chemotherapy with fludarabine and cyclophosphamide. Clinical outcome data were only available for 60 evaluable patients, but 68 patients had reported safety data.

The primary end point was objective response rate (ORR) by Independent Radiology Review Committee (IRRC) using the Lugano Classification. The secondary end points included overall survival (OS), progression-free survival (PFS), duration of response (DOR), toxicity profile, and levels of CAR T cells in the blood and cytokines in serum.

With 17.5 months of median follow-up (range, 12.3-37.6), there was an ORR of 92% (95% CI, 82%-97%) from the combination of a 67% CR rate and 25% partial response rate. There was stable disease observed in 3% of patients and progressive disease in another 3%. Almost half of the evaluable patients had ongoing responses at follow-up (48%), and 70% of those who achieved CR remained in response.

For the first 28 patients treated on ZUMA-2, 39% remained in continued remission with no further therapy at a median follow-up of 32.3 months (range, 30.6-37.6). For all 74 of the patients enrolled on the trial, the ORR was 84% with a 59% CR rate.

The median OS, PFS, and DOR were not reached by the median 17.5 months follow-up. In the 60 evaluable patients, there was a 15-month OS, PFS, and DOR rate of 76% (63%-85%), 59% (45%-71%), and59% (43%-72%), respectively.

None of the prognostic subgroups had ongoing response rate hazard ratios crossing 1.00. The subgroup who did the best was the patients with blastoid morphological characteristics (HR, 0.36; 95% CI, 0.13-0.65) and patients under the age of 65 at baseline (HR, 0.43; 95% CI, 0.24-0.63). The subgroups who did the worst were the patients with pleomorphic morphological characteristics (HR, 0.75; 95% CI, 0.19-0.99)¾this was the second smallest subgroup (n = 4), only behind patients with stage I-II disease (n = 2)—and patients with no TP53 mutation detected (HR, 0.57; 95% CI, 0.37-0.75).

In this trial, any grade adverse events (AEs) were observed in 81% of the 68 patients with safety data and grade 3 or more AEs were observed in 48% in the 3 or more months post-infusion. Six or more months post-infusion, 72% had any grade AEs and 37% had grade 3 or more AEs. The most common grade 3 or more AE in either of these groups was neutropenia, at 24% in the 3 or more months post-infusion category and 16% in the 6 or more months post-infusion category. The rate of AEs decreased over time.

Between July 24, 2019 and December 31, 2019, there were 19% of patients with any grade AEs and 13% with grade 3 or more AEs. The most common was still neutropenia at 9% for any grade and grade 3 or more. There were no new safety signals with additional follow-up, no cytokine release syndrome, and no new grade 5 events since the original data were reported.

For the robust expansion of CAR T cells required to achieve a response to KTE-X19, the investigators wrote in the poster, “Peak CAR T‑cell expansion was higher in patients with an ongoing response at 12 months or those who relapsed at 12 months compared with that in nonresponding patients. Additional mechanistic studies are ongoing to further understand the observed pharmacokinetic relationship with response and durability.”

There were 57 patients with data available at baseline, 84% had detectable B cells. The recovery of B cells increased over time for patients who had ongoing responses at 12 months, whereas gene-marked CAR T cells decreased over time. There was no association between CAR T-cell expansion measured within 2 weeks post-infusion and B-cell aplasia.

_References:

_{1. Wang M, Munoz J, Goy A, et al. One‑year follow‑up of ZUMA‑2, the multicenter, registrational study of KTE‑X19 in patients with relapsed/refractory mantle cell lymphoma. Poster presented at: 2021 Transplantation & Cellular Therapies Meetings; February 8-12, 2021; virtual. Poster 414.}

_{2. Wang M, Munoz J, Goy A, et al. One‑year follow‑up of ZUMA‑2, the multicenter, registrational study of KTE‑X19 in patients with relapsed/refractory mantle cell lymphoma. Blood. 2020;136(suppl 1):20-22. doi:10.1182/blood-2020-136382}