Interim analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL).

Abstract

8008 Background: Advanced stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is considered incurable as most pts experience multiple relapses (Wang, et al. Ther Adv Hematol. 2017), highlighting a need for novel therapies. Here, we present interim results from ZUMA-5, a Phase 2, multicenter study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in pts with R/R iNHL. Methods: Adults with R/R FL (Grades 1-3a) or MZL (nodal or extranodal) after ≥ 2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG of 0 – 1 were eligible. Pts were leukapheresed and received conditioning chemotherapy followed by axi-cel infusion at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T cells. Results: As of 8/20/19, 94 pts (80 FL; 14 MZL) received axi-cel with a median follow-up of 11.5 mo (range, 4.2 – 24.9). Median age was 63 y (range, 34 – 79), 47% of pts were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 59% had high tumor bulk (GELF). Pts had a median 3 prior lines of therapy, 66% progressed < 2 y after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment. Of 87 pts evaluable for efficacy, ORR was 94% (79% complete response [CR] rate). Pts with FL (n = 80) had an ORR of 95% (80% CR rate). Pts with MZL (n = 7) had an ORR of 86% (71% CR rate). Overall, 68% of pts had ongoing responses as of the data cutoff. Updated data, including DOR, PFS, and OS with longer follow-up, will be included in the presentation. Of 94 pts evaluable for safety, 83% experienced Grade ≥ 3 adverse events (AEs), most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al, Blood 2014) and neurologic events (NEs; per CTCAE v4.03) occurred in 11% and 19% of pts, respectively. Median times to onset of CRS and NEs were 4 and 7 d, with median durations of 6 and 14.5 d. There were 2 Grade 5 AEs: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak and AUC0-28 CAR T cell levels were 44 cells/µL and 490 cells/µL × d, respectively. Conclusions: Axi-cel demonstrated significant and durable clinical benefit, with high rates of ORR and CR, and a manageable safety profile in pts with R/R iNHL. Clinical trial information: NCT03105336 .

Immunotherapy with cells (article not eligible for CME credit)

“…In 80 patients with FL and 14 patients with marginal zone lymphoma that relapsed after 2 prior therapies, axi-cel treatment produced a 94% ORR with CR of 80%. 30 For the tisa-cel construct, similar FL responses were observed (80% ORR) with 60% of patients responding at 4 years. 8,23 Taken together, the limited long-term data suggest that remissions after anti-CD19 CAR-T in indolent lymphoma are durable.…”

“…Studies have demonstrated high response rates 8,9,23,30 and longterm remissions 8,9,23 after CAR-T administration for FL (Table 2). In 80 patients with FL and 14 patients with marginal zone lymphoma that relapsed after 2 prior therapies, axi-cel treatment produced a 94% ORR with CR of 80%.…”

How we treat mature B-cell neoplasms (indolent B-cell lymphomas)

“…CAR T is associated with CR rates up to 88% with sustained remission in up to 89% of FL patients with an initial response, over median follow-up of 28.6 months [ 234 – 236 ]. Recently presented data from the phase 2 ZUMA-5 trial which evaluated commercially available axicabtagene ciloleucel in patients with FL and MZL demonstrated ORR 94% (95% in FL, 86% in MZL), with CR rate of 79% [ 237 ]. While high-grade CRS and neurotoxicity remain concerns, occurring at rates of 13% and 28%, respectively, our growing experience utilizing appropriately-timed anti-cytokine blockade and corticosteroids should help mitigate severe toxicities [ 234 , 237 , 238 ].…”

Hematopoeitic Cell Transplantation and CAR T-Cell Therapy: Complements or Competitors?

“…With a median follow-up of 11.5 months, 68% of patients had ongoing responses. CRS and ICANS occurred in 11% and 19% of patients ( 43 ). While the high response rates and manageable toxicities are promising in multiply recurrent FL, the length of follow-up in these trials is limited.…”