Axicabtagene-ciloleucel: also an option for patients with relapsed/refractory indolent non-Hodgkin lymphoma?
The third-line treatment options for patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL) rarely lead to complete responses and responses are rarely sustained for more than one year. As such, novel treatment options are urgently needed in this setting. In this respect, results of the phase II ZUMA-5 trial demonstrate a considerable and durable clinical benefit of axicabtagene-ciloleucel (Axi-cel) as a third line (or beyond) treatment option for patients with relapsed/refractory iNHL, with a high overall response and complete response rate. In addition, the Axi-cel therapy also proved to come with a manageable safety profile.
Background
Patients with advanced-stage indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with the currently available treatment options. Axicabtagene-ciloleucel (Axi-cel) is an autologous anti-CD19 CAR-T cell therapy that is already approved in the treatment of adult patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who received at least two prior lines of systemic therapy. In this setting, the pivotal ZUMA-1 trial demonstrated an overall response rate (ORR) of 82% in modified intent-to-treat patients, with a complete response (CR) rate of 58%. In the multi-centre, single-arm, phase II ZUMA-5 study, Axi-cel was evaluated in patients with R/R iNHL (FL or MZL) after at least two lines of therapy (including an anti-CD20 monoclonal antibody combined with an alkylating agent). In total, 146 adults with R/R FL (Grades 1-3a) or MZL (nodal or extranodal) underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of Axi-cel at 2 × 106 CAR T-cells/kg.
Results
Patients in the study had a median of three prior lines of therapy and 64% had received ≥ 3 prior lines. Progression within two years after initial chemo-immunotherapy occurred in 55% of patients and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients and was delivered to the study site within a median of 17 days after leukapheresis. As of March 12, 2020, the median follow-up for the efficacy analysis was 17.5 months. The ORR in all patients by independent radiology review committee (IRRC) was 92%, with a CR in 76% of patients. For the FL cohort, the ORR was 94% with a CR rate of 80%. The median time to first response was one month. Interestingly, among the 25 patients with FL who initially had a partial response, 13 (52%) subsequently converted to a CR after a median of 2.2 months. The IRRC-assessed ORR was consistent among key subgroups. With a median follow-up of 17.5 months, the estimated median duration of response (DoR) was not yet reached for all patients with iNHL and 64% of patients with FL had an ongoing response at data cut-off. The 12-month DoR rate was 71.7% in all patients. Patients who achieved a CR were much more likely to maintain their response (78%) as compared to patients whose best response was a partial response (17%). The median progression-free survival (PFS) and overall survival (OS) were not yet reached (12-month PFS rate of 73.7% and 12 months OS rate of 92.9%).
Grade ≥3 adverse events (AEs) occurred in 126 patients (86%), with cytopenia (70%) and infections (16%) being the most common. Grade 5 AEs were reported in three patients (one Axi-cel related multisystem organ failure in the context of CRS, one unrelated aortic dissection and one unrelated coccidioidomycosis infection). Cytokine release syndrome (CRS) was reported in 82% of patients, with 7% of patients experiencing grade ≥3 CRS. The median time to onset of CRS was four days and the median duration was six days. No patients had ongoing CRS as of the cut-off date. Neurologic events were reported in 60% of patients, with 19% experiencing grade ≥3 neurotoxicity. Median time to onset was 7 days with a median duration of 14 days. Events were ongoing at the cut-off date in six patients: grade 1 memory impairment (N= 2) and attention disturbance, intermittent paresthesia and tremor (N= 1 each) and grade 2 facial paresthesia (N= 1).
The median time to peak of anti-CD19 CAR-T cell levels after Axi-cel infusion was nine days. In patients with FL, peak CAR-T cell levels were numerically greater among those who had an ongoing response at 12 months. Patients who developed high-grade CRS and neurotoxicity had significantly higher peak CAR-T levels as compared to those who did not. Serum cytokines were measured over time and time to peak for most analytes was within eight weeks, with most resolving within four weeks. The median fold increase in key analytes, previously shown to be associated with toxicity following Axi-cel infusion, appeared greater in patients with MZL than in those with FL. In patients with FL, peak levels of selected cytokines were associated with grade ≥3 neurologic events. Although the numbers are smaller, similar trends were observed in patients with MZL.
Conclusions
Axi-cel demonstrated high rates of durables responses, with an ORR of 92% in patients with iNHL (94% in FL) and a complete response in 76% of patients (80% in FL). With a median follow-up of 17.5 months, 64% of patients with FL remained in response and responses were ongoing in 78% of patients who achieved a CR. In addition, the safety profile was manageable and appeared favourable in patients with FL compared with that previously reported in large B-cell lymphoma. Furthermore, results of pharmacokinetic and pharmacodynamics analyses were consistent with the safety profile observed in patients with FL. Altogether, these data identify CAR-T cell therapy with Axi-cel as a very promising therapeutic approach for patients with R/R iNHL.
Reference
Jacobson C, Chavez JC, Sehgal AR, et al. Primary Analysis of Zuma-5: A phase 2 study of axicabtagene ciloleucel (Axi-cel) in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Presented at ASH 2020; Abstract 700.
