Findings from the phase 2 DALY II USA trial showed that the 28-day objective response rate was 78% with freshly administered zamtocabtagene autoleucel, exceeding the prespecified efficacy threshold for interim analysis.
When freshly administered, the dual CD19- and CD20-directed, chimeric antigen receptor (CAR) T-cell therapy zamtocabtagene autoleucel (zamto-cel; MB CART2019.1) showed encouraging safety, including a high response rate with deepening responses over time in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to prespecified interim results from the phase 2 DALY II USA trial (NCT04792489).1
Findings presented at the 2023 Transplantation & Cellular Therapy Meetings showed that the 28-day objective response rate (ORR) per independent radiology review (IRC) was 78% (complete response [CR], 32%; partial response [PR], 46%), exceeding the prespecified efficacy threshold for interim analysis. The best objective response rate was 82% (CR, 46%; PR, 36%).
“DALY-II-USA is the first bispecific anti-CD20/anti-CD19 CAR T trial utilizing fresh infusion with a CAR T-cell product for patients with relapsed/refractory LBCL who received at least 2 lines of treatment,” lead study author Nirav N. Shah, MD, associate professor, Medical College of Wisconsin, said in a presentation of the data.
Although CD19-directed CAR T-cell therapy is approved for the treatment of patients with relapsed/refractory DLBCL, relapse remains an issue. Downregulation of the CD19 receptor or loss of epitope recognition may be one mechanism responsible for resistance. As such, dual-targeted products may help overcome resistance, leading to improved outcomes.
In a first-in-human trial (NCT03019055), investigators demonstrated the feasibility of administering fresh cells with LTG 1497––a construct identical to MB CART2019.1––with a high response rate and remissions lasting over 4 years following infusion.2 Additionally, the phase 1/2 DALY I trial (NCT03870495) showed that the MB CART2019.1 product was well tolerated without severe cytokine release syndrome (CRS) or neurotoxicity and an ORR of 75% and a CR rate of 42% (n = 5/12).3
The single-arm, open-label phase 2 DALY II study was designed to evaluate the efficacy, safety, and pharmacokinetic persistence of zamto-cel in 59 adults with relapsed/refractory DLBCL.
To be eligible for enrollment, patients had to be at least 18 years of age and have an ECOG performance status of 0 or 1, histologically confirmed LBCL, measurable disease confirmed by PET/CT per Lugano 2014 criteria, and received at least 2 prior lines of therapy, including rituximab (Rituxan) and anthracycline-based chemotherapy.
Patients underwent screening on day –45 and leukapheresis on day –14. Patients received lymphodepleting chemotherapy consisting of 30 mg/m2 of fludarabine and 300 mg/m2 of cyclophosphamide on days –5, –4, and –3, or 90 mg/m2 of bendamustine on day -4 and -3. On day 0, patients received zamto-cel at 2.5 x 106 CAR T cells/kg.
“[A] rapid centralized manufacturing process allowed for 14 days ‘vein to vein’ fresh CAR T-cell infusions throughout the United States with lymphodepletion initiated during this process,” Shah said.
The primary end point of the study was the 28-day ORR per IRR. Secondary end points included CR rate, duration of response, best objective response, progression-free survival (PFS), overall survival, safety, cellular kinetics, and cytokine levels.
Of the 36 patients screened, 28 were leukapheresed and 28 received zamto-cel. Twenty-seven patients received the fresh product, but 5 were nonconforming and 1 was cryopreserved, leaving 22 patients evaluable for the analysis.
Regarding baseline characteristics in the evaluable population, the median age was 59 years (range, 37-75) and most patients were male (60%) with an ECOG performance status of 1 (77%). The population was representative of “advanced disease,” Shah said, with an International Prognostic Index of 3 to 5 (68%), elevated lactate dehydrogenase (68%), at least 2 extranodal sites (55%), and receipt of 2 prior lines of therapy (72%).
Patient characteristics were similar in all treated patients (n = 28), Shah noted. Regarding histology, DLBCL (46%) and germinal center B-cell like (35%) were the most common, followed by high-grade B-cell lymphoma (11%), primary mediastinal large B-cell lymphoma (4%), and transformed lymphoma (4%).
Notably, prior treatment for the evaluable population included anti-CD19 antibodies (13%) and polatuzumab vedotin-piiq (Polivy; 9%), “representing contemporary prior treatment algorithms including agents not available in earlier pivotal trials,” Shah said.
At a median follow-up of 10.3 months, 8 deaths occurred, owing to DLBCL (n = 6) and COVID-19 (n = 2).
Additional findings indicated that the 6-month PFS rate in the all-treated and evaluable populations were similar at 61% and 64%, respectively.
“Durable responses were observed in the majority of treated patients, with durable persistence of CD19 and CD20 CAR T cells,” Shah said.
Among the patients with disease progression (n = 14), 2 patients experienced CD20 loss and 1 experienced both CD19 and CD20 loss.
Regarding safety among all treated patients, CRS occurred in 61% of patients (grade 1, 43%; grade 2, 18%; grade 3, 0%) and immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 22% of patients (grade 1, 4%; grade 2, 11%; grade 3, 7%). Management strategies consisted of steroids (21%), tocilizumab (18%), and anakinra (7%).
“Zamto-cel was well tolerated with only 2 [instances of] reversible grade 3 ICANS and no grade 3/4 CRS,” Shah said.
Early onset of cytopenia within the first 28 days after infusion occurred in 85% of patients (grade 3, 21%; grade 4, 64%). Late onset of cytopenia after day 28 occurred in 18% of patients (grade 3, 14%; grade 4, 4%).
Most manifestations of CRS and ICANS were low grade compared with hematologic, autoimmune, and infection-related events.
Editor’s note: Dr Shah reported serving as an advisor for Legend, Epizyme, TG-therapeutics, Kite Pharma, Novartis, LOXO-Lilly Oncology, Janssen, BMS-Juno, and Seattle Genetics; receiving research funding from Miltenyi Biotec and LOXO-Lilly Oncology; serving as a consultant for Miltenyi Biotec, Lilly Oncology, and Incyte; and being a member/founder of Tundra Therapeutics.