Anbalcabtagene Autoleucel Generates Responses in Relapsed/Refractory LBCL

The novel, autologous, anti-CD19 CAR T-cell therapy anbalcabtagene autoleucel (anbal-cel; CRC01) produced durable responses and was well tolerated in patients with relapsed/refractory large B-cell lymphoma (LBCL), according to interim data from a phase 2 trial (NCT04836507) presented at the 17th AnnualInternational Conference on Malignant Lymphoma.^1,2

Findings showed that evaluable patients treated with anbal-cel (n = 38) achieved an objective response rate (ORR) of 84% per independent review committee (IRC) assessment. This included a complete response (CR) rate of 71% and a partial response (PR) rate of 13%. Additionally, 3% of patients had stable disease, 5% experienced progressive disease, and 8% were not evaluable.

The investigator-assessed ORR was 87%, including a 74% CR rate and a 13% PR rate. The stable disease, progressive disease, and not evaluable rates were 0%, 13%, and 0%, respectively.

“During the primary evaluation, we saw excellent and encouraging efficacy with anbal-cel,” lead study author Won-Seog Kim, MD, PhD, a professor in the Division of Hematology-Oncology at Samsun Medical Center in Seoul, South Korea, said in a presentation of the data. “[Responses] seem quite durable, particularly after 3 months.”

Anbal-cel is based on the first-in-class CAR T platform, OVIS, which is being developed by Curocell. OVIS downregulates PD-1 and TIGIT expression on CAR T cells with the goal of delivering improved cytotoxicity to tumor cells in the tumor microenvironment.²

Prior data from the phase 1 dose-escalation portion of the trial presented at the 2022 EHA Congress showed that 11 patients treated across 3 different dose levels of anbal-cel experienced an ORR of 82%, with all responders achieving a CR. The CR rates at doses of 2 x 105 cells/kg (n = 4), 7 x 105 cells/kg (n = 3), and 2 x 106 cells/kg (n = 4) were 75%, 67%, and 100%, respectively.³

The phase 2 trial enrolled patients with diffuse LBCL not otherwise specified (DLBCL-NOS), high-grade B-cell lymphoma (HGBL), primary mediastinal LBCL, or transformed follicular lymphoma who received at least 2 prior lines of therapy; however, prior CD19 targeted therapy was not allowed. Other inclusion criteria included measurable disease and an ECOG performance status of 0 or 1.1

Following leukapheresis, bridging chemotherapy was optional. All patients received lymphodepleting chemotherapy with 30 mg/m2 of fludarabine and 500 mg/m2 of cyclophosphamide on days –5, –4, and –3. Patients in phase 2 received a single infusion of anbal-cel at 2 x 106 cells/kg.

Efficacy was evaluated at day 28 following anbal-cel infusion, then at month 3, and then every 3 months thereafter. IRC-assessed ORR and CR rate served as the trial’s primary end points. Secondary end points included duration of response and progression-free survival assessed by IRC, ORR and CR rate per investigator assessment, cellular kinetics, and safety.

In phase 2, 47 patients underwent leukapheresis as of the April 11, 2023, data cutoff. Six patients did not receive the CAR T-cell therapy due to a failure in manufacturing (n = 4) and not meeting the dosing requirements for anbal-cel (n = 2). Twenty-five patients underwent bridging therapy consisting of bendamustine plus rituximab (Rituxan; n = 9); gemcitabine, dexamethasone, and cisplatin (n = 5); cyclophosphamide, vincristine, and prednisone (n = 4); dexamethasone, high-dose cytarabine, and cisplatin (n = 2); vincristine (n = 2); and other (n = 3).

The 41 patients who received lymphodepletion and anbal-cel were included in the safety population. Three patients were excluded from the efficacy population due to less than 50% of anbal-cel being dosed (n = 1) and a CR following bridging therapy (n = 2).

Among the safety-evaluable population, the median age was 62.8 years (range, 53-72), and 54% of patients were at least 65 years of age. Most patients were male (63%), had DLBCL-NOS (93%), had non–germinal center B-cell cell of origin (76%), and had double expressor type (66%). Twenty-four percent of patients had an ECOG performance status of 1.

Seventy-three percent of patients received 1 or 2 prior lines of therapy, 17% had 3 prior lines of therapy, and 10% were given 4 or more prior lines of therapy. Fifty-six percent of patients were refractory to their last line of therapy, and 56% of patients were refractory to their first line of therapy. Additionally, 71% of patients received prior stem cell transplant.

The median sum of the product of perpendicular diameters (SPD) was 2951 mm2 (range, 1099-4361), and 20% of patients had a SPD of at least 5000 mm2. The median total metabolic tumor volume was 78 (range, 27-218).

Additional data showed that at a median follow-up of 6.3 months, 68% of patients (n = 26/38) were in CR at 1 month, 61% (n = 19/31) were in CR at 3 months, and 60% (n = 12/20) were in CR at 6 months, per IRC assessment. The investigator-assessed CR rates at 1, 3, and 6 months were 66%, 68%, and 65%, respectively.

Regarding safety, all patients experienced any-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs). Thirty-four percent of patients experienced any serious AE, 5% had a TEAE with a fatal outcome, and 5% dropped out of the study due to a TEAE. The rates of drug-related TEAEs, grade 3 or higher TEAEs, and serious AEs were 90%, 88%, and 24%, respectively. One patient (2%) experienced a drug-related TEAE with a fatal outcome, and 1 patient dropped out of the study due to a drug-related TEAE.

The most common AEs included neutropenia, cytokine release syndrome (CRS), thrombocytopenia, anemia, decreased appetite, immune effector cell–associated neurotoxicity syndrome, nausea, stomatitis, fatigue, increased aspartate aminotransferase, asthenia, increased alanine transaminase, chest discomfort, depressed consciousness, epiglottitis, headache, hypofibrinogenemia, mucosal inflammation, myalgia, optic neuritis, fungal pneumonia, pneumonitis, and vomiting.

Any-grade CRS was reported in 63.4% of patients, and 14.6% of patients had grade 3 CRS. The median time to CRS onset was 2.0 days (range, 2-3), and the median duration of CRS was 6.5 days (range, 4-10). Eighty-one percent of patients with CRS received tocilizumab (Actemra), 35% were given steroids, and 23% received a vasopressor.

Any-grade neurologic events occurred in 19.5% of patients, including grade 1 (4.9%), grade 2 (7.3%), and grade 3 (7.3%). The median time to onset of neurologic events was 6.5 days (range, 3-8), and the median duration was 10.5 days (range, 2-91). Recuse medication for neurologic events included tocilizumab (13%), steroids (88%), and antiepileptics (38%).

Other AEs of special interest included prolonged neutropenia (31.7%), prolonged thrombocytopenia (34.1%), prolonged anemia (14.6%), and serious infection (9.8%).

Cellular kinetic data showed that patients who achieved a CR had a greater mean Cmax (58,500 vs 31,300) and a greater mean AUC0-28D (653,600 vs 343,800) vs non responders.

Disclosures: Dr Kim reported receiving research funding from Sanofi, Merck, BeiGene, Roche, Boryong, Celltrion, and Kyowa-Kirin; honorarium from Takeda and ImmuneOncia; and consultation with Celltrion.

References

1. Kim WS, Kim SJ, Yoon SE, et al. Phase 2 study of anbalcabtagene autoleucel novel anti-CD19 CAR-T therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma–interim analysis result. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 045.
2. Curocell announced encouraging updates on the next-generation anti-CD19 CAR-T, Anbalcabtagene-autoleucel at International Conference on Malignant Lymphoma (ICML) 2023. News release. Curocell. June 19, 2023. Accessed June 20, 2023. https://www.prnewswire.com/news-releases/
3. Kim WS, Kim SJ, Yoon SE, et al. Phase 1/2 study of anbalcabtagene autoleucel novel anti-CD19 CAR-T therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B-cell lymphoma. J Clin Oncol. 2022;40(suppl 16):7522. doi:10.1200/JCO.2022.40.16_suppl.7522