NXC-201 Demonstrates Feasibility of BCMA-Directed CAR T-Cell Therapy in Relapsed/Refractory AL Amyloidosis

AL Amyloidosis

The novel anti-BCMA CAR T-cell therapy NXC-201 (formerly HBI0101) displayed safety and elicited hematologic and organ responses in patients with relapsed/refractory amyloid light chain (AL) amyloidosis, including frail patients; however, deaths due to cardiac disease within the first year of treatment were frequent, according to data from a phase 1/2 trial (NCT04720313) presented at the 2023 International Myeloma Society (IMS) Annual Meeting.¹

Findings showed that evaluable patients (n = 9) experienced a hematologic overall response rate (ORR) of 100% with 6 complete responses (CR), 2 very good partial responses (VGPR), and 1 partial response (PR). At day 30, all 6 patients in CR were minimal residual disease (MRD) negative. Organ responses were observed in 5 patients.

During follow-up, 5 patients died due to cardiac disease, including 3 who had progressive disease, 1 who was in VGPR, and 1 who was in PR. One additional patient died due to COVID-19 while in CR. Among patients who died, overall survival (OS) ranged from 3.3 months to 12.2 months.

Regarding safety, 7 patients experienced cytokine release syndrome (CRS) that was grade 1 (n = 2), grade 2 (n = 3), or grade 3 (n = 2). The median time to onset of CRS was 2 days (range, 1-3), and the median duration of CRS was 1 day (range, 1-4). Six of 7 patients who experienced CRS received tocilizumab (Actemra). There were no instances of immune effector cell–associated neurotoxicity syndrome (ICANS).

Although BCMA-targeted CAR T-cell therapies have an established role in the treatment of patients with relapsed/refractory multiple myeloma, unmet needs remain for patients with relapsed/refractory AL amyloidosis. However, BCMA expression on AL plasma cells is lower compared with multiple myeloma plasma cells, and patients with AL amyloidosis are generally frailer due to heart disease, kidney disease, and multi-organ involvement, according to Eyal Lebel, MD, who presented data on NXC-201 at the 2023 IMS Annual Meeting. Lebel is a senior physician and researcher at Hadassah Medical Center in Jerusalem, Israel.

Previously, the FDA granted orphan drug designations to NXC-201 as a potential therapeutic option in patients with multiple myeloma and AL amyloidosis in August 2023 and September 2023, respectively.^2,3

After efficacy and safety was displayed by the investigational CAR T-cell therapy in patients with relapsed/refractory multiple myeloma, patients with relapsed/refractory AL amyloidosis were also enrolled and evaluated on the phase 1 portion of the study.¹

Three prior lines of therapy were required for enrollment, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Patients with AL amyloidosis were also required to have a platelet count of 30 x 10⁹/L, a creatine clearance of at least 20 mL/min, a left ventricular ejection fraction of 40% or higher, and an ECOG performance status of 0 to 2. Lebel noted that the organ function criteria were more permissive than historical inclusion criteria for patients with AL amyloidosis.

The manufacturing time for NXC-201 was 10 days. Patients underwent lymphodepletion consisting of 25 mg/m² of fludarabine and 250 mg/m² of on days –5 to –3 prior to the infusion of the CAR T-cell therapy. Notably, bendamustine was given at 90 mg/m² on days –4 and –3 for patients who had a creatinine clearance of less than 30 mL/min.

In 3x3 dose-escalation, phase 1a portion of the study, patients received NXC-201 at target doses of 150 x 10⁶ CAR T-cells (n = 1), 450 x 10⁶ CAR T cells (n = 2), and 800 x 10⁶ CAR T cells (n = 1). Five patients then received 800 x 10⁶ CAR T cells in phase 1b/2. Among the 9 patients with AL amyloidosis enrolled, 2 were treated on a compassionate basis.

Among the cohort of 9 patients with AL amyloidosis, the median age was 64 years, and 6 patients were male. Two patients had concurrent multiple myeloma, and 7 patients exhibited cardiac involvement. New York Heart Association (NYHA) stages included I (n = 2), II (n = 2), III (n = 2), and IV (n = 3). Notable cytogenetics included t(11;14) (n = 4), t(14;16) (n = 1), 14q deletions (n = 2), and 17p deletions (n = 1). Mayo amyloidosis stages included I (n = 3), II (n = 2), IIIA (n = 3), and IIIB (n = 1).

After treatment, 5 patients experienced an improvement in NYHA stage, including 2 patients who improved from stage III to stage II, 2 patients who improved from stage IV to stage III, and 1 patient who saw a reduction from stage IV to stage II.

Within the initial 2 weeks, patients experienced temporary deterioration in organ function, particularly in the heart and kidneys, Lebel noted. However, these events were manageable and reversible through close monitoring and the provision of supportive care, he said. Acute renal failure occurred in 2 patients, and 1 patient had grade 3 hepatic dysfunction.

Additional safety data showed that 7 patients experienced neutropenia that was grade 1 (n = 1), grade 2 (n = 1), grade 3 (n = 3), and grade 4 (n = 2). Instances of anemia occurred at grade 1 (n = 2), grade 2 (n = 1), and grade 3 (n = 2). Thrombocytopenia was observed at grade 1 (n = 2), grade 2 (n = 1), and grade 4 (n = 1). Four patients experienced grade 3 febrile neutropenia.

Infections were reported in 7 patients, including grade 1 (n = 1), grade 2 (n = 1), and grade 3 (n = 5). All patients experienced hypogammaglobulinemia.

Lebel also highlighted data from the first 50 patients with relapsed/refractory multiple myeloma treated NXC-201 at a target dose of 800 x 10⁶ CAR T cells. This population received a median of 4 prior lines of therapy, 94% were triple-class refractory, and 40% were penta-drug refractory. The ORR was 90%, including a CR/stringent CR rate of 78%. The MRD-negativity rate was 70%. The median progression-free survival was 334 days, and the median OS was not reached.

Ninety-six percent of these patients experienced any-grade CRS; however, the grade 3 CRS rate was 14%. Four percent of patients had grade 1 or 2 ICANS.

References

1. Lebel E, Erenfeld SK, Asherie N et al. Feasibility of a novel academic anti-BCMA chimeric antigen receptor T-cell (CART) (HBI0101) for the treatment of relapsed and refractory AL amyloidosis. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-34.
2. US Food and Drug Administration approves orphan drug designation for NXC-201 as a treatment for multiple myeloma. News release. Nexcella, Inc. August 23, 2023. Accessed September 30, 2023. https://nexcella.com/2023/08/23/u-s-food-and-drug-administration-approves-orphan-drug-designation-for-nxc-201-as-a-treatment-for-multiple-myeloma/
3. U.S. Food and Drug Administration approves orphan drug designation for Nexcella NXC-201 as a treatment for amyloid light chain (AL) amyloidosis. News release. Nexcella, Inc. September 21, 2023. Accessed September 30, 2023. https://nexcella.com/2023/09/21/u-s-food-and-drug-administration-approves-orphan-drug-designation-for-nexcella-nxc-201-as-a-treatment-for-amyloid-light-chain-al-amyloidosis/