NXC-201 CAR T-Cell Therapy Displays Early Activity in Relapsed/Refractory Light Chain Amyloidosis

NXC-201 in relapsed/refractory light chain amyloidosis

| © Oleksandr - stock.adobe.com

The BCMA-directed CAR T-cell therapy NXC-201 led to fast-onset responses that proved durable and were characterized by low-grade cytokine release syndrome (CRS) and no neurotoxicity in patients with relapsed/refractory light chain (AL) amyloidosis, according to initial data from the phase 1/2 NEXICART-2 trial (NCT06097832) that were presented at the 2025 ASCO Annual Meeting.¹

At a median follow-up of 121 days (range, 29-289), the percentage change in the difference between the involved and uninvolved free light chain (dFLC)/M-spike level from baseline ranged from 96.75% to 100.00%. A total of 70% (n = 7/10) of patients achieved a complete hematologic response (CRh), and the time to first response ranged from 7 days to 15 days. At data cutoff, no hematologic relapse or disease progression had occurred. The remaining 3 patients were immunofixation positive but minimal residual disease negative in the bone marrow.

Investigators also showed evidence of rapid normalization of pathologic paraprotein levels associated with organ responses (n = 4/5). Notably, both patients with cardiac-evaluable disease achieved a cardiac response at months 1 and 3; 2 of 3 patients with renal-evaluable disease responded at months 1 and 4. The third patient developed renal progression within the first month, but none developed cardiac progression. Additionally, one patient improved from New York Heart Association (NYHA) class II to class I at day +15.

“Initial results from NEXICART-2 suggest NXC-201 can be administered safely and efficiently to patients with relapsed/refractory AL amyloidosis,” Heather Jolie Landau, MD, lead study author and bone marrow transplant specialist and cellular therapist at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation.

Trial Background, Enrollment Criteria, and Baseline Characteristics

In January 2021, the FDA granted accelerated approval to daratumumab plus hyaluronidase (Darzalex Faspro) in combination with bortezomib (Velcade), cyclophosphamide and dexamethasone for patients with newly diagnosed AL amyloidosis.² However, upon disease progression, patients are left with limited options.

“The anti-CD38 antibody daratumumab has transformed the treatment of [patients with] this disease in the upfront setting based on the phase 3 ANDROMEDA trial [NCT03201965] results, which showed a 60% CR rate in that population. That means [approximately] 40% of patients have lesser responses and may need alternative therapy, and of the patients who do respond to daratumumab, there will be subsequent relapses,” Landau said.

“BCMA has emerged as an extremely valuable target in patients with plasma cell diseases, and NXC-201 is a unique CAR T-cell [therapy] that targets BCMA. NXC-201 is a sterically optimized construct that has been modified in three key locations to decrease non-specific activation, reduce cytokine release, and enhance plasma cell binding, and it can be manufactured in 10 days,” Lindau added.

The open-label, single-arm, multi-site trial enrolled 40 patients with relapsed/refractory AL amyloidosis.¹ Inclusion criteria consisted of exposure to at least 1 line of therapy, including a CD38 monoclonal antibody and proteasome inhibitor, and measurable hematologic disease, defined by one of the following: dFLC above 50 mg/L, M-spike above 0.5 mg/dL, and dFLC above 20 mg/L with an abnormal kappa lambda ratio.

“We also allowed patients with dFLC greater than 20 mg/L based on several lines of evidence that show patients with even low levels of circulating amyloidogenic light chains can have further organ deterioration and poor outcomes, and suppression of that light chain to lower levels results in more optimal outcomes,” Landau stated.

Exclusion criteria included prior BCMA-directed therapy, Mayo stage 3b and NYHA class III/IV cardiac function, and concomitant symptomatic multiple myeloma.

Key outcome measures for phase 1 included safety and independent review committee–assessed efficacy based on CRh. In phase 2, outcome measures included safety and efficacy by CR based on validated criteria in AL amyloidosis.

The study opened for accrual in June 2024. Data cutoff was April 11, 2025, at which point the phase 1 portion of the trial had concluded. Within this phase, no dose-limiting toxicities occurred at the two investigational doses: 150 x 10⁶ (n = 3) and 450 x 10⁶ (n = 7). Phase 2, which is ongoing, is evaluating a dose of 450 x 10⁶ (n = 5), with an additional 25 patients expected to enroll.

Baseline patient characteristics revealed that the median age was 67 years (range, 56-82). Patients were heavily pretreated having received a median of 4 (range, 2-12) prior lines of therapy. Seventy percent of patients had prior autologous stem cell transplant and 70% had cardiac involvement. “While at diagnosis most patients had advanced cardiac disease at enrollment the disease was less advanced, or they had lower levels of Mayo stage because our practice is to treat patients before they develop progression or further advanced disease,” Landau said.

Laboratory values indicated that the median dFLC was 56 mg/L (range, 24-121) and the median NT-ProBNP was 425 ng/L (range, 143-1297). The median high-sensitivity troponin-I level was 9 ng/L (range, 6-52), median creatinine was 1.0 mg/dL (range, 0.7-2.7) and median albuminuria was 143 mg/24-hour period. “We also were liberal in our eligibility criteria, and at least one patient had very advanced kidney disease with significant proteinuria, and two others had more modest kidney disease,” Landau noted.

All patients received treatment within 14 days.

Key Safety Findings and Next Steps

With respect to safety, the following adverse effects occurred in evaluable patients (n = 10): CRS (grade 1, n = 7; grade 2, n = 1), neutropenia (grade 2, n = 2; grade 3, n = 3; grade 4, n = 5), febrile neutropenia (grade 3, n = 1), anemia (grade 1, n = 6; grade 2, n = 2; grade 3, n = 2), thrombocytopenia (grade 1, n = 5; grade 2, n = 1; grade 3, n = 2; grade 4, n = 1), acute kidney injury (grade 4, n = 1), liver function test abnormalities (grade 1, n = 1; grade 2, n = 1), grade 3 or greater infections (grade 3, n = 2; grade 5, n = 1), fatigue (grade 1, n = 1; grade 2, n = 3), and cardiac events (grade 2, n = 2).

“Two of our patients also had additional grade 3 infections that were easily managed with intravenous antibiotics and none of our patients had any unexpected cardiac toxicity or any lasting cardiac toxicity,” Lindau said.

The median grade of CRS was 1 (range, 1-2), and the median time to onset was 1 day (range 1-3). The median duration of CRS was 1 day (range, 1-4). “The onset of CRS in this trial was quick and the duration was short because we mandated prompt initiation of tocilizumab [Actemra],” Lindau said. No neurotoxicity occurred. One death occurred 5 months after treatment, but it was deemed unrelated to NXC-201.

Based on these data a multicenter trial evaluating NXC-201 is ongoing and open to accrual, Landau concluded.

Disclosures: Landau has consulting or advisory roles with Abbvie/Genentech, Nexcella, and Prothena. She also received research funding from Alexion Pharmaceuticals, Janssen Oncology, Nexcella, Protego Biopharma, and Prothena.

References

1. Landau HJ, Hughes C, Rosenberg A, et al. Safety and efficacy data from Nexicart-2, the first US trial of CAR-T in R/R light chain (AL) amyloidosis, Nxc-201. J Clin Oncol. 2025;43(suppl 16):7508. doi:10.1200/JCO.2025.43.16_suppl.7508
2. FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis. FDA. January 15, 2021. Accessed June 3, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis