Deep and Durable Responses Still Observed With JNJ-4528 in Relapsed/Refractory Myeloma

Jesus G. Berdeja, MD

JNJ-4528, a chimeric antigen receptor (CAR) T-cell therapy, showed continuted deep and durable responses in patients with heavily pretreated relapsed/refractory multiple myeloma in updated findings from the phase 1b/2 CARTITUDE-1 (NCT03548207) trial, which were presented in the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.¹

According to the lead study author Jesus G. Berdeja, MD, the overall response rate (ORR) was 100%, with a stringent complete response (sCR) rate of 86% (25 out of 29 patients). Further, the progression-free survival (PFS) rate was 86% (95% CI, 67%-95%) at 9 months.

The objective of the phase 1b portion of CARTITUDE-1 was to determine the safety of the B-cell maturation antigen (BCMA) and confirm the dose for future research. Phase 2 is investigating the efficacy in terms of ORR, defined by the International Myeloma Working Group (IMWG) response criteria.

Patients were eligible to enroll in CARTITUDE-1 if they had progressive multiple myeloma per IMWG criteria, received 3 or more prior therapy regimens for their disease or were double refractory to a proteasome inhibitor and an immunomodulatory drug, and received an anti-CD38 antibody.

After undergoing screening for 28 days followed by apheresis, patients underwent bridging therapy as needed. From day -5 to day -3, patients received 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine. JNJ-4528 was given as a single infusion on day 1, with a target dose of 0.75 × 106 CAR-positive viable T cells/kg.

“A total of 35 patients were enrolled and underwent apheresis, 30 patients were lymphodepleted, and 29 patients were dosed,” said Berdeja, the director of Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee.

The median age of treated patients was 60 years (range, 50-75) and the median number of years since initial diagnosis was 5 (range, 2-16). High-risk cytogenetic profiling revealed 4 patients (15%) with del(17p), 2 (8%) with translocation t(14;16), and 1 (4%) with translocation t(4;14). Patients underwent a median of 5 (range, 3-18) prior lines of therapy, with 76% of patients being penta-exposed, 86% as triple-refractory, 28% considered penta-refractory, and 97% refractory to the last line of therapy.

Phase 1b enrollment (N = 29 treated) is complete and as of the data cut off of January 17, 2020, median follow up was 9 months (range, 3-17 months).

No unusual safety signals were observed in the study, said Berdeja. Cytokine release syndrome (CRS) was common, with 93% of patients demonstrating all-grade severity and 7% of patients with grade 3 or higher toxicity. The median time to onset of CRS was 7 days (range, 2-12) and the median duration was 4 days (range, 2-64). Twenty-three patients (27%) received tocilizumab (Actemra) and 6 (21%) each received anakinra or corticosteroids.

All-grade neurotoxicity consistent with ICANS (immune effector cell–associated neurologic syndrome) was observed in 10% of patients, with 3% of patients having grade 3 or higher toxicity.

“Other toxicities were hematologic, with 100% of patients experiencing grade 3 or 4 neutropenia,” Berdeja said. All-grade thrombocytopenia was observed in 86% patients with 69% (20 of 29) determined to be grade 3 or higher.

Nonhematologic toxicities were infrequent but were led by all-grade diarrhea in 35%, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in 31% of patients each, and headache in 28%. Grade 3 or higher AST and ALT levels were seen in 7% of patients each.

Regarding cytopenia, Berdeja reported that the median time to first onset of grade 3/4 neutropenia (n = 29) was 0.7 weeks (range, 0.0-1.3) and the median time to recovery was 1.6 weeks (95% CI, 1.3-2.0). For grade 3/4 thrombocytopenia (n = 19), the median time to first onset was 1.9 weeks (range, 0.4-3.5) and the median time to recovery was 5.3 weeks (95% CI, 2.4-8.1).

“Interestingly, we saw that recurrent grade 3/4 cytopenias were observed in some patients but it is unclear if this is a pattern, which we are monitoring closely,” Berdeja said, “Regardless, prolonged severe cytopenias were infrequent.”

All-grade upper respiratory tract infections were reported in 31% of patients. Infections of grade 3/4 severity included pneumonia in 7% of patients, and 3% each for atypical pneumonia, cryptosporidiosis, encephalitis, and sepsis. All infections were reversible, said Berdeja.

Regarding tumor burden reduction, Berdeja said that all but 1 patient had a reduction in their paraprotein.

A very good partial response rate of 97% was reported and Berdeja noted that ORR and depth of response were independent of BCMA expression on myeloma cells at baseline. Median time to response was 1 month (range, 1-3), and median time to CR was 3 months (range, 1-13).

With a median follow-up of 11.5 months (range, 3-17), 22 of 29 patients were alive and progression-free. Berdeja noted 3 deaths in the study that were attributed to CRS, acute myeloid leukemia (treatment unrelated), and disease progression.

Minimal residual disease (MRD) assessment showed that the majority of patients continue to show MRD-negative responses beyond day 28 of treatment. Of the 16 patients with a CR who were evaluable for MRD assessment, 81% were MRD negative at 10-5 or better and 69% were MRD-negative at 10-6.

JNJ-4528 continues to demonstrate a good safety profile, with deep and durable responses. “CRS events were mostly grade 1 to 2 with a median time of onset of 7 days, suggesting that outpatient dosing is feasible,” said Berdeja. He noted that the phase 2 portion of the study is fully enrolled, and phase 2 and 3 studies have been initiated.

In December 2019, the FDA granted JNJ-4528 a Breakthrough Therapy designation based on initial results of the trial that were presented at the American Society of Hematology Annual Meeting.²

_References

1. _{Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38:(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505}
2. _{Janssen announces BCMA CAR-T therapy JNJ-4528 granted U.S. FDA breakthrough therapy designation for the treatment of relapsed or refractory multiple myeloma. News release. December 6, 2019. Accessed May 29, 2019. https://www.janssen.com/janssen-announces-bcma-car-t-therapy-jnj-4528-granted-us-fda-breakthrough-therapy-designation}