Rapid Readout: Updated Results From CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucal In Patients With Relapsed/Refractory Multiple Myeloma

OncLive® Rapid Readout from CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucal In Patients With Relapsed/Refractory Multiple Myeloma

Segment Description: Thomas G. Martin, MD, explains the updated results from CARTITUDE-1, a clinical trial that studied ciltacabtagene autoleucal in patients with relapsed/refractory multiple myeloma, that were presented at the ASH 63rd Annual Meeting in 2021. (Abstract 549)

Segment Body Content:

• Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA) targeting single-domain antibodies, demonstrated early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study in patients with relapsed/refractory multiple myeloma (RRMM) who had been heavily pretreated (Berdeja, Lancet, 2021).
• After a median follow-up of 12.4 months, the overall response rate (ORR; as assessed by independent review committee) was 97%, with 67% of patients achieving stringent complete response (sCR). The 12-month progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively.
• Here, we report updated results from CARTITUDE-1 with longer duration of follow-up (median 18 months).

Methods

• Eligible patients had MM and received ≥ 3 prior therapies, or were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and had received a PI, IMiD, and an anti-CD38 antibody. After apheresis, bridging therapy was permitted.
• Patients received a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg; range 0.5-1.0×106) 5–7 days (d) after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d).
• Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate cilta-cel efficacy (phase 2).
• Response was assessed per IMWG criteria by an independent review committee and minimal residual disease (MRD) negativity at 10-5 by next-generation sequencing. In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS; per Lee et al Blood 2014 grading criteria) and neurotoxicity (by CTCAE v5.0) were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively.

Results

• As of Feb 11, 2021, 97 patients (58.8% male; median age 61.0 years [range 43–78]) received cilta-cel. Patients had received a median of 6 (range 3–18) prior lines of therapy; 83.5% were penta-drug exposed, 87.6% were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to last line of therapy.
• ORR was 97.9% (95% CI: 92.7–99.7); 80.4% of patients achieved sCR, and 94.8% achieved very good partial response or better. The median time to first response was 1 month (range 0.9–10.7), median time to best response was 2.6 months (range 0.9–15.2), and median time to complete response or better was 2.6 months (range 0.9–15.2).
• The median duration of response was 21.8 months (95% CI: 21.8–not estimable). Of 61 patients evaluable for MRD, 91.8% were MRD negative at the 10-5 threshold; MRD 10-5 negativity was sustained for ≥ 6 months in 44.3% (27/61) of patients and ≥ 12 months in 18% (11/61) of patients.
• The 18-month PFS and OS rates were 66.0% (95% CI: 54.9–75.0) and 80.9% (95% CI: 71.4–87.6), respectively. 18-month PFS rates in patients who achieved sustained MRD for ≥ 6 months and ≥ 12 months were 96.3% (95% CI: 76.5–99.5) and 100%, respectively.
• The most common grade 3/4 hematologic AEs in ≥ 25% of patients were neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), thrombocytopenia (59.8%), and lymphopenia (49.5%). There were no fatalities related to cytopenias, and no new safety signals with longer follow-up. CRS occurred in 94.8% of patients (mostly grade 1/2); median time to onset was 7 d (range 1–12), and CRS resolved within 14 d in 98.9% of patients. There was no new CAR T-cell neurotoxicity since the previous report.
• Post cilta-cel infusion, 21 deaths occurred during the study: 0 within first 30 d, 2 within 100 d, and 19 more than 100 d post infusion. Ten deaths were due to disease progression, 6 were treatment-related (as assessed by the investigator), and 5 were due to AEs unrelated to treatment.
• One patient was retreated with cilta-cel (for progressive disease) and had stable disease (per computerized algorithm) post-retreatment with no incidence of CAR T-cell neurotoxicity.

Conclusions

At a longer median follow-up of 18 months, a single cilta-cel infusion led to early, deep, and durable responses in heavily pre-treated patients with MM. Follow-up is ongoing and updated data will be presented. Cilta-cel demonstrated a manageable safety profile with no new safety signals observed with longer follow-up. Further investigations of cilta-cel are ongoing in earlier lines of therapy (CARTITUDE-2 [NCT04133636], CARTITUDE-4 [NCT04181827], and CARTITUDE-5 [NCT04923893]) and in outpatient settings.