LEGEND-2 and CARTITUDE-1: CAR T for relapsed/refractory multiple myeloma

During the 61^st American Society of Hematology annual meeting, two abstracts reported results from trials using the chimeric antigen receptor (CAR) T-cell product known as LCAR-B38M in China and JNJ 68284528 (JNJ 4528) in the United States (U.S), in patients with relapsed/refractory (R/R) multiple myeloma (MM, RRMM).^1,2 This article summarizes these presentations, and provides context to the future directions of this CAR T-cell therapy in MM.

Background^1–3

LCAR-B38M is a structurally differentiated CAR T-cell therapy with a 4-1BB costimulatory domain and two B-cell maturation antigen (BCMA)-targeting domains.¹ JNJ 4528 is an identical CAR to LCAR B38M.²

The first reported results from LEGEND-2 (NCT03090659), a phase I, first-in-human (FIH) trial in 57 patients with RRMM treated at four sites in China, were published in December 2018 in the Journal of Hematology and Oncology. The conditioning regimen, number of CAR T infusions and number of CAR T-cells administered, varied between sites. The published results showed that LCAR-B38M had a manageable safety profile and elicited durable responses at a median of eight months follow-up. The overall response rate (ORR) was 88% (95% CI, 76–95) with 68% of patients achieving a complete response (CR). Additionally, 63% of patients were minimal residual disease (MRD) negative, and median overall survival (OS) was not reached (NR).³ Read more about these results on the MM hub here.

LEGEND-2¹

Long-term follow-up data from the phase I LEGEND-2 trial were presented by Bai-Yan Wang, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, CH at the 61^st ASH meeting on Monday 9^th December 2019. The data were from the Xi’an site specifically and reported results from 57 patients at a median follow-up of 25 months.

Patient characteristics

• Patients (N= 57) with active RRMM who had relapsed to prior regimens were enrolled:
  • Median age: 54 (27–72)
  • Eastern Cooperative Oncology Group (ECOG) performance score (0 vs 1 vs 2): 37% vs 47% vs 16%
  • Median prior lines of therapy: 3 (1–9)
  • Prior proteasome inhibitor (PI) exposure: 68%
  • Prior immunomodulatory drug (IMiD) exposure: 86%
  • Prior PI + IMiD: 60%

Xi’an site protocol

• Lymphodepletion: cyclophosphamide (300mg/m²) alone for three days
• LCAR-B38M was administered across three infusions:
  • Day 1: 20%
  • Day 3: 30%
  • Day 7: 50%
  • Median CAR T-cell dose: 0.5x10⁶ cells/kg (range, 0.07–2.1x10⁶ CAR T-cells/kg)
• Primary objective: safety
• Secondary objective: anti-myeloma response

Safety

• Adverse events (AEs) were reported by all patients
• Cytokine release syndrome (CRS): 90%
  • Grade 1 vs 2 vs 3: 47% vs 35% vs 7%
  • No grade 4 or 5 CRS events
  • Median time to onset of CRS: 9 (1–19) days
  • Median duration of CRS: 9 (3–57) days
  • Tocilizumab was given in 46% of cases to treat CRS
• Other grade ≥3 AEs were:
  • Pyrexia: 20%
  • Thrombocytopenia: 23%
  • Leukopenia: 30%
  • Increased aspartate aminotransferase (AST): 21%
  • Anemia: 18%
  • Hypotension: 5%
• One patient reported a neurotoxicity event, which was grade 1
• Deaths on study and during follow-up: 17
  • Predominantly due to progressive disease (PD): 11

Efficacy

Efficacy results were comparable between subgroups, including when based on prior lines of therapy. Full efficacy results are shown below in Table 1. Median time to first response was 1.1 month (95% CI, 0.4–3.6) and median duration of response (mDOR) was 27 months (14.3–not evaluable [NE]).

Table 1. Efficacy results from LEGEND-2 study at the Xi’an site

Median PFS was prolonged over two years in patients who achieved a CR, with a 30-month PFS of 48.5% compared to 0% for patients who did not achieve a CR. This was also true of OS with a 30-month OS of 75.5% for patients in CR and 20% for those not in CR. Patients achieving a CR also had a longer mDOR of 29.1 months (95% CI, 19.9–NE).

Conclusion

Long-term follow-up of the LEGEND-2 trial showed a high ORR with deep responses at a median follow up of 25 months. Results from 17 patients treated at the three remaining sites in China were reported as a poster at the 61^st ASH meeting with a median follow-up of 26 months. These results were consistent with the results presented by Dr Wang as above, despite differing conditioning regimens and number of CAR T infusions.⁴

CARTITUDE-1²

On Monday 9^th December 2019, Deepu Madduri, Icahn School of Medicine at Mount Sinai, New York, US, presented the phase Ib results from the CARTITUDE-1 (NCT03548207) trial of JNJ 4528 in patients with RRMM in the U.S. CARTITUDE-1 is a phase Ib/II dose confirmation study based on the FIH LEGEND-2 study.² The median follow-up was 6 months, as per a data cut-off of 6^th November 2019.

Patients with RRMM who had received ≥3 prior regimens or were double refractory to a PI and IMiD and had received anti-CD38 therapy were enrolled. Patients also had measurable, progressive disease with an ECOG performance score ≤1.²

Bridging chemotherapy was permitted, if necessary, following the screening and apheresis process and was followed by conditioning with cyclophosphamide (300mg/m²) and fludarabine (30mg/m²) over three days. Five to seven days after conditioning began, JNJ 4528 was administered as a single infusion at a target dose of 0.75x10⁶ cells/kg (aim: 0.5–1.0x10⁶, median: 0.73x10⁶).² This is in comparison to the three infusions administered in LEGEND-2.¹  Median follow-up at data cut off was six months.

The primary objective of the phase Ib study, as reported here, was to determine the safety of JNJ 4528 and confirm recommended phase II dose (RP2D).²

Patient characteristics (N= 29):²

• Median age: 60 (50–75)
• Median prior lines of treatment: 5 (3–18)
• High-risk cytogenetics: 25%
• Bridging therapy was administered to 83% of patients
• Patients were heavily pretreated:
  • Triple refractory to PI, IMiD, and anti-CD38 antibody: 86%
  • Penta-exposed: 72%
  • Penta-refractory: 31%

Safety

• CRS: 93%
  • Maximum CRS grade (1 vs 2 vs 3 vs 4 vs 5): 48% vs 38% vs 3% vs 0% vs 3%
    • One patient experienced a grade 5 AE
  • Median time to onset: 7 (2–12) days
    • Over 90% of the events were between day 5 and day 9
  • Median duration of CRS: 4 (1–60) days
  • For CRS management, tocilizumab was given to 76% of patients and corticosteroids were given to 21%
  • Three events of CAR T-cell related neurotoxicity were observed, with one grade 3 event
• Hematologic grade ≥3 AEs:
  • Neutropenia: 93%
  • Thrombocytopenia: 69%
  • Anemia: 55%
  • Leukopenia: 52%
  • Lymphopenia: 31%
• Non-hematologic grade ≥3 AEs were uncommon

Efficacy

• ORR was 100%, with 69% achieving ≥CR, and 86% achieving ≥very good PR (VGPR; Table 2)
• All patients had a reduction in tumor volume and none had progressed at data cut-off
• Response rates were independent of baseline BCMA expression and deepened over time
• Twenty-seven patients were progression-free at a median of 6 months follow-up
• The patient who experienced a grade 5 AE was in CR at the time of death
• MRD status: 23 patients had evaluable bone marrow samples at baseline and at 28-days post-infusion, as assessed by next generation sequencing:
  • Seventeen were evaluable for response
  • 100% of these patients were MRD-negative (10^-4–10^-6) at day 28
• Median time to first response: 1 month (range, 1–3)
• Median time to ≥CR: 1 month (range, 1–9)

Table 2. Efficacy of JNJ 4528 from CARTITUDE-1 trial

Expansion and persistence

• Median time to peak expansion: 13 days post-infusion
• 40% of patients had detectable CD3⁺ CAR T-cells at three months. These did not correlate with deepening of response
• At peak expansion, there was a preferential CD8⁺ central memory phenotype observed

Conclusion

CARTITUDE-1 confirmed the RP2D of 0.75x10⁶ cells/kg for patients with RRMM. This dose delivered early responses that continued to deepen over time. The ORR was 100%, with 86% of patients achieving a VGPR or better. The safety profile was manageable, with mainly grade 1–2 CRS events. The safety and efficacy of JNJ 4528 was consistent with that reported in LEGEND-2, which indicates that this CAR T-cell product is efficacious across ethnicities since LEGEND-2 enrolled Chinese patients and CARTITUDE-1 enrolled American patients.

Watch the interview with Deepu Madduri in the Video Interview section below or click here.

Regulatory approvals

In December 2019, the US Food & Drug Administration (FDA) announced that JNJ 4528 had been granted breakthrough therapy designation.⁵ This followed previous announcements by the FDA and European Medicines Agency (EMA) that JNJ 4528 had been granted orphan drug designation, and Priority Medicines (PRIME) designation, respectively, for the treatment of RRMM.^5,6

Future directions

In China, the confirmatory CARTIFAN-1 study (NCT03758417) is ongoing.⁷  In the US, the CARTITUDE-1 trial is ongoing, with CARTITUDE-2 (NCT04133636) and CARTITUDE-4 (NCT04181827) also enrolling patients.^8,9

• CARTIFAN-1: phase II study to evaluate the efficacy and safety of LCAR-B38M CAR T-cells in Chinese patients with RRMM. The primary outcome measure of this study is ORR.⁷
• CARTITUDE-2: phase II multicohort study to investigate the efficacy and safety of JNJ 4528. Primary outcome measure: MRD-negative rate. Patients will receive a single infusion of JNJ 4528, with patients in cohort D additionally receiving oral lenalidomide⁸
  • Cohort A: progressive disease following one to three prior lines of therapy
  • Cohort B: early relapse after frontline therapy
  • Cohort C: patients with RRMM following PI, IMiD, daratumumab, and anti-BCMA therapy
  • Cohort D: patients in <CR following autologous stem cell transplant frontline therapy
• CARTITUDE-4: phase III study of JNJ 4528 compared to standard therapy in patients with relapsed and lenalidomide-refractory MM. Primary outcome measure: PFS⁹
  • Arm A: pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd)
  • Arm B: One or two cycles of PVd or DPd and then JNJ 4528 single infusion at a target dose of 0.75 x 10⁶ cells/kg

Conclusion

CAR T-cell therapy is a hot topic in MM, with several presentations at the recent 61^st ASH meeting presenting promising results in patients with R/R disease. However, there are still many outstanding questions that will need to be answered before CAR T finds its place in the treatment pathway for MM. For example, will bispecific antibodies challenge the role of CAR T? Additionally, there is debate surrounding when CAR T should be used; should it be in first relapse, or remain in the R/R setting?  

Read more about CAR T therapy in myeloma here, about bispecific antibodies in hematological malignancies here and about the debate surrounding the use of CAR T in first relapse here.