SUMMARY

• Janssen does not recommend the use of CARVYKTI in a manner inconsistent with approved labeling.
• CARTITUDE-2 is a phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings. Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with relapsed/refractory multiple myeloma (RRMM) after a proteasome inhibitor (PI), an immunomodulatory drug, an anti-CD38 monoclonal antibody and non-cellular B-cell maturation antigen (BCMA)-directed therapy.^1-4
  • Non-cellular BCMA directed therapy included bispecific antibodies (BsAbs) or antibody-drug conjugates (ADC) as monotherapy or combination line of therapy (LOT).²
• Efficacy outcomes are presented in Table: CARTITUDE-2 Cohort C: Efficacy - Response.
  • At a median follow-up of 18 months, (range 0.6-22.7), 10 patients had minimal residual disease (MRD)-evaluable samples; 7 patients were MRD negative at the 10^-5 threshold (primary endpoint).^3,4
• The most common hematologic adverse events (AEs) (≥20%) of any grade in the ADC-exposed group were neutropenia (92%), anemia (77%), thrombocytopenia (69%), leukopenia (54%) and lymphopenia (46%). The most common hematologic AEs (≥20%) of any grade in the BsAb-exposed group were thrombocytopenia (100%), neutropenia (86%), anemia (57%), leukopenia (57%) and lymphopenia (29%).³
• Cytokine release syndrome (CRS) occurred in 60% of patients (n=12) overall with no grade 3/4 CRS reported. The median time to CRS onset was 7.5 days (range, 2-10) with a median duration of 5.5 days (range, 3-10). CRS resolved in all patients.^3,4
• Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4 patients overall with grade 3/4 events occurring in 2 patients. The median time to ICANS onset was 9 days (range, 4-13) with a median duration of 7 days (range, 4-20). ICANS resolved in 3 patients.³
• No cases of movement and neurocognitive treatment emergent adverse events (TEAEs) (MNTs)/parkinsonism, were reported for patients in Cohort C.^3,4
• A total of 12 deaths have occurred after CARVYKTI infusion; 7 deaths occurred in the ADC-exposed group and 5 deaths occurred in the BsAb-exposed group.^3,4

CLINICAL DATA

CARTITUDE-2 (MMY2003; clinicaltrials.gov identifier: NCT04133636) is an ongoing, phase 2, multicohort, open-label study evaluating CARVYKTI in patients with MM in various clinical settings.^1-4

Cohort C is evaluating the efficacy and safety of CARVYKTI in RRMM after a PI, an immunomodulatory drug, an anti-CD38 monoclonal antibody and non-cellular BCMA-directed therapy.^1-3

• • Non-cellular BCMA directed therapy included BsAbs or ADCs as monotherapy or combination LOT.^2,3

Study Design/Methods

• Key eligibility criteria for Cohort C: adult patients previously treated with a PI, an immunomodulatory drug, an anti-CD38 monoclonal antibody, and a non-cellular BCMA-directed therapy (ADC or BsAb as monotherapy or combination LOT); diagnosis of MM per International Myeloma Working Group (IMWG) criteria and evidence of progressive MM within 12 months of last LOT, or within 6 months of prior therapy and refractory to their most recent LOT; measurable disease at baseline; Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1; BCMA expression was not required for eligibility.^1,2
• Key exclusion criteria for Cohort C: prior treatment with chimeric antigen receptor T (CAR-T) cell therapy directed at any target; ongoing toxicity from previous anticancer therapy must resolve to baseline levels or to grade ≤1 except alopecia or peripheral neuropathy; received a cumulative dose of corticosteroids equivalent to ≥70 mg of prednisone within 7 days prior to apheresis; serious underlying medical condition including active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection; active or history of autoimmune disease within 3 years of study; overt clinical evidence of dementia or altered mental status; history of Parkinson's disease or other neurodegenerative disorder; known active, or prior history of central nervous system (CNS) involvement, or clinical signs of meningeal involvement of MM.^1,2
• Washout Period: patients were excluded from participation in the study if they received prior antitumor therapy as follows, prior to apheresis⁵:
  • Targeted therapy, epigenetic therapy, or treatment with an investigational drug, investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 14 days or at least 5 half-lives, whichever is less, or currently enrolled in an investigational study.
  • Monoclonal antibody treatment for multiple myeloma within 21 days.
  • BCMA-directed ADC or Bispecific T-cell Engager Antibody therapy for multiple myeloma within 5 half-lives of the drug. However, if treated with belantamab mafodotin (GSK2857916) then within 21 days of the drug
  • Cytotoxic therapy within 14 days, PI within 14 days, immunomodulatory agent within 7 days.
  • Radiotherapy within 14 days. However, if the radiation portal covered ≤5% of the bone marrow reserve, the patient is eligible irrespective of the end date of radiotherapy.
• The enrolled patients were screened for up to 28 days followed by apheresis and bridging therapy as needed.^1,3
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75x10⁶ CAR+ T cells/kg (target range, 0.5-1.0 x10⁶) 5-7 days after the start of lymphodepletion/conditioning regimen (cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² daily for 3 days on days -‍5 to -3).^2-4,6
• Retreatment with CARVYKTI was permitted within the same dose range in patients with documented disease progression ≥6 months after CARVYKTI infusion, with at least minimal response, who had no ongoing hematologic (grade ≥3) or non-hematologic (grade ≥2) toxicities.²
• Primary endpoint: percentage of patients with MRD negativity at the 10^-5 sensitivity level defined by IMWG criteria (assessed by next-generation sequencing; clonoSEQ^® V2.0 or next-generation flow).^2-4
  • MRD negativity was assessed in samples that passed calibration or quality control and included sufficient cells for evaluation at the testing threshold of 10⁻⁵ at day 56, and at 6 months, 12 months, 18 months, and 24 months regardless of disease status. An additional sample was collected and assessed at the time of suspected complete response (CR) and every 12 months until disease progression for patients who remained on the study.²
  • A patient was considered to have achieved MRD negativity if ≥1 postbaseline assessment was negative. CR was not a criterion for the primary endpoint.²
• Key secondary endpoints: overall response rate (ORR), rates of very good partial response (VGPR) or better per IMWG criteria, duration of response (DOR), time to response and duration of MRD negativity, incidence and severity of AEs.^1-3
• Exploratory endpoint: progression free survival (PFS).²
• T-cell phenotype analyses: markers included CD45RO/CD27. For better resolution in this analysis, the memory T-cell phenotype specific marker CD27 replaced a previously used CCR7 T-cell marker.⁴
  • Central memory cells: CD45RO⁺/CD27⁺
  • Effector memory cells: CD45RO⁺/CD27^-
  • Naïve T-cells: CD45RO^-/CD27⁺
  • Terminally differentiated effector memory (TEMRA) T-cells: CD45RO^-/CD27^-

Results

Patient Demographics and Disease/Treatment Characteristics

• Overall, 24 patients were enrolled/apheresed and 20 patients (7 patients in BsAb-exposed group and 13 patients in the ADC-exposed group) were treated with CARVYKTI in Cohort C of the CARTITUDE2 study.³
  • Prior to lymphodepletion and CARVYKTI infusion, 4 patients discontinued the study due to low cellular yield (n=2; 1 patient with prior ADC exposure and 1 patient with prior BsAb exposure) or death due to progressive disease (n=2; 1 patient in each group).³
  • As of the June 2022 data cutoff, 8 patients were ongoing in the study (2 patients in BsAb-exposed group and 6 patients in the ADC-exposed group).^3,4
• Patient details are presented in Table: CARTITUDE-2 (Cohort C): Demographics and Disease Characteristics).
• A summary of prior therapies is provided in Table: CARTITUDE-2 (Cohort C): Prior Therapies.
  • Patients received a median of 8 prior LOTs (range, 4-13); 90% of patients were anti-BCMA refractory and 95% of patients were refractory to their last LOT.^2-4
  • In total, 30% of patients (n=6) received anti-BCMA as their last line of treatment (n=4 ADC-exposed; n=2 BsAb-exposed).^2,3
  • One patient had been treated with 2 different ADCs and 1 patient received both ADC and BsAb. This patient was counted in the ADC group for analysis.²
  • The median time from last anti-BCMA agent to CARVYKTI infusion was 180 days (range, 62-749) in the ADC-exposed group and 227 days (range, 84-329) in the BsAb-exposed group.⁴
  • Best responses to prior anti-BCMA treatment were as follows³:
    • Stringent complete response (sCR): ADC (n=1)
    • CR: BsAb (n=1)
    • VGPR: ADC (n=2); BsAb (n=1)
    • Stable/progressive disease: Full cohort (n=15)
• A total of 18 of 20 patients received bridging therapy prior to CARVYKTI infusion.²
  • Of the 18 patients who received bridging therapy: 6 patients had decreased tumor burden between screening and infusion; 3 patients were not evaluable (NE); 8 patients had increased tumor burden and 1 patient had no change.²
  • Of the 2 patients who did not receive bridging therapy, 1 patient had increased tumor burden; 1 patient was NE.²
  • No patient achieved CR after bridging therapy.²
• The median CARVYKTI dose administered was 0.61x10⁶ CAR+ T cells/kg (range, 0.21x10⁶  to 0.83x10⁶). One patient received a below-target dose.⁴
• The median follow-up at data cut-off for the full cohort was 18 months (range, 0.6-22.7).³

Efficacy

• At the time of data cut-off, 8 of 20 patients (6 patients in the ADC-exposed group and 2 patients in the BsAb-exposed group) remained in the study.^3,4
• Efficacy outcomes are presented in Table: CARTITUDE-2 Cohort C: Efficacy – Response.
  • At a median follow-up of 18 months (range, 0.6-22.7), 10 patients had MRD-evaluable samples. A total of 7 patients achieved MRD-negativity at the 10^-5 threshold.³
    • MRD-negativity was achieved in 5 of 7 patients in the ADC-exposed group.^3,4
    • MDR-negativity was achieved in 2 of 3 patients in the BsAb-exposed group.^3,4
• Additional details on factors associated with response in CARVYKTI responders vs non-responders can be found in Tables: CARTITUDE-2 Cohort C: Timing of Anti-BCMA ADC Treatment and CARTITUDE-2 Cohort C: Timing of Anti-BCMA BsAb Treatment.³
  • Response to CARVYKTI was associated with a shorter duration of exposure to last anti-BCMA agent and longer time from last anti-BCMA treatment to apheresis.³
• One patient in the ADC group was retreated with CARVYKTI approximately 16 months after initial infusion (doses of 0.58x10^-6 and 0.53x10^-6 CAR-positive viable T cells/kg). This patient achieved CR after initial infusion but had PD 8 months later. No therapy was administered between CARVYKTI infusions. The second infusion was given 4 days prior to current data cutoff date therefore response is unknown at this time.²

CARTITUDE-2 Cohort C: Timing of Anti-BCMA BsAb Treatment³

Safety

• The most common (all grade) nonhematologic AEs occurring in ≥20% of patients in the full cohort at a median follow-up of 11.3 months are noted in Table: CARTITUDE-2 (Cohort C): Nonhematologic Adverse Events (≥20%, All Grade).²
• The most common hematologic AEs occurring in ≥20% of patients at a median follow-up of 18 months are noted in Table: CARTITUDE 2 (Cohort C): Hematologic Adverse Events (≥20%).³
• The incidence of initial grade 3/4 cytopenias not recovered to grade ≤2 by day 60 was as follows³:
  • Thrombocytopenia: ADC, 31%; BsAb, 43%
  • Lymphopenia: ADC, 23%; BsAb, 0%
  • Neutropenia: ADC, 23%, BsAb, 0%
• A total of 12 deaths have occurred after CARVYKTI treatment.³ Complete details can be found in Table: CARTITUDE-2 (Cohort C): Deaths.
  • A total of 7 deaths occurred in the ADC-exposed group due to progressive disease (n=6) and coronavirus disease of 2019 (COVID-19) pneumonia (n=1; not treatment related).³
  • A total of 5 deaths occurred in the BsAb-exposed group due to progressive disease (n=2), COVID-19 pneumonia (n=1; not treatment related), Clostridium difficile colitis (n=1; treatment related), and subarachnoid hemorrhage (n=1; not treatment related).³

Cytokine Release Syndrome

• CRS occurred in 60% of patients (n=12) overall.^3,4 The incidence and timing/duration of CRS are detailed in Table: CARTITUDE 2 (Cohort C): CRS.
  • The median time to onset of CRS was 7.5 days (range, 2-10) with a median duration of 5.5 days (range, 3-10).³
  • All patients who experienced CRS received ≥1 treatment for it (tocilizumab n=9; anakinra n=3, corticosteroids n=6). CRS resolved in all patients.^2,3

Neurotoxicity

• The incidence of neurotoxicity is detailed in Table: CARTITUDE-2 (Cohort C): Neurotoxicities.³
  • Overall, 4 patients experienced ICANS (2 patients in the ADC-exposed group and 2 patients in the BsAb-exposed group).^3,4 The median time to onset of ICANS was 9 days (range, 4-13) with a median duration of 7 days (range 4-20).³ ICANS resolved in 3 of 4 patients.^3,4
    • For the 1 patient in which ICANS did not resolve, the patient had several other severe conditions, including clostridium difficile (C. difficile) colitis, kidney failure, respiratory failure, and hemophagocytic lymphohistiocytosis. This patient died on study day 17 from C. difficile colitis.^3,6
• No cases of MNTs/parkinsonism, were reported for patients in Cohort C.^2-4
  • Since implementation, patient management strategies across the CARTITUDE program have reduced the incidence of MNTs/parkinsonism.³

Pharmacokinetics and Biomarkers

• CARVYKTI pharmacokinetics was characterized by CAR transgene levels and CAR-positive cells in peripheral blood and bone marrow.²
• Post infusion, an initial expansion phase of the CAR transgene, with time to maximum concentration around 15 days (range, 9-41), followed by a rapid decline phase and then a slower decline over months was observed. The median time to last measurable CAR transgene was approximately 127 days (range, 15-213).²
• CAR transgene exposure parameters including maximum concentration (C_max) and area under the concentration-time curve from time 0 to 28 days (AUC_0-28d) showed slightly higher mean values in the BsAb group compared to the ADC group. Similar observations were noted when measuring CAR-positive cells in the blood.²
• Prior to CARVYKTI infusion, the mean serum BCMA baseline level was 211 ug/L (range, 0.4-943) and 203 ug/L (range, 1.3-541) for the ADC and BsAb groups, respectively. Serum BCMA decreased after CARVYKTI infusion, with mean serum concentrations reaching nadir levels near the lower limit of quantification around day 100.^2,3
  • All patients with PD on study (n=9) had serum BCMA levels at the time of progression similar to baseline levels prior to CARVYKTI treatment. No correlation was identified between baseline BCMA and clinical response.²
• At baseline, 3 patients in the ADC group (23%) were positive for antidrug antibodies (ADA). There was no increase in ADA observed during follow-up. No patients in the BsAb group were positive for ADA at baseline or during follow-up.²

CD4+ and CD8+ T-cell phenotype

• The majority of CD4⁺ T-cells were central memory cells and CD8⁺ T-cells consisted of high proportions of central memory cells, stem cell-like memory cells and TEMRA cells at apheresis. Patients with prior ADC vs prior BsAb exposure exhibited similar T-cell phenotypes. See Figure: T-cell Phenotype at Apheresis in Patients with Prior ADC or BsAb Exposure for additional details.⁴
• In ADC-exposed and BsAb-exposed groups, central memory CAR⁺ T-cells were dominant in both CD4⁺ and CD8⁺ T-cell compartments at peak of CAR⁺ T-cell expansion (T_max). See Figure: CAR+ T-cell Phenotype at Peak Expansion in Patients With Prior ADC or BsAb Exposure for additional details.⁴

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 23 August 2024.