SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• Deaths have been reported in the CARTITUDE-1, CARTITUDE-2 and CARTITUDE-4 studies.^1-9
• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-cluster of differentiation 38 (CD38) antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,3,7
  • At a median follow-up of 33.4 months, a total of 35 deaths occurred after CARVYKTI infusion (6 deaths were due to treatment-related adverse events [AEs]; 12 deaths were due to AEs unrelated to treatment; 17 deaths were due to progressive disease).⁷ Study deaths are detailed in Table: CARTITUDE-1: Deaths.
• CARTITUDE-2 (MMY2003) is a phase 2, multicohort, open-label study evaluating CARVYKTI in patients with multiple myeloma (MM) in various clinical settings.⁸ Janssen does not recommend the use of CARVYKTI in a manner that is inconsistent with the approved labeling.
  • Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior lines of therapy (LOTs) and were refractory to lenalidomide.^4,9-11
    • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^4,9
      • At a median follow-up of 29.9 months (range, 3.3-35.6), 5 deaths had occurred after CARVYKTI infusion. The reasons for death were as follows: progressive disease (n=3; day 426, day 550, and day 666), sepsis (n=1; not treatment related; day 394), and pneumonia (n=1; also had an AE of sepsis in addition to coronavirus disease 2019 (COVID-19) pneumonia and was treatment related; day 100).^4,10,11
    • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.¹²
      • At a median follow-up of 15.6 months (range, 1.0-29.2), 1 treatment-related death occurred after CARVYKTI infusion (sepsis, diagnosed on day 30).¹²
  • Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had early relapse after initial therapy with a PI and an immunomodulatory agent.^2,6,13
    • At a median follow-up of 27.9 months (range, 5.2-32.1), 4 deaths had occurred after CARVYKTI infusion. The reasons for death were as follows: progressive disease (n=3) and cardiac arrest (n=1; new event since the last data cutoff and was not treatment related).¹⁰
  • Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after receiving a PI, an immunomodulatory agent, an anti-CD38 antibody, and a noncellular B-cell maturation antigen (BCMA)-directed therapy. Non-cellular BCMA-directed therapy included bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC).^5,14
    • At a median follow-up of 18 months, a total of 12 deaths had occurred after CARVYKTI infusion. A total of 7 deaths occurred in the ADC-exposed group due to progressive disease (n=6) and COVID19 pneumonia (n=1; not treatment related). 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).⁵ Additional details are provided in Table: CARTITUDE-2 (Cohort C) Deaths.
  • Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients who achieved less than complete response (CR) after frontline autologous stem cell transplantation (ASCT).^8,15
    • At a median follow-up of 22.4 months (range, 4.7-39.3), no deaths due to treatment-emergent adverse events (TEAEs) were reported.¹⁵
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI  versus standard care (physician's choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.^16,17
  • AEs were evaluated in the safety population which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arm).¹⁶
  • At a median follow-up of 15.9 months, a total of 39 CARVYKTI patients (18.8%) and 46 standard care patients (22.1%) died in the safety population. Complete details can be found in Table: CARTITUDE-4: Deaths (Median Follow-up of 15.9 Months).^16,18
  • At a median follow-up of 33.6 months, a total of 50 CARVYKTI patients and 82 standard care patients in the safety population died. Complete details can be found in Table: CARTITUDE-4: Deaths (Median Follow-up of 33.6 Months).¹⁷
  • Subgroup Analysis in Patients with Functional High-Risk MM: efficacy and safety outcomes were evaluated in patients who received 1 prior LOT, including the subset of patients with functionally high-risk MM in the CARTITUDE-4 study.¹⁹
    • Among patients who received 1 prior LOT, 11 patients in each of the CARVYKTI and standard care arms died. Of these patients, 7 patients in the CARVYKTI arm and 9 patients in the standard care arm had functionally high-risk MM.¹⁹

PRODUCT LABELING

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;  https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

clinical data - Cartitude-1 - Phase 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI in patients with RRMM who had previously received a PI, an immunomodulatory drug, and an antiCD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^1,3,7

Study Design/Methods

• The study design is presented in the Figure: CARTITUDE-1 Study Design.

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• Overall, of the 113 patients enrolled/apheresed, 101 patients were lymphodepleted and 97 patients were treated with CARVYKTI in the combined phase 1b/2 study.³
• Prior to lymphodepletion, a total of 12 patients discontinued (progressive disease, n=2; withdrawal by subject, n=2; deaths, n=8). Prior to CARVYKTI infusion, 3 patients withdrew from treatment, and 1 patient died.³
• Patients received a median of 6 prior LOT (range, 3-18), 88% of patients were triplerefractory, 42% of patients were penta-refractory, and 99% of patients were refractory to last LOT.^3,7

Safety - Adverse Event - Mortality

• At a median follow-up of 33.4 months (range, 1.5-45.2), a total of 35 deaths had occurred during the study.⁷ Study deaths are presented in Table: CARTITUDE-1: Deaths.
  • A total of 5 new deaths, unrelated to CARVYKTI were reported since the 27.7-month follow-up, including progressive disease (n=3), pneumonia (n=1) and sepsis (n=1).⁷

clinical data - CARTITUDE-2 - PHASE 2 STUDY

CARTITUDE-2 (MMY2003; clinicaltrials.gov identifier: NCT04133636) is an ongoing,      phase 2, open-label, multicohort, single-arm, multicenter study evaluating the efficacy and safety of CARVYKTI in patients with MM in various clinical settings.⁸

• Cohort A is evaluating the efficacy and safety of CARVYKTI in patients who had progressive MM after 1-3 prior LOT and were refractory to lenalidomide.^4,9,12
  • Initial Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with the clinical trial process in 20 patients.^4,9
  • Expansion Subgroup: evaluated the efficacy and safety of CARVYKTI manufactured with a commercial process in 23 patients.¹²
• Cohort B is evaluating the efficacy and safety of CARVYKTI in 19 patients who had early relapse after initial therapy with a PI and an immunomodulatory agent.^2,6,13
  • Early relapse was defined as progression within 12 months after ASCT or from start of anti-MM therapy for patients who have not had an ASCT.^2,6,13
• Cohort C is evaluating the efficacy and safety of CARVYKTI in 20 patients with RRMM after receiving a PI, an immunomodulatory agent, an anti-CD38 antibody, and a noncellular BCMA-directed therapy. Non-cellular BCMA-directed therapy included BsAbs and ADCs.^5,14
• Cohort D is evaluating the efficacy and safety of CARVYKTI with or without lenalidomide maintenance in 17 patients who achieved less than CR response after frontline ASCT.¹⁵

Study Design/Methods

• Key eligibility criteria for Cohort A: adult patients with progressive MM after 13 prior LOT, including a PI and an immunomodulatory drug, who were lenalidomide refractory, had no prior exposure to BCMA-targeting agents or chimeric antigen receptor (CAR) T-cell therapy directed at any target, and had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1.⁸
• Key eligibility criteria for Cohort B: adult patients who received 1 prior LOT including a PI and an immunomodulatory agent, had disease progression per International Myeloma Working Group (IMWG) criteria ≤12 months after ASCT or ≤12 months from the start of anti-MM therapy (for patients who did not receive ASCT), had no prior exposure to BCMAtargeting agents or CAR T-cell therapy directed at any target, and had an ECOG PS of ≤1.⁸
• Key eligibility criteria for Cohort C: adult patients who were previously treated with a PI, an immunomodulatory agent, an anti-CD38 antibody, and a noncellular BCMAdirected therapy (ADC or BsAb as monotherapy or combination therapy), having a diagnosis of MM per IMWG criteria and evidence of progressive MM ≤12 months of last LOT or ≤6 months of prior therapy and refractory to their most recent LOT, with measurable disease at baseline and an ECOG PS of ≤1. BCMA expression was not required for eligibility.^8,14
• Key eligibility criteria for Cohort D: adult patients with a history of 4-8 total cycles of initial therapy (including induction, high-dose therapy and ASCT with or without consolidation), overall best response <CR.^8,15
• Dosing: patients received a single infusion of CARVYKTI at a target dose of 0.75x10⁶ viable CAR+ T cells/kg (target range, 0.5-1.0x10⁶) 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).^4-6
• Primary endpoint: percentage of patients with minimal residual disease (MRD) negativity at the 10^-5 sensitivity level defined by IMWG criteria (assessed by nextgeneration sequencing; clonoSEQ^®).^4-6
• Key secondary endpoints: overall response rate per the IMWG response criteria, duration of response, time and duration of MRD-negativity, and incidence and severity of AEs.^4-6,8

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

Cohort A

• Initial Subgroup: Overall, 20 patients were enrolled, lymphodepleted and treated with CARVYKTI manufactured with the clinical trial process.⁴
  • Patients received a median of 2 prior LOTs (range, 1-3); 95% of patients were refractory to their last LOT.⁴
• Expansion Subgroup: Overall, 24 patients were enrolled and 23 were treated with CARVYKTI manufactured with a commercial process.¹²
  • Patients received a median of 3 prior LOTs (range, 1-3); 95% of patients were refractory to their last LOT.¹²

Cohort B

• Overall, 19 patients were lymphodepleted and treated with CARVYKTI in Cohort B of the CARTITUDE2 study.⁶
• Patients received a median of 1 prior LOT (range, 1-1); 78.9% of patients were refractory to their last LOT.⁶

Cohort C

• 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.⁵
• 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. In total, 30% of patients (n=6) received anti-BCMA as their last line of treatment (n=4 ADC-exposed; n=2 BsAb-exposed).^5,14

Cohort D

• Overall, 17 patients were treated with CARVYKTI in Cohort D of the CARTITUDE-2 study.¹⁵
• In total, all 17 patients had prior ASCT and were previously exposed to a PI and immunomodulatory drug; 17.6% of patients had received prior anti-CD38 monoclonal antibody therapy.¹⁵

Safety - Adverse Event - Mortality - Cohort A

• Initial Subgroup: at a median follow-up of 29.9 months (range, 3.3-35.6), 5 deaths had occurred after CARVYKTI infusion. The reasons for death were as follows: progressive disease (n=3; day 426, day 550, and day 666), sepsis (n=1; not treatment related; day 394), and pneumonia (n=1; also had an AE of sepsis in addition to COVID-19 pneumonia and was treatment related; day 100).^4,10,11
• Expansion Subgroup: at a median follow-up of 15.6 months (range, 1.0-29.2), 1 treatment-related death occurred after CARVYKTI infusion (sepsis, diagnosed on day 30).¹²

Safety - Adverse Event - Mortality - Cohort B

• At a median follow-up of 27.9 months (range, 5.2-32.1), 4 deaths had occurred after CARVYKTI infusion. The reasons for death were as follows: progressive disease (n=3) and cardiac arrest (n=1; new event since the last data cutoff and was not treatment related).¹⁰

Safety - Adverse Event - Mortality - Cohort C

• At a median follow-up of 18 months (range, 0.622.7), 12 deaths had occurred after CARVYKTI infusion.⁵ 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 COVID-19 pneumonia (n=1; not treatment related).⁵

Safety - Adverse Event - Mortality - Cohort D

• At a median follow-up of 22.4 months (range, 4.7-39.3), no deaths due to TEAEs were reported.¹⁵

CLINICAL DATA - CARTITUDE-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is an ongoing, phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.¹⁶

Study Design/Methods

• The study design is shown in Figure: CARTITUDE-4 Study Design.

Results

Treatment Disposition, Patient Demographics, and Disease/Treatment Characteristics

• Overall, 419 patients were randomized to receive CARVYKTI (n=208) or standard care (n=211; DPd [n=183] or PVd [n=28]).¹⁶
  • CARVYKTI as study treatment was administered to 176 patients (84.6%; as-treated population).¹⁶
    • Overall, 33 patients discontinued trial due to disease progression (n=17) or death (n=16); 2 patients died during the survival follow-up.¹⁶
  • Prior to receipt of CARVYKTI, 32 patients discontinued study treatment mainly due to disease progression (n=30) or death (n=2) during bridging therapy or lymphodepletion.¹⁶
    • A total of 10 patients never received CARVYKTI as study treatment; 9 of these patients died during survival follow-up.¹⁶
    • A total of 20 patients received subsequent therapy with CARVYKTI; 10 of these patients died during survival follow-up.¹⁶
  • A total of 208 patients (98.6%) were dosed with standard care. Treatment discontinuation was reported in 131 standard care patients; discontinuation due to death was reported in 5 patients.¹⁶
• High-risk cytogenetics were present in 59.4% of CARVYKTI patients and 62.9% of standard care patients. The median prior LOT in both the CARVYKTI and standard care arms were 2 (range, 1-3).¹⁶

Safety - Adverse Event - Mortality

• AEs were evaluated in the safety population which included all patients who received any part of study treatment (n=208 in both the CARVYKTI and standard care arm).¹⁶

Median Follow-up of 15.9 Months

• At the data cut-off date of November 1, 2022, 143 CARVYKTI patients were ongoing in the post-treatment phase and 77 patients were ongoing on standard care therapy.¹⁶
• At a median follow-up of 15.9 months (range, 0.1-27.3), a total of 39 CARVYKTI patients (18.8%) and 46 standard care patients (22.1%) in the safety population died (one patient in the standard care group died prior to treatment). Complete details can be found in Table: CARTITUDE-4: Deaths (Median Follow-up of 15.9 Months).^16,18

Median Follow-up of 33.6 Months

• At the data cut-off date of May 1, 2024, 117 CARVYKTI patients were ongoing in the post-treatment phase and 43 patients were ongoing on standard care therapy.¹⁷
• At a median follow-up of 33.6 months (range, 0.1-45.0), a total of 50 CARVYKTI patients and 82 standard care patients in the safety population died. Complete details can be found in Table: CARTITUDE-4: Deaths (Median Follow-up of 33.6 Months).¹⁷

CARTITUDE-4: Deaths (Median Follow-up of 33.6 Months)¹⁷

CARTITUDE-4 Subgroup Analysis in Patients with Functional High-Risk MM  

Treatment Disposition, Patient Demographics and Disease/Treatment Characteristics

• A total of 136 patients received 1 prior LOT in CARTITUDE-4.¹⁹
  • In the CARVYKTI arm, 136 patients underwent apheresis/bridging therapy; 40 patients had functionally high-risk MM. Of the 68 patients, 60 received CARVYKTI as study treatment; 35 patients had functionally high-risk MM.¹⁹
  • A total of 68 patients received standard care; 39 of these patients had functionally high-risk MM.¹⁹
  • Functional high-risk MM defined as progressive disease ≤18 months after receiving ASCT or the start of initial frontline therapy in patients with no ASCT.¹⁹

Safety - Adverse Event - Mortality

• Among patients who received 1 prior LOT, 11 patients in each of the CARVYKTI and standard care arms died. Of these, 7 patients in the CARVYKTI arm and 9 patients in the standard care arm had functionally high-risk MM.¹⁹
  • Among the 7 patients that died in the CARVYKTI arm, death occurred in 2 patients that did not receive CARVYKTI as study treatment and in 3 patients that received CARVYKTI as subsequent therapy.¹⁹

CARTITUDE-4 (ONCOLOGY DRUGS ADVISORY COMMITTEE)

• The Food and Drug Administration Oncologic Drugs Advisory Committee (ODAC) reviews and evaluates data regarding the safety and efficacy of marketed and investigational human drug products used in the treatment of cancer and makes appropriate recommendations to the Commissioner of Food and Drugs.²³
• In March 2024, the ODAC reviewed the overall survival data and the risk and benefit of CARVYKTI from the CARTITUDE-4 clinical trial.²⁴
  • With a data cut-off date of December 13, 2023, information on patient deaths within the first 6 months of CARVYKTI infusion can be found in Table: CARTITUDE-4: Total Deaths and Causes of Deaths at 0-≤3 and >3-≤6 Months (ITT Analysis Set).²⁴
  • For more information, reference the following: March 15, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement.²⁴

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 04 November 2024.