Carvykti

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XL05 Mechanism of action CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA.​‍​​​​​‍​‍‍‍‍​‍‍ BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3‑zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells. Pharmacodynamic effects In vitro co-culture experiments demonstrated that ciltacabtagene autoleucel-mediated cytotoxicity and cytokine release (interferon-gamma, [IFN-γ], tumour necrosis factor alpha [TNF-α], interleukin [IL]-2) were BCMA-dependent. Clinical efficacy and safety CARTITUDE-1 (Study MMY2001) MMY2001 was an open label, single-arm, multicentre, Phase 1b/2 study evaluating the efficacy and safety of CARVYKTI for the treatment of adult patients with relapsed and refractory multiple myeloma who had received at least 3 prior lines of antimyeloma therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody and who had disease progression on or within 12 months after the last regimen. Patients with known active, or prior history of significant central nervous system (CNS) disease including CNS multiple myeloma, patients previously exposed to other anti-BCMA treatments, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance < 40 mL/min, absolute lymphocyte concentration < 300/µL, hepatic transaminases > 3 times the upper limit of normal, cardiac ejection fraction < 45%, or with active serious infection were excluded from the trial. In total, 113 patients underwent leukapheresis; CARVYKTI was manufactured for all patients. Sixteen patients were not treated with CARVYKTI (n=12 after leukapheresis and n=4 after lymphodepleting therapy), due to either withdrawal by patient (n=5), progressive disease (n=2) or death (n=9). Of the 97 patients treated, the median time from the day after receipt of leukapheresis material at manufacturing facility to release of medicinal product for infusion was 29 days (range: 23 to 64 days) and the median time from initial leukapheresis to CARVYKTI infusion was 47 days (range: 41 to 167 days). Following leukapheresis and prior to administration of CARVYKTI, 73 of the 97 patients (75%) received bridging therapy. The most commonly used agents as bridging therapies (≥20% of patients) included dexamethasone: 62 patients (63.9%), bortezomib: 26 patients (26.8%), cyclophosphamide: 22 patients (22.7%), and pomalidomide: 21 patients (21.6%). CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy (cyclophosphamide 300 mg/m2 intravenously daily and fludarabine 30 mg/m2 intravenously daily for 3 days). Ninety-seven patients received CARVYKTI at a median dose of 0.71 × 106 CAR-positive viable T cells/kg (range: 0.51 to 0.95 × 106 cells/kg). All patients were hospitalised for the CARVYKTI infusion and for a minimum of 10 days afterward. Table 6: Summary of patient demographic and baseline characteristics Analysis set All Treated (N=97) All Leukapheresed (N=113) Age (years) Category n (%) < 65 65 – 75 > 75 Median (range) 62 (64) 27 (28) 8 (8) 61.0 (43; 78) 70 (62) 34 (30) 9 (8) 62 (29; 78) Sex Male n (%) Female n (%) 57 (59) 40 (41) 65 (57.5) 48 (42.5) Race American Indian or Alaska native Asian Black or African American Native Hawaiian or other Pacific islander White Multiple Not reported 1 (1) 1 (1) 17 (17.5) 1 (1) 69 (71) 0 8 (8) 1 (1) 1 (1) 17 (15) 1 (1) 83 (73.5) 0 10 (9) ECOG score prior to infusion n (%) 0 1 2 39 (40) 54 (56) 4 (4) 55 (49) 58 (51) - ISS staging at study baseline n (%) N I II III 97 61 (63) 22 (23) 14 (14) 58 32 (55) 21 (36) 5 (9) Creatinine Clearance/eGFR (MDRD) (mL/min/1.73m 2 ) Median (range) 88.44 (41.8, 242.9) 73.61 (36.2, 177.8) Time since initial multiple myeloma diagnosis to enrollment (years) Median (range) 5.94 (1.6; 18.2) 5.73 (1.0; 18.2) Presence of extramedullary plasmacytomas n (%) Yes No 13 (13) 84 (87) NA a NA a Cytogenetic risk at study baseline n (%) Standard risk High risk Del17p T(4;14) T(14;16) Unknown 68 (70) 23 (24) 19 (20) 3 (3) 2 (2) 6 (6) 70 (62) 28 (25) 22 (19.5) 5 (4) 3 (3) 15 (13) Tumour BCMA expression (%) Median (range) 80 (20; 98) 80 (20; 98) Number of lines of prior therapies for multiple myeloma Median (range) 6 (3,18) 5 (3, 18) Prior treatment with PI+IMiD+anti-CD38 antibodies n (%) 97 (100) 113 (100) Prior autologous SCT n (%) 87 (90) 99 (88) Prior allogeneic SCT n (%) 8 (8) 8 (7) Refractory at any point to prior therapy n (%) 97 (100) 113 (100) Refractory to PI+IMiD+anti-CD38 antibody n (%) 85 (88) 100 (88.5) Refractory to last line of prior therapy n (%) 96 (99) 112 (99) ECOG= Eastern Cooperative Oncology Group; ISS= International Staging System; PI= Proteasome inhibitor; IMiD= Immunomodulatory drug; SCT= Stem cell transplant; NA= not applicable. a Plasmacytomas were not assessed until prior to lymphodepletion. Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 7). Table 7: Efficacy results for Study MMY2001 Analysis set All Treated (N=97) All Leukapheresed (N=113) Overall Response Rate (sCR a + VGPR + PR) n (%) 95% CI (%) 95 (97.9) (92.7, 99.7) 95 (84.1) (76.0, 90.3) Stringent complete response (sCR) a n (%) 80 (82.5) 80 (70.8) Very good partial response (VGPR) n (%) 12 (12.4) 12 (10.6) Partial response (PR) n (%) 3 (3.1) 3 (2.7) Duration of Response (DOR) (months) Median (95% CI) NE (28.3, NE) - DOR if best response is sCR a (months) Median (95% CI) NE (28.3, NE) - Time to Response (months) Median (Range) 0.95 (0.9; 10.7) - MRD negativity rate n (%) c 95% CI (%) 56 (57.7) (47.3, 67.7) 56 (49.6) (40.0, 59.1) MRD negative patients with sCR n (%) c 95% CI (%) 42 (43.3) (33.3, 53.7) 42 (37.2) (28.3, 46.8) CI=confidence interval; MRD= Minimal Residual Disease; NE= not estimable Notes: Based on a median duration of follow up of 28 months a All complete responses were stringent CRs. b The estimated DOR rate was 60.3% (95% CI: 49.6%, 69.5%) at 24 months and 51.2% (95% CI: 39.0%, 62.1%) at 30 months. c Only MRD assessments (10 -5 testing threshold) within 3 months of achieving CR/sCR until death / progression / subsequent therapy (exclusive) are considered. All complete responses were stringent CRs. MRD negativity rate [(%) 95% CI] in evaluable patients (n=61) was 91.8% (81.9%, 97.3%). CARTITUDE-4 (Study MMY3002) MMY3002 is a Phase 3 randomised, open label, multicentre trial evaluating the efficacy of CARVYKTI for the treatment of patients with relapsed and lenalidomide-refractory multiple myeloma, who previously received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. A total of 419 patients were randomised to received either a sequence of apheresis, bridging therapy, lymphodepletion and CARVYKTI (n=208) or standard of care which included physician's choice of daratumumab, pomalidomide and dexamethasone or bortezomib, pomalidomide and dexamethasone (n=211). The trial excluded patients with known active or prior history of central nervous system involvement, clinical signs of meningeal involvement of multiple myeloma, a history of Parkinson's disease or other neurodegenerative disorder, previous exposure to other anti BCMA treatments or CAR T cell therapy directed at any target, allogenic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, or autologous stem cell transplant within 12 weeks before apheresis. Of the 419 patients who were randomised (208 to CARVYKTI and 211 to standard of care), 57% were male, 75% were caucasian, 3% were black or african-american, and 7% were hispanic or latino. The median patient age was 61 years (range: 28 to 80 years). Patients had received a median of 2 (range: 1 to 3) prior lines of therapy and 85% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-nine percent of patients were refractory to their last line of prior therapy. Forty-eight percent were refractory to a proteasome inhibitor (PI) and 100% were refractory to an immunomodulatory agent. All 208 patients randomised to the CARVYKTI arm underwent apheresis. Following apheresis and prior to administration of CARVYKTI, all 208 randomised patients received protocol mandated bridging therapy (standard of care). Of these 208 patients, 12 were not treated with CARVYKTI due to progressive disease (n=10) or death (n=2), and 20 progressed prior to infusion with CARVYKTI but were able to receive CARVYKTI as subsequent therapy. In the 176 patients that received CARVYKTI as study treatment, the median time from the day after receipt of apheresis material at manufacturing facility to release of product for infusion was 44 days (range: 25 to 127 days) and the median time from first apheresis to CARVYKTI infusion was 79 days (range: 45 days to 246 days). CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy (cyclophosphamide 300 mg/m2 intravenously daily and fludarabine 30 mg/m2 intravenously daily for 3 days) at a median dose of 0.71×106 CAR-positive viable T-cells/kg (range: 0.39 to 1.07×106 cells/kg). The primary efficacy measure was progression-free survival (PFS) analysed based on the Intent-To-Treat Analysis Set. After a median follow-up of 15.9 months, median PFS was 11.8 months (95% CI: 9.7, 13.8) for the standard of care arm and NE (95% CI: 22.8, NE) for the CARVYKTI arm (Hazard ratio: 0.26 [95% CI: 0.18, 0.38], p-value <0.0001). The estimated PFS rate at 12 months was 75.9% (95% CI: 69.4%, 81.1%) in the CARVYKTI arm and 48.6% (95% CI: 41.5%, 55.3%) in the standard of care arm. In the CARVYKTI arm, the estimated median duration of response (DOR) has not been reached. In the standard of care arm, the estimated median DOR was 16.6 months (95% CI: 12.9, NE). After a median follow-up of 15.9 months, median overall survival (OS) was NE (95% CI: NE, NE) for the CARVYKTI arm and 26.7 months (95% CI: 22.5, NE) for the standard of care arm (Hazard ratio: 0.78 [95% CI: 0.50, 1.20]; p-value = 0.2551). Of the 176 patients who received CARVYKTI as study treatment, the median progression‑free survival (PFS) was not estimable (95% CI: not estimable, not estimable) with a 12 months PFS rate of 89.7%. The overall response rate (ORR) in these patients was 99.4% (95% CI: 96.9%, 100.0%). The rate of CR/sCR was 86.4% (95% CI: 80.4%, 91.1%). MMY3002 updated efficacy results At the protocol specified second interim analysis in Study MMY3002 at a median follow-up of 33.6 months, median PFS was not reached in the CARVYKTI arm. Median OS was not reached for either arm. A one time infusion of CARVYKTI demonstrates a statistically significant improvement in OS for participants treated with CARVYKTI as compared with standard of care therapy. PFS results are presented in Table 8 and Figure 1. OS results are presented in Table 8 and Figure 2. Table 8: Summary of efficacy results for Study MMY3002 (Intent-To-Treat Analysis Set) CARVYKTI (N=208) Standard of Care (N=211) Progression-Free Survival a,b Number of events, n (%) 89 (42.8) 153 (72.5) Median, months [95% CI] c NE [34.5, NE] 11.8 [9.7, 14.0] Hazard ratio [95% CI] d 0.29 [0.22, 0.39] Complete Response or Better Rate b,e , % [95% CI] 73.1 [66.5, 79.0] 21.8 [16.4, 28.0] p-value f <0.0001 Overall Response Rate (ORR) b,e , % [95% CI] 84.6 [79.0, 89.2] 67.3 [60.5, 73.6] p-value f <0.0001 Overall MRD Negativity Rate e , % [95% CI] 60.6 [53.6, 67.3] 15.6 [11.0, 21.3] p-value g <0.0001 Overall Survival (OS) a Number of events (%) 50 (24.0%) 83 (39.3%) Number of censored (%) 158 (76.0%) 128 (60.7%) Median, months [95% CI] c NE [NE, NE] NE [37.75, NE] Hazard ratio [95% CI] h 0.55 [0.39, 0.79] p-value i 0.0009 Key: NE=not estimable, CI = confidence interval. Notes: Intent-to-treat analysis set consists of subjects who were randomized in the study. a Second Interim analysis (data cut-off: 01 May 2024), with a median duration of follow-up of 33.6 months. b Per the International Myeloma Working Group (IMWG) consensus, as assessed by computerised algorithm c Kaplan-Meier estimate d Based on a stratified Cox proportional hazards model, including only PFS events that occurred more than 8 weeks post-randomisation. A hazard ratio <1 indicates an advantage for the CARVYKTI arm. For all stratified analyses, stratification was based on investigator's choice (PVd or DPd), ISS staging (I, II, III) and number of prior lines (1 vs. 2 or 3) as randomised. e Primary analysis (data cut-off: 01 November 2022), with a median duration of follow-up of 15.9 months. f Stratified Cochran-Mantel-Haenszel Chi-Squared test g Fisher's exact test h Hazard ratio and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with investigator's choice (PVd or DPd), ISS staging (I, II, III) and number of prior lines (1 vs. 2 or 3) as randomized. A hazard ratio <1 indicates an advantage for the CARVYKTI arm. i p-value is based on the log-rank test stratified with investigator's choice (PVd or DPd), ISS staging (I, II, III) and number of prior lines (1 vs. 2 or 3) as randomized. Figure 1: Kaplan-Meier Plot for updated PFS results; Intent-to-Treat Analysis Set (Study MMY3002) Notes: PFS based on the second interim analysis with a median duration of follow up of 33.6 months. Intent-to-treat analysis set consists of subjects who were randomized in the study. Key: Standard of Care Arm = PVd or DPd; Ciltacabtagene autoleucel Arm = A sequence of apheresis, bridging therapy (PVd or DPd), conditioning regimen (cyclophosphamide and fludarabine), and cilta-cel infusion. Key: PVd=pomalidomide-bortezomib-dexamethasone; DPd=daratumumab-pomalidomide-dexamethasone. Figure 2: Kaplan-Meier Plot for updated Overall Survival results; Intent-to-Treat Analysis Set (Study MMY3002) Notes: OS based on the second interim analysis with a median duration of follow up of 33.6 months. Intent-to-treat analysis set consists of subjects who were randomized in the study. Key: Standard of Care Arm = PVd or DPd; Ciltacabtagene autoleucel Arm = A sequence of apheresis, bridging therapy (PVd or DPd), conditioning regimen (cyclophosphamide and fludarabine), and cilta-cel infusion. Key: PVd=pomalidomide-bortezomib-dexamethasone; DPd=daratumumab-pomalidomide-dexamethasone. Paediatric population The licensing authority has waived the obligation to submit the results of studies with CARVYKTI in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).