Legend Biotech Shares Data on the Earliest Use to Date of CARVYKTI® in the Treatment of Multiple Myeloma and Important Subgroup Analyses at ASCO and EHA

Latest industry news
  • First analysis of CARTITUDE-2 Cohort D study investigating CARVYKTI® in multiple myeloma with suboptimal response after front-line ASCT featured in an oral presentation at the 2024 ASCO Annual Meeting show deep and durable responses with one-time infusion of CARVYKTI®
  • Subgroup analysis from the CARTITUDE-4 study in an oral presentation at ASCO shows CARVYKTI® improved PFS vs standard therapy in a functionally high-risk population as early as second line associated with poor clinical outcomes
  • Results of a CARTITUDE-4 subgroup analysis by cytogenetic risk showing the favorable efficacy results of CARVYKTI® across different cytogenetic abnormalities to be released in a poster presentation at the 2024 EHA Congress

SOMERSET, N.J.–(BUSINESS WIRE)–Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global leader in cell therapy, announced today results for the first time from the Phase 2 CARTITUDE-2 Cohort D study in multiple myeloma patients. Results showed patients with less than a complete response (CR) after front-line autologous stem cell transplant (ASCT) experienced deep and durable responses following a single infusion of CARVYKTI® (ciltacabtagene autoleucel; cilta-cel) with or without lenalidomide maintenance.1 These data were presented as an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #7505) and will also be shared as an encore oral presentation at the 2024 European Hematology Association (EHA) Congress (Abstract #S205).1 CARVYKTI® is the first and only B-cell maturation antigen (BCMA)-targeted therapy approved for the treatment of patients with relapsed/refractory multiple myeloma as early as after first relapse.


“Patients who achieve a less than complete response following ASCT may experience less durable response with future treatments,” said Melissa Alsina, M.D., Head Myeloma BMT-CI Program, H. Lee Moffitt Cancer Center, and Research Institute. The outcomes from this study showed encouraging efficacy results and indicated the potential benefit of CARVYTKI in this patient population.” ‡

At a median follow-up of 22 months, patients treated with CARVYKTI® (n=17) demonstrated a 94% (n=16/17) overall response rate (ORR) with all 16 patients achieving a CR or better.1 Of the 15 minimal residual disease (MRD)-evaluable patients, 80% achieved MRD negativity at the 10–5 threshold.1 The median duration of response (mDOR) was not reached (NR) and the median time to first response was one month.1 Eighteen-month progression-free survival (PFS) and overall survival (OS) rates were 94% each.

Safety signals were consistent with the known safety profile of CARVYKTI®.1 All patients had grade 3 or 4 treatment emergent adverse events (TEAEs) including neutropenia (94%), lymphopenia (65%), thrombocytopenia (47%), leukopenia (41%), infections (71%), or CRS (82%; median onset of 8 days).1 One patient had a secondary malignancy of grade 3 myelodysplastic syndromes (MDS). No cases of movement and neurocognitive treatment-emergent adverse events (MNTs)/parkinsonism were observed.1

“We are excited to unveil these results from our CARTITUDE-2 Cohort D study which show the significant impact of CARVYKTI on multiple myeloma patients in the earliest treatment setting to date,” said Mythili Koneru, M.D., Ph.D., Chief Medical Officer of Legend Biotech. “We believe CARVYKTI may produce deep and durable responses earlier in the multiple myeloma treatment paradigm, so we are conducting Phase 3 studies to determine if patients will benefit from CARVYKTI as early as frontline treatment.”

CARTITUDE-4: Results of a subgroup analysis show CARVYKTI® improved progression-free survival versus standard therapy for patients with functional high-risk multiple myeloma (Abstract #7504)

CARTITUDE-4 is a Phase 3 study evaluating CARVYKTI® vs two standard of care therapies of pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, dexamethasone (DPd) in patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). Results from this subgroup analysis showed CARVYKTI® significantly improved PFS for patients with functional high-risk (FHR) multiple myeloma, defined as disease progression within 18 months following ASCT or following initiation of first-line treatment.2

The subgroup analysis included patients (n=136) who received one prior line of therapy, including a PI and an IMiD and were lenalidomide-refractory, including patients (n=79) who had FHR multiple myeloma.2 Patients were randomized to CARVYKTI® (n=68) or standard therapies (n=68), including those with FHR multiple myeloma (CARVYKTI®, n=40; standard therapies, n=39).2

Median PFS was NR among patients who received CARVYKTI® compared to 17 months (95% Confidence Interval,11-NE) for the control arm as a second-line treatment (HR=0.35 [95% CI, 0.2-0.7; P=.0007]), including those who had FHR multiple myeloma (CARVYKTI®, NR [95% CI,18-NE]; standard therapies, 12 months [95% CI, 8-NE]), (HR=0.27 [95% CI, 0.1-0.6; P=.0006]).2 Patients treated with CARVYKTI® who had FHR multiple myeloma compared to those treated with standard therapies had consistently higher rates of overall responses (88%; 80%), CR or better (68%; 39% ), MRD negativity (65%; 10%), and longer mDOR (NR [16-NE]; 16 [8-NE]).

The safety profile in this subgroup analysis was consistent with the known safety profile of cilta-cel.2 The proportion of patients with grade 3 or higher TEAEs was comparable among patients who received CARVYKTI® versus standard therapies as second-line treatment (96%, 96%), including those with FHR multiple myeloma (100%, 97%).2 Overall, 11 patients who received CARVYKTI® after one prior line of therapy and 11 patients who received standard therapies after one prior line of therapy died.2 Of the patients with FHR multiple myeloma, 7 patients from the CARVYKTI® arm, and 9 who received standard therapies died.2 Of the 7 deaths in patients with one prior line of therapy and functionally high-risk multiple myeloma, 2 did not receive CARVYKTI® as study treatment, and 3 received CARVYKTI® as subsequent therapy.

CARTITUDE-4: Subgroup analysis of patients with high-risk cytogenetics demonstrates favorable efficacy for CARVYKTI® vs standard therapy (Abstract #P978)

CARVYKTI® demonstrated favorable efficacy outcomes – including higher ORR, ≥CR rates, and MRD negativity rates and improved PFS – vs SOC in patients with high-risk and standard-risk cytogenetics.3 In patients with standard-risk cytogenetics, median PFS was not reached (NR; 95% CI, NE-NE) with CARVYKTI® vs 20.6 months (95% CI, 11.2-NE) with SOC. In patients with high-risk cytogenetics, median PFS was not reached (95% CI, 18.4–NE) with CARVYKTI® vs 10.3 months (95% CI, 7.6–12.5) with SOC.

Results from the Phase 3 CARTITUDE-4 subgroup analysis demonstrate the efficacy of CARVYKTI® versus SOC in patients with high-risk-cytogenetics, supporting the role of CARVYKTI® as a potential new SOC in this patient population.

Data from the CARTITUDE-4 study supported the U.S. FDA approval of CARVYKTI® on April 5, 2024, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy (LOT), including a PI and an IMiD, and are refractory to lenalidomide.

CARVYKTI® IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES

 

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI®. Do not administer CARVYKTI® to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

 

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI®, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI®. Provide supportive care and/or corticosteroids as needed.

 

Parkinsonism and Guillain-Barré syndrome (GBS) and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI®.

 

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI®. HLH/MAS can occur with CRS or neurologic toxicities.

 

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI®.

 

Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred in patients following treatment with CARVYKTI®. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI®.

 

CARVYKTI® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI® REMS Program.

WARNINGS AND PRECAUTIONS

INCREASED EARLY MORTALITY – In CARTITUDE-4, a (1:1) randomized controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI® treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI® arm compared to (25/211; 12%) in the control arm. Of the 29 deaths that occurred in the CARVYKTI® arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI® infusion, and 19 deaths occurred after CARVYKTI® infusion. Of the 10 deaths that occurred prior to CARVYKTI® infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI® infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12).

CYTOKINE RELEASE SYNDROME (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® for RRMM in the CARTITUDE-1 & 4 studies (N=285), CRS occurred in 84% (238/285), including ≥ Grade 3 CRS (ASCT 2019) in 4% (11/285) of patients. Median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). CRS resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥ 10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia. CRS occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4). Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.4; Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS).

Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI®.

Of the 285 patients who received CARVYKTI® in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least one dose of corticosteroids for treatment of CRS.

Monitor patients at least daily for 10 days following CARVYKTI® infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

NEUROLOGIC TOXICITIES, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI®. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies for RRMM, one or more neurologic toxicities occurred in 24% (69/285), including ≥ Grade 3 cases in 7% (19/285) of patients. Median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated myelitis in 0.4% of the patients.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients receiving CARVYKTI® may experience fatal or life-threatening ICANS following treatment with CARVYKTI®, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.

Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, ICANS occurred in 13% (36/285), including Grade ≥3 in 2% (6/285) of the patients. Median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 30 of 36 (83%) of patients with a median time to resolution of 3 days (range: 1 to 143 days). Median duration of ICANS was 6 days (range: 1 to 1229 days) in all patients including those with ongoing neurologic events at the time of death or data cut-off. Of patients with ICANS, 97% (35/36) had CRS. The onset of ICANS occurred during CRS in 69% of patients, before and after the onset of CRS in 14% of patients respectively.

Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3) and in 23% of patients in CARTITUDE-1 (3% Grade 3). The most frequent ≥2% manifestations of ICANS included encephalopathy (12%), aphasia (4%), headache (3%), motor dysfunction (3%), ataxia (2%), and sleep disorder (2%) [see Adverse Reactions (6.1)].

Monitor patients at least daily for 10 days following CARVYKTI® infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see Dosage and Administration (2.3)].

Parkinsonism: Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, parkinsonism occurred in 3% (8/285), including Grade ≥ 3 in 2% (5/285) of the patients. Median time to onset of parkinsonism was 56 days (range: 14 to 914 days). Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days. Median duration of parkinsonism was 243.5 days (range: 62 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut-off. The onset of parkinsonism occurred after CRS for all patients and after ICANS for 6 patients.

Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (4% Grade 3 to 4).

Manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes. Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI® treatment.

Guillain-Barré Syndrome: A fatal outcome following GBS occurred following treatment with CARVYKTI® despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Immune Mediated Myelitis: Grade 3 myelitis occurred 25 days following treatment with CARVYKTI® in CARTITUDE-4 in a patient who received CARVYKTI® as subsequent therapy. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral Neuropathy occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥3 in 1% (3/285) of the patients. Median time to onset of peripheral neuropathy was 57 days (range: 1 to 914 days). Peripheral neuropathy resolved in 11 of 21 (52%) of patients with a median time to resolution of 58 days (range: 1 to 215 days). Median duration of peripheral neuropathy was 149.5 days (range: 1 to 692 days) in all patients including those with ongoing neurologic events at the time of death or data cut-off.

Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4). Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS.

Cranial Nerve Palsies occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, cranial nerve palsies occurred in 7% (19/285), including Grade ≥3 in 1% (1/285) of the patients. Median time to onset of cranial nerve palsies was 21 days (range: 17 to 101 days). Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range: 1 to 209 days). Median duration of cranial nerve palsies was 70 days (range: 1 to 262 days) in all patients including those with ongoing neurologic events at the time of death or data cut-off. Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (1% Grade 3 to 4) and in 3% of patients in CARTITUDE-1 (1% Grade 3 to 4).

The most frequent cranial nerve affected was the 7th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected.

Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)/MACROPHAGE ACTIVATION SYNDROME (MAS): Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI®, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia, and multi-organ dysfunction, including renal dysfunction and respiratory failure.

Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI®.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI® REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI® REMS.

Further information is available at https://www.carvyktirems.com or 1-844-672-0067.

PROLONGED AND RECURRENT CYTOPENIAS: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI® infusion.

Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI® infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285). After Day 60 following CARVYKTI® infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI® infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

INFECTIONS: CARVYKTI® should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI® infusion.

Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, infections occurred in 57% (163/285), including ≥Grade 3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI® had an increased rate of fatal COVID-19 infections compared to the standard therapy arm.

Monitor patients for signs and symptoms of infection before and after CARVYKTI® infusion and treat patients appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in

Contacts

INVESTOR:


Jessie Yeung

Tel: (732) 956-8271

[email protected]

PRESS:


Mary Ann Ondish

Tel: (914) 552-4625

[email protected]

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