Ciltacabtagene Autoleucel (cilta-cel) Reduced Risk of Disease Progression or Death by 74% vs Standard Regimens for Adult Patients with Relapsed and Refractory Multiple Myeloma in CARTITUDE-4 Study

• First analysis data from CARTITUDE-4 demonstrated a statistically significant improvement in progression-free survival, with a hazard ratio of 0.26
• CARTITUDE-4 is the first randomized study investigating the efficacy of a cell therapy versus standard of care (DPd or PVd) as early as after first relapse in lenalidomide-refractory multiple myeloma
• Long-term results from CARTITUDE-1 and LEGEND-2 demonstrated sustained deep and durable responses

SOMERSET, N.J.--(BUSINESS WIRE)--$LEGN--Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, announced today that results from the Phase 3 CARTITUDE-4 study showed that, at a median follow up of 16 months, cilta-cel reduced the risk of disease progression or death by 74 percent compared to standard of care regimens in adult patients with multiple myeloma who have received one to three prior lines of therapy and are refractory to lenalidomide (Hazard ratio [HR]=0.26 (95% CI, 0.18–0.38); P-value [P] <0.0001).¹ The study data were featured in a press briefing and presented in an oral session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA106) and were presented in the New England Journal of Medicine. On Saturday, June 10, 2023, results will also be presented in a plenary session at the 2023 European Hematology Association (EHA) Hybrid Congress (Abstract #S100).

Eligible patients in the CARTITUDE-4 study had one to three prior lines of treatment, including proteasome inhibitors (PI) and immunomodulatory drugs and were lenalidomide-refractory.¹ Four hundred and nineteen patients were randomized, with 208 patients in the cilta-cel arm and 211 patients in the SOC arm. At the median follow up of 16 months, the median PFS had not yet been reached in the cilta-cel arm (95% CI, 22.8-NE), compared to a median PFS of 11.8 months in the SOC arm (95% CI: 9.7-13.8). In patients who had one prior line of therapy, there was a 65 percent (HR=0.35; 95 percent CI, 0.19-0.66; P<0.0001) reduction in the risk of disease progression or death. Among the secondary endpoints, the overall response rate (ORR) was 85 percent, 73 percent achieved a complete response (CR) or better, and the rate of overall minimal residual disease (MRD) negativity reached 61 percent in the cilta-cel arm.¹ Among patients treated with SOC therapies, the ORR was 67 percent, and 22 percent achieved a CR or better, while 33 percent of patients treated with SOC therapies were MRD negative.¹

“There continues to be a serious unmet need in multiple myeloma, particularly in earlier lines of treatment,” said Binod Dhakal, M.D., M.S., Associate Professor of Medicine at the Medical College of Wisconsin, Division of Hematology, and study investigator. “The CARTITUDE-4 results demonstrate the potential for cilta-cel to be an additional treatment option for appropriate patients with relapsed and refractory multiple myeloma who have had one to three prior lines of therapy.”

In the study, 97 percent and 94 percent of patients treated in the cilta-cel and SOC groups, respectively, had grade 3 or 4 adverse events, including infections (27 percent versus 25 percent) and cytopenias (94 percent versus 86 percent).¹ Overall, 39 patients in the cilta-cel arm and 46 patients in the SOC arms died, of which 10 cilta-cel and 5 SOC patients passed due to treatment-emergent adverse events (TEAEs).¹ In patients who received cilta-cel as study treatment (n=176), 76 percent had cytokine release syndrome (1 percent grade 3; no grade 4 or 5) and 5 percent had immune effector cell associated neurotoxicity syndrome (all grade 1 or 2).¹ One grade 1 movement and neurocognitive treatment-emergent adverse event was reported in the cilta-cel group.¹

“Data from CARTITUDE-4 demonstrated strong results for study patients after first relapse,” said Mythili Koneru, M.D., Chief Medical Officer at Legend Biotech. “We are inspired by the potential of cilta-cel for patients with multiple myeloma who continue to have a high need for another treatment option.”

Final Analysis of CARTITUDE-1 Study Demonstrated Deep and Durable Responses

A final analysis of data from the Phase 1b/2 CARTITUDE-1 (NCT03548207) study showed sustained deep and durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma treated with cilta-cel (Abstract #8009).² At a median follow-up of 33.4 months (range, 1.5-45.2), the median PFS was 34.9 months (95 percent CI, 25.2–not estimable [NE]), with an estimated 47.5 percent of patients progression-free and alive at 36 months.²

In the study, 97 patients received cilta-cel, with a median of six prior lines of therapy.² Forty-two percent of patients were penta-drug refractory, 88 percent were triple-class refractory and 99 percent were refractory to the last line of treatment.² At data cut-off, the median duration of response was 33.9 months (95 percent CI, 25.5–NE).² Median overall survival (OS) was not reached in the study, with an estimated 62.9 percent OS rate at 36 months.² Of 49 MRD-evaluable patients, 26 had MRD-negativity sustained for 12 months or longer, of which 20 had a sustained MRD-negative CR or better.² Eighteen patients were MRD-negative with a CR or better at 24-months post infusion.² No new safety signals and no new neurotoxicity events were reported since the 27.7-month median follow-up.² Six new cases of second primary malignancy were reported, including two cases of basal cell carcinoma and one case each of myelodysplastic syndrome, B-cell lymphoma, melanoma and prostate cancer.² Five additional deaths occurred in the study (PD, n=3; pneumonia and sepsis, n=1 each, both determined by the investigators to be unrelated to cilta-cel), for a total of 35 deaths in the study (PD, n=17; unrelated to cilta-cel, n=12; related, n=6, as determined by investigators).²

Five-Year Follow-up Data from LEGEND-2 Highlights Sustained, Durable Responses

Five-year follow-up data from LEGEND-2, the longest follow-up for any BCMA-targeted CAR-T cell therapy study investigating LCAR-B38M, a similar CAR construct to cilta-cel, showed a median OS of 55.8 months, with 18 percent of patients with heavily pretreated multiple myeloma remaining disease-free.³

At the data cut-off, median follow-up in the LEGEND-2 study was 65.4 months (range, 0.4-78.8).³ Seventy-four patients received LCAR-B38M, with a median of three prior lines of therapy (range, 1-9); 35.7 percent of patients had high risk cytogenic profiles.³ In the study, the ORR was 87.8 percent, and 73 percent of patients achieved a CR.³ The median duration of response in the study was 23 months, and median PFS was 18 months at maturity, consistent with previously reported data.³ The rate of MRD-negative CR was 67.6 percent.³ No new CAR-T cell-related toxicities were reported in the analysis.³

Disclosure: Dr. Dhakal has provided consulting, advisory, and speaking services to Legend Biotech and Janssen Biotech, Inc.

CARVYKTI^® Important Safety Information

CARVYKTI^® INDICATIONS AND USAGE

CARVYKTI^® (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

CARVYKTI^® IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI^® in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 112 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

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.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI^®.

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, Guillain-Barré Syndrome, 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.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients 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. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

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.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

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 Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel 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.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. 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): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. 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 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. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) 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. Six and 11 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.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

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 10% of patients after ciltacabtagene autoleucel infusion, and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI^® and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI^® treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI^® treatment, and until immune recovery following treatment with CARVYKTI^®.

Hypersensitivity Reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI^®. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI^® infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information including Boxed Warning for CARVYKTI^®.

About CARVYKTI^® (ciltacab

Press Contact:
Tina Carter, Corporate Communications Lead, Legend Biotech
tina.carter@legendbiotech.com
(908) 331-5025

Investor Contacts:
Joanne Choi, Senior Manager of Investor Relations, Legend Biotech
joanne.choi@legendbiotech.com

Crystal Chen, Manager of Investor Relations, Legend Biotech
crystal.chen@legendbiotech.cn