- 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, NJ, USA I June 05, 2023 I 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® 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.
Please read full Prescribing Information including Boxed Warning for CARVYKTI®.
About CARVYKTI® (ciltacabtagene autoleucel; cilta-cel)
Ciltacabtagene autoleucel 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 cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.4
In February 2022, cilta-cel was approved by the U.S. Food and Drug Administration (FDA) under the brand name CARVYKTI® for the treatment of adults with relapsed or refractory multiple myeloma.5 In May 2022, the European Commission (EC) granted conditional marketing authorization of CARVYKTI® for the treatment of adults with relapsed and refractory multiple myeloma.6 In September 2022, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI®.7 Cilta-cel was granted Breakthrough Therapy Designation in the U.S. in December 2019 and in China in August 2020. In addition, cilta-cel received a PRIority MEdicines (PRIME) designation from the European Commission in April 2019. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, from the European Commission in February 2020, and from the Pharmaceuticals and Medicinal Devices Agency (PMDA) in Japan in June 2020. In March 2022, the European Medicines Agency’s Committee for Orphan Medicinal Products recommended by consensus that the orphan designation for cilta-cel be maintained on the basis of clinical data demonstrating improved and sustained complete response rates following treatment.8
In December 2017, Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel.
About CARTITUDE-4
CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study evaluating the efficacy and safety of a CAR-T therapy versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy. After apheresis, patients randomized to the cilta-cel arm of the study received either PVd or DPd as bridging therapy, followed by an infusion of cilta-cel five to seven days after lymphodepletion. In total, 176 patients received planned cilta-cel treatment and 20 received cilta-cel after disease progression during bridging therapy.1 In the SOC group, 28 patients were treated with PVd and 183 patients were treated with DPd until disease progression.1 The primary endpoint of the study is PFS. Secondary endpoints include safety, overall survival (OS), minimal residual disease (MRD) negative rate and overall response rate (ORR). Patients will continue to be followed for primary and secondary endpoints as part of the CARTITUDE-4 study.
About CARTITUDE-1
CARTITUDE-1 (NCT03548207) is a Phase 1b/2, open-label, single arm, multi-center trial evaluating cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma, who previously received at least three prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody. Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.
About LEGEND-2
LEGEND-2 (NCT03090659) is a Phase 1/2, single-arm, open-label program in China comprised of four independent institutional studies conducted at participating hospitals evaluating the efficacy and safety of LCAR-B38M for the treatment of patients with R/R multiple myeloma. LCAR-B38M identifies the investigational product being studied in China and Ciltacabtagene autoleucel (cilta-cel) identifies the investigational product being studied in the U.S./EU, both of which are representative of the same CAR-T therapy.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.9 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.10 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.11 Although treatment may result in remission, unfortunately, patients will most likely relapse.12 Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody, have poor prognoses and few treatment options available.13,14
About Legend Biotech
Legend Biotech is a global biotechnology company dedicated to treating, and one day curing, life-threatening diseases. Headquartered in Somerset, New Jersey, we are developing advanced cell therapies across a diverse array of technology platforms, including autologous and allogeneic chimeric antigen receptor T-cell, gamma-delta T cell (γδ T) and natural killer (NK) cell-based immunotherapy. From our three R&D sites around the world, we apply these innovative technologies to pursue the discovery of safe, efficacious and cutting-edge therapeutics for patients worldwide.
Learn more at www.legendbiotech.com and follow us on Twitter and LinkedIn.
References
1 Dhakal, B. First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. To be presented at the 2023 American Society of Oncology Annual Meeting and European Hematology Association 2023 Hybrid Congress.
2 Lin, Y. CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. To be presented at the 2023 American Society of Oncology Annual Meeting and European Hematology Association 2023 Hybrid Congress.
3 Mi, J-Q. Long-Term Remission and Survival in Patients with Relapsed or Refractory Multiple Myeloma After Treatment of LCAR-B38M CAR-T – At Least 5-Year Follow-Up in LEGEND-2. To be presented at the 2023 American Society of Oncology Annual Meeting and European Hematology Association 2023 Hybrid Congress.
4 CARVYKTI™ Prescribing Information. Horsham, PA: Janssen Biotech, Inc.
5 CARVYKTI™ (ciltacabtagene autoleucel), BCMA-Directed CAR-T Therapy, Receives U.S. FDA Approval for the Treatment of Adult Patients with Relapsed or Refractory Multiple Myeloma. Available at: https://legendbiotech.com/legend-news/carvykti-ciltacabtagene-autoleucel-bcma-directed-car-t-therapy-receives-u-s-fda-approval-for-the-treatment-of-adult-patients-with-relapsed-or-refractory-multiple-myeloma/. Accessed October 2022.
6 CARVYKTI (ciltacabtagene autoleucel) Granted Conditional Approval by the European Commission for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma. Available at: https://legendbiotech.com/legend-news/carvykti-ciltacabtagene-autoleucel-granted-conditional-approval-by-the-european-commission-for-the-treatment-of-patients-with-relapsed-and-refractory-multiple-myeloma/. Accessed October 2022.
7 CARVYKTI™ (ciltacabtagene autoleucel) Receives Approval from Japan’s Ministry of Health, Labour and Welfare (MHLW) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma. Available at: https://www.businesswire.com/news/home/20220926005847/en/CARVYKTI%E2%84%A2-ciltacabtagene-autoleucel-Receives-Approval-from-Japan%E2%80%99s-Ministry-of-Health-Labour-and-Welfare-MHLW-for-the-Treatment-of-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma. Accessed October 2022.
8 European Commission. Community Register of Orphan Medicinal Products. Available at: https://ec.europa.eu/health/documents/community-register/html/o2252.htm. Accessed October 2022.
9 American Society of Clinical Oncology. Multiple myeloma: introduction. https://www.cancer.net/cancer-types/multiple-myeloma/introduction. Accessed October 2022.
10 American Cancer Society. “Key Statistics About Multiple Myeloma.” Available at: https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html#:~:text=Multiple%20myeloma%20is%20a%20relatively,men%20and%2015%2C370%20in%20women). Accessed January 2023.
11 American Cancer Society. Multiple myeloma: early detection, diagnosis and staging. https://www.cancer.org/content/dam/CRC/PDF/Public/8740.00.pdf. Accessed October 2022.
12 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(5),548-567. doi:10.1002/ajh.25791.
13 Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443- 2448.
14 Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38- targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275.
SOURCE: Legend Biotech
