On December 7, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported initial results from the Phase 1b/2 CARTITUDE-1 study (NCT03548207) evaluating the efficacy and safety of JNJ-68284528 (JNJ-4528), an investigational B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy being evaluated in the treatment of patients with relapsed or refractory multiple myeloma (Press release, Janssen Pharmaceuticals, DEC 7, 2019, View Source [SID1234552058]). The study enrolled patients who had received at least three prior lines of therapy or were double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD); had received a PI, IMiD and an anti-CD38 antibody. The CARTITUDE-1 study results, premiered at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, were featured as an oral presentation and highlighted in the official ASH (Free ASH Whitepaper) press programme (Abstract #577).1

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Results from the Phase 1b portion of the CARTITUDE-1 study showed early and deep responses among patients (n=29) with a median of five prior multiple myeloma treatment regimens (range, 3–18) treated with JNJ-4528 (median administered dose 0.73×106 CAR+ viable T cells/kg).1 One hundred percent of patients achieved a response at a median follow-up of six months.1 Eighty-six percent of patients were triple-refractory to a PI, IMiD, and anti-CD38 antibody, 72 percent were penta-exposed, and 31 percent were penta-refractory).1 The overall response rate (ORR) included 69 percent of patients achieving a complete response (CR) or better (66 percent achieved a stringent CR); 86 percent of patients achieved a very good partial response (VGPR) or better; and 14 percent of patients achieved a partial response (PR). In addition, all 15 out of a total of 29 patients (100 percent evaluable) at the 10-5 sensitivity level were MRD negative at the latest sample available.1 At the median follow-up of six months, 27 of 29 patients were progression-free. Based on the Phase 1b results, a recommended Phase 2 dose of 0.75×106 CAR+ viable T cells/kg was confirmed.1

"These initial results from the Phase 1b portion of the CARTITUDE-1 study highlight a compelling clinical profile for JNJ-4528 in heavily pre-treated patients with relapsed or refractory multiple myeloma," said Deepu Madduri, M.D., Assistant Professor of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute at Mount Sinai, New York, and principal study investigator. "With the CARTITUDE-1 expansion cohort fully enrolled and all patients dosed, we look forward to collecting additional efficacy and safety data to further define the profile of this BCMA-targeted CAR-T therapy."

Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag, adds, "Janssen has a long-standing commitment to improving outcomes for patients with multiple myeloma and patients with relapsed or refractory disease remain in urgent need of new treatment options. We are excited to further explore the potential of JNJ-4528 and build on the early promising data seen in CARTITUDE-1."

The most common adverse events (AEs) observed in the CARTITUDE-1 study were cytokine release syndrome (CRS) (93 percent); neutropenia (93 percent); anaemia (86 percent); and thrombocytopenia (86 percent).1 In patients who experienced grade 3 and above AEs (25 percent); the most common were neutropenia (93 percent); thrombocytopenia (69 percent); and anaemia (55 percent).1 A majority of patients (86 percent) experienced grade 1-2 CRS. One patient experienced grade 3 CRS and one patient died of complications from CRS at day 99.1 The median onset of CRS was generally predictable at seven days (range, 2-12) post-infusion, with a median duration of four days (range, 1-60).1

"We are encouraged by the overall response reported in patients receiving JNJ-4528, results that build upon the LEGEND-2 study data as reported in Chinese patients and now show promise in U.S. patients," said Sen Zhuang, M.D., Ph.D., Vice President, Oncology Clinical Development, Janssen Research & Development, LLC. "We are committed to advancing this novel BCMA-targeted CAR-T therapy through clinical development and bringing this immunotherapy to patients who are still in need of effective therapies to rapidly control their disease."

JNJ-4528 is a structurally differentiated CAR-T with two BCMA targeting single domain antibodies.2 LCAR-B38M identifies the investigational product in China, sponsored by Janssen development partner, Legend Biotech. JNJ-4528 identifies the investigational product with the same CAR construct being studied in the U.S. and Europe.

Safety and efficacy results observed in the CARTITUDE-1 study were consistent with the LEGEND-2 study of LCAR-B38M, sponsored by Legend Biotech. In follow-up data from the LEGEND-2 study presented at ASH (Free ASH Whitepaper) (Abstract #579), investigators reported the long-term response and safety profile for LCAR-B38M.3 Overall response rates of 88 percent were observed, with 46 percent of all-treated patients and 64 percent of the MRD-negative patients with CR remaining progression-free.3 The median progression-free survival (PFS) for all-treated patients was 20 months (range, 10–28); median PFS for MRD-negative patients with CR was 28 months (range, 20–31).3

In a separate oral presentation (Abstract #928), data highlighting post-infusion CAR+ T cell expansion in the bone marrow and blood of patients enrolled in the CARTITUDE-1 study will be reported. While both CD4+ and CD8+ CAR+ T cells expanded in vivo, a preferential expansion of memory CD8+ CAR+ T cells was observed at peak expansion.4 These and other correlative studies are being conducted to better understand the immune mechanisms associated with response to JNJ-4528, and suggest that the high anti-myeloma activity of JNJ-4528 seen at a relatively low T cell dose is potentially related to its preferential and consistent in vivo expansion of CD8+ CAR+ T cells.4

#ENDS#

About CARTITUDE-1

CARTITUDE-1 (NCT03548207) is an ongoing Phase 1b/2, open-label, multicentre study evaluating the safety and efficacy of JNJ-68284528 (JNJ-4528) in adults with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy or are double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD); have received a PI, IMiD and an anti-CD38 antibody.1 The primary objective of the Phase 1b portion of the study is to characterise the safety and confirm the dose of JNJ-68284528 (JNJ-4528), which was informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2). The primary objective for the Phase 2 portion of the study is to evaluate the efficacy of JNJ-68284528 (primary endpoint: overall response rate as defined by the International Myeloma Working Group response criteria).5

About LEGEND-2

LEGEND-2 (NCT03090659) is an ongoing Phase 1, single-arm, open-label study in China comprised of four independent institutional studies being conducted at participating hospitals evaluating the efficacy and safety of LCAR-B38M for the treatment of patients with relapsed or refractory multiple myeloma.6

About JNJ-68284528 (LCAR-B38M)

JNJ-68284528 (LCAR-B38M) is an investigational chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of patients with relapsed or refractory multiple myeloma. The design comprises a structurally differentiated CAR-T with two BCMA targeting single domain antibodies. In December 2017, Janssen entered into an exclusive worldwide license and collaboration agreement with Legend to develop and commercialise JNJ-68284528/LCAR-B38M. In May 2018, Janssen initiated a Phase 1b/2 trial (NCT03548207) to evaluate the efficacy and safety of JNJ-68284528 in adults with relapsed/refractory multiple myeloma, informed by the LEGEND-2 study results.5,7

In April 2019, JNJ-68284528 was granted PRIME (PRIority MEdicines) designation by the European Medicines Agency (EMA).8 PRIME offers enhanced interaction and early dialogue to optimise development plans and speed up evaluation of cutting-edge, scientific advances that target a high unmet medical need.9

About CAR-T and BCMA

CAR-T cells are an innovative approach to eradicating cancer cells by harnessing the power of a patient’s own immune system.10 BCMA is a protein that is highly expressed on myeloma cells.11 By targeting BCMA via a CAR-T approach, CAR-T therapies may have the potential to redefine the treatment paradigm for multiple myeloma and potentially advance towards cures for patients with the disease.

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.12 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.13 Around 60 percent of newly diagnosed patients do not reach five-year survival,14 and almost 29 percent of patients with multiple myeloma will die within one year of diagnosis.15

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.16 Refractory MM is when a patient’s disease progresses within 60 days of their last therapy.17 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.18 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.19 Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.20