On April 17, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), and SpringWorks Therapeutics, Inc. (NASDAQ: SWTX), reported that they will present updated clinical data from the Phase 1b trial of BeiGene’s RAF dimer inhibitor, lifirafenib, in combination with SpringWorks’ MEK inhibitor, mirdametinib, in patients with advanced or refractory solid tumors with RAS mutations, RAF mutations and other MAPK pathway aberrations (Press release, BeiGene, APR 17, 2023, View Source [SID1234630140]). The data are being presented today in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place in Orlando, Florida.

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This press release features multimedia. View the full release here: View Source

"The lifirafenib plus mirdametinib combination represents a novel targeted approach to treat solid tumors driven by RAS/RAF mutations, and other MAPK pathway aberrations. The early clinical data reported here demonstrate the potential of this vertical combination strategy in addressing the substantial unmet medical need represented by patients with tumors driven by these genetic alterations." said Lusong Luo, Ph.D. Senior Vice President, External Innovation at BeiGene. "We are very excited about our continued study of this combination with its advancement into dose expansion this year."

"We are pleased by the progress of our collaboration with BeiGene on the lifirafenib and mirdametinib combination," said Saqib Islam, CEO of SpringWorks. "We view vertical inhibition approaches, such as this novel combination, as a promising strategy to improve outcomes in biomarker-defined subgroups of patients that lack efficacious treatments for their cancers."

Oral Presentation at the AACR (Free AACR Whitepaper) Annual Meeting 2023:

Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors

Presenter: Benjamin Solomon, M.D., Peter MacCallum Cancer Centre, Melbourne, Australia

Session Title: Mini-symposium Session CTMS02 – Targeting the KRAS Pathway in the Clinic

Abstract #: CT033

Session Date and Time: Monday, April 17, 2023, 3:50-4:00 PM ET

This ongoing Phase 1b trial (NCT03905148) is an open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics (PK) and antitumor activities of mirdametinib in combination with lifirafenib, BeiGene’s RAF dimer inhibitor, in patients with advanced or refractory solid tumors harboring RAS mutations, RAF mutations, and other MAPK pathway aberrations.

Results from the Part A dose-escalation and dose-finding study are being presented at AACR (Free AACR Whitepaper). This portion of the study was designed to evaluate the safety, tolerability, and pharmacokinetics of the combination, and determine the maximum tolerated dose and/or recommended Phase 2 dose.

As of the data cut-off of January 20, 2023, 71 patients were treated across 9 dose levels evaluating different dosing regimens. Results suggest that lifirafenib in combination with mirdametinib demonstrated a favorable safety profile, with low incidence of dose limiting toxicities and treatment-emergent adverse events that led to dose discontinuations. The most common treatment-related adverse events related to lifirafenib and/or mirdametinib (>15%) were dermatitis acneiform (42%), fatigue (32%), diarrhea (27%), platelet count decreased (18%), alopecia (18%), nausea (17%) and alanine aminotransferase increased (16%).

The combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), and endometrial cancer. Among 62 efficacy-evaluable patients, 14 patients (23%) had confirmed objective responses. Of 17 patients with LGSOC treated, 10 patients (59%) had objective responses, with median duration of treatment of approximately 26 months. Of the 4 endometrial cancer patients treated, 2 (50%) had objective responses in tumors that harbor BRAF fusion mutation or KRAS mutation, respectively. Of the 11 patients with NSCLC treated, 2 (18%) had objective responses in tumors that harbor NRAS mutation or BRAF V600E mutation, respectively. These data support the advancement of this combination into the dose-expansion portion of the study, which will focus on a biomarker selected patient population with a tumor agnostic approach. The expansion is expected to start in the second half of 2023.

"Our findings indicate that the combination of lifirafenib and mirdametinib treatment demonstrated antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types known to be driven by the MAPK pathway and for which current treatment options are limited," said Benjamin Solomon, MBBS, PhD, FRACP, medical oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia. "We are pleased with the risk-benefit profile seen to date with this combination and look forward to the further clinical investigation in the dose-expansion portion of the study."

About Lifirafenib

Lifirafenib (BGB-283) is an investigational novel small molecule designed to inhibit both monomeric and dimeric RAF kinase. Lifirafenib has demonstrated antitumor activity in preclinical models and in cancer patients with tumors harboring BRAF V600E mutations and non-V600E BRAF mutations, in which the monomeric form of RAF is implicated, as well as KRAS/NRAS mutations, in which the dimeric form of RAF is implicated.

About Mirdametinib

Mirdametinib is an investigational, oral, allosteric small molecule MEK inhibitor. Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and that plays a central role in multiple oncology and rare disease indications when genetically altered.

Mirdametinib is in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. To date, over 300 subjects have been exposed to treatment with mirdametinib across clinical trials, with preliminary evidence of clinical activity against tumors driven by over-activated MAPK signaling.

The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity.

On April 17, 2023 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a pre-commercial-stage biopharmaceutical company focused on oncology, reported the publication of data from the Company’s GENESIS Phase 3 clinical trial in the peer-reviewed journal Nature Medicine (Press release, BioLineRx, APR 17, 2023, View Source [SID1234630138]). The international GENESIS trial evaluated the safety and efficacy of the Company’s lead investigational candidate motixafortide plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF for the mobilization of hematopoietic stem cells in patients with multiple myeloma prior to autologous stem cell transplantation (ASCT).

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Multiple myeloma is the second most common hematologic malignancy and ASCT has been shown to improve survival and plays a central role in the treatment of these patients. A meaningful number of patients, however, are unable to collect a desired number of peripheral blood CD34+ hematopoietic stem and progenitor cells (HSPC) with current treatment modalities.

The primary objective of the study was to demonstrate that one dose of motixafortide with G-CSF, compared to placebo with G-CSF, allowed more patients to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight, in up to two apheresis sessions. A secondary objective of the study was to demonstrate that one dose of motixafortide with G-CSF was superior to placebo with G-CSF in its ability to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight in just one apheresis session. The clinical trial found that all primary and secondary endpoints were achieved with a statistical significance of p<0.0001.

"Despite improvements in survival that ASCT offers patients with multiple myeloma, there has not been significant innovation in stem cell mobilization treatments in over a decade," said John DiPersio, MD, PhD, Professor of Medicine and Director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine in St. Louis, and principal investigator of the GENESIS study. "With today’s increased use of multiple drug induction therapies and transplants in increasingly older patients, there is a corresponding increased need for new treatment options. These data highlight the potential of motixafortide plus G-CSF, if approved, to enhance the treatment options for clinicians and patients with multiple myeloma undergoing ASCT."

"This first peer-reviewed publication of results from the Phase 3 GENESIS trial is an important validation of the potential of motixafortide to address critical clinical challenges and the evolving needs of today’s ASCT treatment landscape in appropriate multiple myeloma patients," said Tami Rachmilewitz, MD, Chief Medical Officer at BioLineRx. "We look forward to continuing the development of motixafortide with the aim of advancing care for patients with multiple myeloma."

Additional GENESIS clinical trial objectives included time to engraftment of neutrophils and platelets and durability of engraftment. The motixafortide-plus-G-CSF regimen resulted in rapid and durable engraftment[i] of HSPCs following transplantation, and the regimen was also shown to have a favorable safety-profile and that it was generally well-tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions.[ii]

The study included patients that are representative of the typical multiple myeloma population undergoing ASCT, with a median age of 63 years and with ~70% of patients in both arms of the trial receiving lenalidomide-containing induction therapy. Increased age, as well as increased exposure to lenalidomide-containing induction regimens, including four-drug combination regimens, have been associated with impaired HSPC mobilization.[iii]

The study authors also performed parallel comparative FACS and single-cell transcriptional profile analyses, using GENESIS data and data from trial cohorts with other mobilization regimens, to better understand the types of cells mobilized.

The FACS analysis, as described by the study authors in Nature, found that motixafortide plus G-CSF resulted in a 10.5-fold increase in primitive HSPCs collected versus placebo plus G-CSF (p<0.0001); and significantly greater numbers of early stem and progenitor cells versus both placebo plus G-CSF (p<0.0001) and plerixafor plus G-CSF (p=0.0327). Primitive HSPCs and early stem and progenitor cells may be associated with enhanced self-renewal and regeneration.[iv] "The cohort analyses were not designed to understand potential clinical outcomes; nevertheless, we believe the findings are of interest and a compelling area for further research," said Dr. DiPersio.

A New Drug Application (NDA) for motixafortide in stem cell mobilization for autologous transplantation in multiple myeloma patients is currently under review with the U.S. Food and Drug Administration (FDA), with an assigned PDUFA date of September 9, 2023.

About the GENESIS Trial

The GENESIS trial (NCT03246529) was initiated in December 2017. GENESIS was an international, randomized, double-blind, placebo-controlled, multicenter study, evaluating the safety and efficacy of motixafortide and G-CSF, compared to placebo and G-CSF, for the mobilization of hematopoietic stem-cells for autologous transplantation in multiple myeloma patients. The primary objective of the study was to demonstrate that one dose of motixafortide with G-CSF, compared to placebo with G-CSF, allowed more patients to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight, in up to two apheresis sessions. A secondary objective of the study was to demonstrate that one dose of motixafortide with G-CSF was superior to placebo with G-CSF in its ability to mobilize ≥ 6 million CD34+ cells per kilogram of bodyweight in just one apheresis session. Additional objectives included time to engraftment of neutrophils and platelets and durability of engraftment, as well as other efficacy and safety parameters.

CD34+ cells in the GENESIS trial were assessed using both central lab and local lab data, both of which achieved statistical significance (p<0.0001) across all primary and secondary endpoints. The Nature Medicine publication focused on the study’s local lab data, as it was used for all clinical decisions in the study.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that affects some white blood cells called plasma cells, which are found in the bone marrow. When damaged, these plasma cells rapidly spread and replace normal cells in the bone marrow with tumors. According to the American Cancer Society, in 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and nearly 13,000 people will die from the disease in the U.S. While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.

About Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) is part of the standard treatment paradigm for a number of blood cancers, including multiple myeloma. In the U.S., nearly 15,000 ASCTs are performed each year with the majority in patients with multiple myeloma. The current standard of care includes the administration of 5-8 daily doses of granulocyte colony stimulating factor (G-CSF), with or without 1-4 doses of plerixafor, and the performance of 1-4 apheresis sessions. For patients unable to mobilize sufficient numbers of cells for harvesting during this primary mobilization phase, rescue therapy is carried out, consisting of 1-4 additional doses of plerixafor on top of G-CSF, and the performance of an additional number of apheresis sessions as necessary.

On April 17, 2023 Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer reported that Cleveland Clinic presented the most up-to-date data from the Phase 1 Trial of its breast cancer vaccine (Press release, Anixa Biosciences, APR 17, 2023, View Source [SID1234630137]). The data presented showed that in the vaccinated women who have been tested to date, various levels of antigen-specific T cell responses were observed at all dose levels. The presentation was made by G. Thomas Budd, M.D., of Cleveland Clinic’s Taussig Cancer Institute and principal investigator of the study. This breast cancer vaccine technology was invented at Cleveland Clinic, where the trial is being conducted, and Anixa is the exclusive worldwide licensee. The trial is funded by a grant from the U.S. Department of Defense to Cleveland Clinic.

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The Phase 1a study is designed to evaluate the safety of the vaccine, identify the Maximum Tolerated Dose (MTD), and monitor the immune response in vaccinated women. All participants in the Phase 1a study are women who have had triple negative breast cancer (TNBC) within the last three years and have been curatively treated having undergone standard of care. At the time of vaccination, these participants are tumor-free, as determined by standard diagnostic techniques, but are at high risk of recurrence.

"We are testing this vaccine to determine if a vaccinated patient’s immune system is trained to destroy cancer cells expressing α-lactalbumin, a protein found on TNBC cancer cells and not on normal cells. To evaluate the vaccination effect, immune mediated biomarkers of T cell activation and antibody production specific against α-lactalbumin are measured. We are heartened by the data, and look forward to additional studies," stated Dr. Amit Kumar, Chairman and CEO of Anixa Biosciences.

"We are pleased that varying degrees of antigen-specific T cell responses were observed at all dose levels tested to date, however, the Phase 1 trial is not designed to determine whether the responses are sufficient to prevent recurrence or primary tumorogenesis, said Dr. Budd. "We expect successive studies to determine how effective the immune responses are in preventing cancer."

About Triple-Negative Breast Cancer

One in eight women in the U.S. will be diagnosed with an invasive breast cancer at some point in their lives. Approximately 10-15% of those diagnoses are TNBC, however TNBC accounts for a disproportionately higher percentage of breast cancer deaths and has a higher rate of recurrence. This form of breast cancer is twice as likely to occur in African-American women, and approximately 70% to 80% of the breast tumors that occur in women with mutations in the BRCA1 genes are triple-negative breast cancer.

On April 17, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported interim data from its Phase 1 TRAVERSE trial of ALLO-316, the Company’s first AlloCAR TTM investigational product candidate for solid tumors, in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Orlando, Florida (Press release, Allogene, APR 17, 2023, View Source [SID1234630136]). The presentation follows the release of initial ALLO-316 data reported at the Company’s R&D Showcase event in November 2022.

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The ongoing Phase 1 TRAVERSE study is enrolling patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed on standard therapies that include an immune checkpoint inhibitor and a VEGF-targeting therapy. Emerging data from this trial have demonstrated the potential of an AlloCAR T to treat CD70 expressing RCC. In this trial, ALLO-316 showed early anti-tumor activity with deepening responses over time.

"CAR T therapy has revolutionized the treatment of several hematologic malignancies, but its application to solid tumors has been an ongoing industry challenge," said Zachary Roberts, M.D., Ph.D., Executive Vice President of Research & Development. "Early safety and efficacy data from the ongoing Phase 1 ALLO-316 dose escalation trial suggest the possibility for an off-the-shelf CAR T product to make inroads into solid tumors. Additionally, preliminary translational data confirm preclinical results showing the potential of our Dagger technology. This feature of ALLO-316 is designed to prevent premature AlloCAR T cell rejection, allowing marked cell expansion and persistence, even at low CAR T cell doses."

"I am encouraged by these data highlighting the potential of an allogeneic CAR T as a new and much needed treatment modality for patients with renal cell carcinoma," said Samer A. Srour, M.D., The University of Texas MD Anderson Cancer Center. "Initial data from the TRAVERSE trial provides a proof-of-concept for the successful application of this novel CAR T product in the treatment of advanced renal cell carcinoma."

As of the March 23, 2023 data cutoff, 19 patients were enrolled in the Phase 1 trial, 10 of whom had RCC confirmed to express CD70. The median time from enrollment to the start of therapy was five days. In the ongoing dose escalation phase of the TRAVERSE trial, patients will receive lymphodepletion followed by ALLO-316 at one of four cell dose levels (DL1= 40M cells, DL2= 80M cells, DL3=120M cells, DL4= 240M cells). The data reported to date is primarily from the DL1 and DL2 cohorts.

Anti-tumor activity was primarily observed in patients with tumors confirmed to express CD70.
Among 18 patients evaluable for efficacy, the disease control rate (DCR) was 89%. In the 10 patients whose tumors were known to express CD70, the disease control rate was 100%, which included three patients who achieved partial remission (two confirmed, one unconfirmed). The longest response lasted until month eight. There was a trend toward greater tumor shrinkage in patients with higher levels of CD70 expression.

All Patients
(n=18) CD70+ Patients
(n=10)
Overall Response Rate (ORR), n (%) 3 (17) 3 (30)
Disease Control Rate (DCR), n (%) 16 (89) 10 (100)
There were 19 patients evaluable for safety. To date, ALLO-316 has demonstrated an adverse event profile generally consistent with autologous CAR T therapies. One dose-limiting toxicity of Grade 3 autoimmune hepatitis occurred in the second dose level. Cytokine release syndrome (CRS) was all low-grade with the exception of one Grade 3. Neurotoxicity, which is now defined more broadly, was generally low grade and reversible with most events being fatigue or headache. There were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS). Infections occurred in eight patients of which four were Grade 3+ including one Grade 5 respiratory failure due to Covid-19 infection deemed unrelated to study treatment. Grade 3+ prolonged cytopenia was observed in three patients (16%). There were no cases of graft-versus-host disease (GvHD).

All Patients
(n=19)
All Grades
N (%) Gr 3+
N (%)
CRS 11 (58) 1 (5)
Infusion-Related Reaction 1 (5) 0
Neurotoxicity 13 (68) 2 (11)
ICANS 0 0
GvHD 0 0
Infection 8 (42) 4 (21)
Prolonged Gr3+ Cytopenia 0 3 (16)
The Dagger technology, which is a feature of ALLO-316, is designed to resist rejection of AlloCAR T cells by the host immune cells, thereby supporting expansion and enabling a prolonged window of persistence during which AlloCAR T cells can target and destroy cancer cells. Initial translational data from the TRAVERSE trial demonstrates the suppression of host T cells and marked peak expansion of ALLO-316 despite the relatively low cell doses tested. In addition to ALLO-316, the Company plans to deploy Dagger technology to potentially enhance the persistence and activity of next generation AlloCAR T products.

About ALLO-316 (TRAVERSE)
ALLO-316, an AlloCAR T investigational product targets CD70, which is highly expressed in renal cell carcinoma (RCC). CD70 is also selectively expressed in several cancers, creating the potential for ALLO-316 to be developed across a variety of both hematologic malignancies and solid tumors. The ongoing Phase 1 TRAVERSE trial is designed to evaluate the safety, tolerability, and activity of ALLO-316 in patients with advanced or metastatic clear cell RCC. In March 2022, the U.S. Food and Drug Administration granted Fast Track Designation (FTD) based on the potential of ALLO-316 to address the unmet need for patients with difficult to treat RCC who have failed standard RCC therapies.

On April 17, 2023 Bristol Myers Squibb (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) reported that the U.S. Food and Drug Administration (FDA) has accepted the companies’ supplemental Biologics License Application (sBLA) for Abecma (idecabtagene vicleucel) with the KarMMa-3 study that investigated the treatment of adult patients with relapsed and refractory multiple myeloma who have received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (Press release, 2seventy bio, APR 17, 2023, View Source [SID1234630135]). The FDA has assigned a Prescription Drug User Fee Act (PDUFA) goal date of December 16, 2023. Data from KarMMa-3 were published in The New England Journal of Medicine on February 10, 2023.

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"Our continued focus on bringing Abecma into earlier lines of treatment demonstrates our commitment to increasing treatment options and improving outcomes for patients living with multiple myeloma," said Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb. "This FDA acceptance marks another step forward in our mission by bringing us closer to offering this potentially transformative, one-time CAR T treatment option to more patients."

"Positive results from our Phase 3 KarMMa-3 study demonstrate a significant clinical benefit of Abecma across lines of care in triple-class exposed multiple myeloma," said Steve Bernstein, M.D., chief medical officer, 2seventy bio. "The acceptance of the sBLA brings us closer to expanding the benefits of Abecma to myeloma patients earlier in their treatment course."

Additional Regulatory Acceptances Granted to Bristol Myers Squibb

The European Medicines Agency (EMA) has also validated Bristol Myers Squibb’s Type II variation application for Abecma based on the KarMMa-3 study. Validation of the application confirms the submission is complete and begins the procedure and scientific assessment.

In addition, Japan’s Ministry of Health, Labour and Welfare has accepted Bristol Myers Squibb’s supplemental New Drug Application (sNDA) for Abecma based on the KarMMa-3 study.

"The KarMMa-3 study has shown the clear clinical benefit of Abecma over existing standard of care regimens and, if approved, the potential for this anti-BCMA CAR T cell therapy to become a standard of care earlier in the treatment course for relapsed and refractory multiple myeloma," said Adam Lenkowsky, senior vice president, head of Major Markets, Bristol Myers Squibb. "These global regulatory acceptances of BMS’ applications represent important additional progress across three regions with significant patient need in triple-class exposed multiple myeloma."

The three regulatory applications were based on interim results from the pivotal, Phase 3, open-label, global, randomized, controlled KarMMa-3 study evaluating Abecma compared with standard combination regimens. The study enrolled patients who were treated with an immunomodulatory agent, a proteasome inhibitor, and daratumumab, which are the most commonly used standard treatments in multiple myeloma. Growing use of daratumumab in frontline and early-line relapse has led to an increasing unmet need for patients following treatment with the three most common classes of antimyeloma agents, for whom there is no clear treatment paradigm and often very poor outcomes with current standards of care. Results of the KarMMa-3 study showed treatment with Abecma demonstrated a statistically significant and clinically meaningful improvement in progression-free survival and overall response rate, and safety results were consistent with the well-established and generally predictable safety profile of Abecma. Based on results from KarMMa-3, Abecma is the first and only CAR T cell therapy to demonstrate superiority over standard regimens in a randomized, controlled Phase 3 trial designed to evaluate patients with triple-class exposed relapsed and refractory multiple myeloma.

Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding cytokine release syndrome, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is also approved in the European Union, Switzerland, the United Kingdom, Japan, Canada, and Israel for adult patients with triple-class exposed relapsed and/or refractory multiple myeloma after three to four or more prior lines of therapy.

About KarMMa-3

KarMMa-3 (BB2121-MM-003, NCT03651128) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab and were refractory to the last treatment regimen. Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen by investigators based on their most recent treatment regimen. The primary endpoint evaluated in this study is progression-free survival, defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first. Key secondary endpoints include overall response rate and overall survival.

About Abecma

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio. Bristol Myers Squibb assumes sole responsibility for Abecma drug product manufacturing and commercialization outside of the U.S.

The companies’ broad clinical development program for Abecma includes ongoing and planned clinical studies (KarMMa-2, KarMMa-3, KarMMa-9) in earlier lines of treatment for patients with multiple myeloma. For more information visit clinicaltrials.gov.

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS
WARNINGS AND PRECAUTIONS:

Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 – 23 days) and the median duration of CRS was 7 days (range: 1 – 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache. Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS.

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. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%). Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

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

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 – 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 – 61 days). The median duration of neurotoxicity was 6 days (range: 1 – 578) in all patients including 3 patients with ongoing neurotoxicity. Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium. Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

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

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 – 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA 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.

Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or after ABECMA 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 ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA 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.

Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

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