On December 8, 2024 CStone Pharmaceuticals ("CStone", HKEX: 2616), an innovation-driven biopharmaceutical company focused on the research and development of anti-cancer therapies, reported the presentation of the latest clinical data for CS5001, an anti-ROR1 ADC and one of the leading assets in CStone Pipeline 2.0, at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, CStone Pharmaceauticals, DEC 8, 2024, View Source [SID1234648881]). These data highlight the compound’s potential as a treatment for lymphoma.

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an embryonic tyrosine kinase-like molecule implicated in multiple pathways promoting oncogenic signaling. ROR1 is overexpressed at high frequency in hematological malignancies and in a broad spectrum of solid tumors while lower or absent in normal tissues, which makes ROR1 an attractive anti-cancer therapy target. CS5001 is so far the first anti-ROR1 ADC known to show clinical anti-tumor activity in both solid tumors and lymphomas.

Dr. Jason Yang, CEO, President of R&D, and Executive Director at CStone, commented,"We are very encouraged that CS5001 continues to demonstrate potent anti-tumor activity and manageable safety and tolerability in the ongoing clinical study. The data presented at ASH (Free ASH Whitepaper) further validate CS5001’s potential, particularly as a monotherapy for patients with advanced lymphomas, most of whom had failed at least 3 prior lines of therapy. We observe encouraging anti-tumor activity in both HLs and NHLs, especially the ORR of 76.9% among the 13 evaluable patients with advanced B-cell lymphoma at DL8 (125 μg/kg). As we move forward with our Phase 1b study, we will further evaluate and optimize the dose. Given CS5001’s initial efficacy in both aggressive and indolent lymphomas, we are confident in its broad clinical potential and significant market competitiveness. We remain committed to accelerate the clinical development of CS5001 in bringing this novel therapy to lymphoma patients as soon as possible."

Patient baseline characteristics

A total of 33 patients with advanced B-cell lymphoma were enrolled, including 17 diffuse large B-cell lymphoma (DLBCL), 11 HLs, 2 follicular lymphoma (FL), 1 mantle cell lymphoma (MCL), 1 marginal zone lymphoma (MZL), and 1 high-grade B-cell lymphoma (HGBCL).

Among them, 84.8% were Asian, and the rest were non-Asian. 81.8% of the patients had received at least 3 prior lines of systemic anti-tumor therapy. In the DL8 cohort, patients who had previously received CART and hematopoietic stem cell transplantation therapy each accounted for over 20%.

Safety and tolerability

Dose escalation has been completed and no DLT has been reported up to DL10 so far.

Efficacy Results

CS5001 demonstrated encouraging anti-tumor activity in B-cell lymphomas, with an ORR of 48.4% across all dose levels; a notably higher ORR of 76.9% was observed at DL8 (125 μg/kg) among 13 evaluable patients.

Hodgkin Lymphoma (HL): objective responses were observed from effective dose of DL5 (50 μg/kg) and above, including 3 complete responses (CRs) and 3 partial responses (PRs) among 10 evaluable patients at DLs 5-9 (ORR: 60.0%). 2 CRs and 1 PR were observed at DL8 (125 μg/kg) among 3 evaluable patients.
Non-Hodgkin Lymphoma (NHL): objective responses were observed from effective dose of DL7 (100 μg/kg) and above, including 3 CRs (2 DLBCL and 1 MCL) and 6 PRs (3 DLBCL, 1 MZL, 1 HGBC and 1 FL) among 16 evaluable patients at DLs 7-9 (ORR: 56.3%). A notably higher ORR of 70.0% was observed at DL8 (125 μg/kg) among 10 evaluable patients.
The global multicenter Phase 1 trial of CS5001 are currently in progress in the United States, Australia, and China. Dose escalation has been completed. Backfilling at DL8 (125 μg/kg) or DL9 (156μg/kg) is still ongoing. A Phase 1b dose-expansion study with potential for registration across multiple tumor types is expected to be initiated soon.

Conference Call and Webcast

CStone will host a conference call and webcast to discuss this announcement on December 9, 2024, at 10:00 AM Beijing Time.

The conference call can be accessed via this link: View Source

About CS5001 (ROR1 ADC)

CS5001 is a clinical-stage antibody-drug conjugate ("ADC") targeting ROR1 (receptor tyrosine kinase-like orphan receptor 1). CS5001 has been uniquely designed with proprietary tumor-cleavable linker and pyrrolobenzodiazepine ("PBD") prodrug. Only after reaching the tumor, the linker and prodrug are cleaved to release the PBD toxin, resulting in lethal DNA cross-links in cancer cells. The use of the linker plus PBD prodrug effectively helps address the toxicity associated with traditional PBD payloads, leading to a better safety profile. CS5001 has demonstrated complete tumor suppression in several preclinical cancer models and demonstrated favorable serum half-life and pharmacokinetic characteristics. CS5001 is a promising candidate drug with precision treatment potential in both hematologic tumors and malignant solid tumors. Additionally, CS5001 utilizes site-specific conjugation for a precise drug antibody ratio of which enables homogeneous production and large-scale manufacturing.

In October 2020, CStone signed a licensing agreement with LigaChem Biosciences, Inc. (LCB) for the development and commercialization of CS5001 which was originally generated by collaboration of LCB and ABL Bio, both South Korea-based leading biotech companies. Under the agreement, CStone obtains the exclusive global right to develop and commercialize CS5001 outside the Republic of Korea.

Preliminary data from the first-in-human study presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting demonstrated that CS5001 is well-tolerated and exhibits encouraging anti-tumor activity across various dose levels in patients with heavily pre-treated advanced solid tumors and lymphomas.

On December 8, 2024 Johnson & Johnson (NYSE: JNJ) reported data highlighting that DARZALEX FASPRO (daratumumab and hyaluronidase-fihj)-based regimens improve overall and sustained minimal residual disease (MRD) negativity rates and progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM), regardless of transplant status (Press release, Johnson & Johnson, DEC 8, 2024, View Source [SID1234648880]). These findings were demonstrated in an expanded MRD analysis of the Phase 3 CEPHEUS study (Abstract #362) and a post hoc analysis of clinically relevant subgroups in the Phase 3 AURIGA study (Abstract #675), which were both featured as oral presentations at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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Data from the expanded MRD analysis of the Phase 3 CEPHEUS study show the addition of DARZALEX FASPRO to bortezomib, lenalidomide and dexamethasone (D-VRd) leads to improved and deepened rates of overall and sustained MRD negativity (both 10-5 and 10-6 sensitivity thresholds in patients who achieved a complete response or better) versus VRd alone, and shows significantly improved progression-free survival.1 CEPHEUS is the fifth Phase 3 study showing the addition of DARZALEX improves depth and duration of response, leading to improved progression-free survival.1,3,4,5

At a median follow-up of 58.7 months, overall MRD-negativity rates were significantly higher with D-VRd versus VRd at both 10–5 (60.9 percent vs. 39.4 percent; odds ratio [OR], 2.37; 95 percent confidence interval [CI], 1.58-3.55; P<0.0001) and 10–6 (46.2 percent vs. 27.3 percent; OR, 2.24; 95 percent CI, 1.48-3.40; P=0.0001) sensitivity thresholds. Treatment with D-VRd shows continued benefit of sustained MRD negativity for two years (10-5: 42.1 percent vs. 22.7 percent; 10-6: 27.9 percent vs. 13.6 percent). Additionally, the deeper and more sustained MRD negativity rates with D-VRd trended with improved progression-free survival (PFS) rates – the estimated 54-month PFS rates were 86.2 percent for D-VRd patients versus 79 percent for VRd in MRD negative (10-6) patients, and 51 percent versus 36.5 percent for MRD-positive patients.1

"This analysis from the CEPHEUS study comparing daratumumab-VRd versus VRd, showed higher rates of both overall and sustained MRD negativity alongside promising trends in progression-free survival," said Sonja Zweegman, MD, PhD, head of the Department of Hematology, Amsterdam University Medical Center.* "This regimen has the potential to improve outcomes for patients with newly diagnosed multiple myeloma who are ineligible for transplant or for whom transplant is not planned as initial therapy."

Addition of DARZALEX FASPRO to maintenance regimens resulted in higher MRD negativity rates across clinically relevant subgroups by age, race, disease stage and cytogenetic risk

In a post hoc analysis of the Phase 3 AURIGA study, an investigational maintenance regimen of DARZALEX FASPRO combined with lenalidomide (R) resulted in consistently improved MRD-negative conversion rates after 12 months. These results were consistent across anti-CD38 naïve patient subgroups who were MRD-positive post-autologous stem cell transplant (ASCT). In patients older than 65 years, MRD-negative rates were higher when treated with D-R maintenance therapy compared to R alone (52.6 percent vs. 17.5 percent; OR, 5.24; 95 percent CI, 1.86-14.74). Maintenance therapy with D-R showed a consistently higher conversion to MRD negativity in Black patients (n=20) compared to R alone (60.0 percent vs 16.7 percent; OR, 7.50; 95 percent CI, 1.85-30.34) and white patients (n=67) (46.3 percent vs. 20.6 percent; OR, 3.32; 95 percent CI, 1.55-7.10).2

Data also show that the investigational maintenance regimen of D-R resulted in higher MRD-negative conversion rates for patients with advanced-stage disease (Stage III) as defined by the International Staging System (ISS) (65.2 percent vs. 13 percent; OR, 12.50; 95 percent CI, 2.83-55.25) and patients with high cytogenetic risk per the standard definition (31.8 percent vs. 6.7 percent; OR, 6.53; 95% CI, 0.71-60.05) or the revised definition (43.8 percent vs. 13.3 percent; OR, 5.06; 95 percent CI, 1.43-17.88).2

"Patients over 65, Black individuals, and those with advanced or high-risk disease are disproportionately impacted by multiple myeloma and historically have had fewer treatment options that yield deep and durable results," said Imran Khan, M.D., Ph.D., Vice President, Medical Affairs, Hematology, Johnson & Johnson Innovative Medicine. "Evaluating MRD negativity in these patients underlies its importance as a recognized predictor of long-term progression-free survival. The data being presented at ASH (Free ASH Whitepaper) this year emphasize the potential of DARZALEX FASPRO in helping newly diagnosed patients achieve MRD negativity."

Final analysis of Phase 3 ANDROMEDA study reinforces DARZALEX FASPRO-based regimen showing significant overall survival in patients with newly diagnosed light chain (AL) amyloidosis

The final analysis of the Phase 3 ANDROMEDA study was also presented (Abstract #891), showing that the addition of DARZALEX FASPRO to bortezomib, cyclophosphamide, and dexamethasone (D-VCd) demonstrated deeper and more rapid hematologic responses, resulting in a statistically significant improvement in both OS and major organ deterioration progression-free survival (MOD-PFS) (i.e., end-stage renal or cardiac disease, hematologic progression, or death) for patients with newly diagnosed AL amyloidosis, a rare plasma cell disorder associated with the deterioration of vital organs. Patients treated with D-VCd showed a 56 percent reduction in the risk of progression or death (hazard ratio [HR] = 0.44, P< 0.0001). The median MOD-PFS was not reached for D-VCd, while it was 30.2 months for VCd. Additionally, D-VCd also provided significant survival benefits with a HR of 0.62 (P=0.0121), indicating a 38 percent reduction in the risk of death compared to VCd. The 5-year survival rate was 76.1 percent for D-VCd versus 64.7 percent for VCd.6

In the CEPHEUS, AURIGA and ANDROMEDA studies, the safety profiles were consistent with the known safety profile for DARZALEX FASPRO.

About the CEPHEUS Study
CEPHEUS (NCT03652064) is an ongoing, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of D-VRd vs VRd in patients with newly diagnosed multiple myeloma who are transplant-ineligible or for whom transplant is not intended as initial therapy. Primary endpoint is MRD negativity rate at 10-5 sensitivity threshold. Secondary endpoints include PFS, MRD-negative rate at one year, durable MRD negativity, ORR, time to and duration of response, PFS on next line of therapy, overall survival and safety. The trial has enrolled 396 patients in 13 countries.

About the AURIGA Study
The randomized study (NCT03901963) included 200 patients aged 18-79 years with newly diagnosed multiple myeloma who are minimal residual disease (MRD)-positive after frontline autologous stem cell transplant. Patients received investigational 1,800 milligram (mg) daratumumab by subcutaneous (SC) injection in combination with lenalidomide (orally) as maintenance therapy for a maximum of 36 cycles. Each cycle is 28 days. Patients in the comparative arm will receive lenalidomide (orally) alone as maintenance therapy for a maximum of 36 cycles. Each cycle is 28 days.4

About the ANDROMEDA Study
ANDROMEDA (NCT03201965) is an ongoing Phase 3, randomized, open-label study investigating the safety and efficacy of DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd), compared to VCd alone, for the treatment of adult patients with newly diagnosed light chain (AL) amyloidosis. The study includes 388 patients with newly diagnosed AL amyloidosis with measurable hematologic disease and one or more organs affected. The primary endpoint is overall complete hematologic response rate by intent-to-treat (ITT). Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks one to eight, once every two weeks from weeks nine to 24 and once every four weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of two years. Among patients who received D-VCd, 74 percent were exposed for 6 months or longer and 32 percent were exposed for greater than one year.

About Multiple Myeloma
Multiple myeloma is a blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.7 In multiple myeloma, these malignant plasma cells proliferate and replace normal cells in the bone marrow.8 Multiple myeloma is the second most common blood cancer worldwide and remains an incurable disease.9 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 will die from the disease.10 People with multiple myeloma have a 5-year survival rate of 59.8 percent. 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.11,12

About AL Amyloidosis
Light chain (AL) amyloidosis is a rare and potentially fatal hematologic disorder that can affect the function of multiple organs. The disease occurs when bone marrow produces abnormal pieces of antibodies called light chains, which clump together to form a substance called amyloid. These clumps of amyloid are deposited in tissues and vital organs and interfere with normal organ function, eventually causing organ deterioration.13,14 It is the most common type of amyloidosis. AL amyloidosis frequently affects the heart, kidneys, digestive tract, liver and nervous system, and is potentially fatal if left untreated.15 Diagnosis is often delayed and prognosis is poor due to advanced, multi-organ, particularly cardiac, involvement.16,17 Each year, an estimated 4,500 people develop AL amyloidosis in the U.S. alone.18

About DARZALEX FASPRO and DARZALEX
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for eight indications in multiple myeloma, three of which are for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible.14 It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

DARZALEX (daratumumab) received U.S. FDA approval in November 2015 and is approved in eight indications, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.6

DARZALEX is the first CD38-directed antibody approved to treat multiple myeloma.6 DARZALEX-based regimens have been used in the treatment of more than 580,000 patients worldwide and more than 239,000 patients in the U.S. alone.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab.

Since 2020, the National Comprehensive Cancer Network (NCCN) has recommended daratumumab-based combination regimens for the treatment of newly diagnosed multiple myeloma and relapsed and refractory multiple myeloma.† For newly diagnosed multiple myeloma in non-transplant candidates, the NCCN guidelines recommend daratumumab in combination with lenalidomide and dexamethasone as a Category 1 preferred regimen; daratumumab in combination with bortezomib, melphalan, and prednisone as another recommended Category 1 regimen; and daratumumab in combination with bortezomib, cyclophosphamide, and prednisone as another recommended Category 2A regimen. For newly diagnosed multiple myeloma in transplant candidates, the NCCN guidelines recommend daratumumab in combination with bortezomib, lenalidomide and dexamethasone as another recommended Category 2A regimen; daratumumab in combination with bortezomib, thalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; daratumumab in combination with carfilzomib, lenalidomide and dexamethasone as a Category 2A regimen useful in certain circumstances; and daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as a Category 2A regimen useful in certain circumstances. For maintenance in transplant candidates, the NCCN guidelines recommend daratumumab in combination with lenalidomide as useful in certain circumstances. In relapsed/refractory myeloma, four daratumumab regimens are listed as Category 1 preferred regimens for early relapses (1-3 prior therapies): daratumumab in combination with lenalidomide and dexamethasone; daratumumab in combination with bortezomib and dexamethasone; daratumumab in combination with carfilzomib and dexamethasone; and daratumumab in combination with pomalidomide and dexamethasone [after one prior therapy including lenalidomide and a proteasome inhibitor (PI)]. The NCCN also recommends daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone as another Category 2A regimen for early relapses (1-3 prior therapies) and as monotherapy as a Category 2A regimen useful in certain circumstances for early relapse patients after at least three prior therapies, including a PI and an immunomodulatory agent, or for patients who are double refractory to a PI and an immunomodulatory agent.

For more information, visit www.DARZALEX.com.

DARZALEX FASPRO INDICATIONS AND IMPORTANT SAFETY INFORMATION 

INDICATIONS

DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with bortezomib, lenalidomide, and dexamethasone for induction and consolidation in newly diagnosed patients who are eligible for autologous stem cell transplant

• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy

• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant

• In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor (PI)

• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy

• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy

• As monotherapy in patients who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent

DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with light chain (AL) amyloidosis

• In combination with bortezomib, cyclophosphamide and dexamethasone in newly diagnosed patients. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Limitations of Use:

DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain (AL) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS  

DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase, or any of the components of the formulation.  

WARNINGS AND PRECAUTIONS  

Hypersensitivity and Other Administration Reactions  

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO.

Systemic Reactions  

In a pooled safety population of 1249 patients with multiple myeloma (N=1056) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or in combination, 7% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 0.7%, Grade 4: 0.1%). Systemic administration-related reactions occurred in 7% of patients with the first injection, 0.2% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 2.9 hours (range: 5 minutes to 3.5 days). Of the 165 systemic administration-related reactions that occurred in 93 patients, 144 (87%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension, tachycardia, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritus, chills, vomiting, nausea, hypotension, and blurred vision.  

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen, and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.  

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with daratumumab-containing products. If ocular symptoms occur, interrupt DARZALEX FASPRO and seek immediate ophthalmologic evaluation prior to restarting DARZALEX FASPRO.  

Local Reactions  

In this pooled safety population, injection-site reactions occurred in 7% of patients, including Grade 2 reactions in 0.8%. The most frequent (>1%) injection-site reaction was injection-site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis

Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone [see Adverse Reactions (6.1)]. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

Neutropenia  

Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed.  

Thrombocytopenia  

Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.  

Embryo-Fetal Toxicity  

Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose.  

The combination of DARZALEX FASPRO with lenalidomide, thalidomide, or pomalidomide is contraindicated in pregnant women because lenalidomide, thalidomide, and pomalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, thalidomide, or pomalidomide prescribing information on use during pregnancy.  

Interference With Serological Testing  

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted.  

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO.  

Interference With Determination of Complete Response  

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.  

ADVERSE REACTIONS  

In multiple myeloma, the most common adverse reaction (≥20%) with DARZALEX FASPRO monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, headache, pyrexia, cough, muscle spasms, back pain, vomiting, hypertension, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.  

The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.  

Please click here to see the full Prescribing Information for DARZALEX FASPRO.

DARZALEX INDICATIONS AND IMPORTANT SAFETY INFORMATION

INDICATIONS

DARZALEX (daratumumab) is indicated for the treatment of adult patients with multiple myeloma:

• In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant

• In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy

• In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant

• In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor

• In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy

• In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy

• As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent

CONTRAINDICATIONS

DARZALEX is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

DARZALEX can cause severe and/or serious infusion-related reactions including anaphylactic reactions. These reactions can be lifethreatening, and fatal outcomes have been reported. In clinical trials (monotherapy and combination: N=2066), infusion-related reactions occurred in 37% of patients with the Week 1 (16 mg/kg) infusion, 2% with the Week 2 infusion, and cumulatively 6% with subsequent infusions. Less than 1% of patients had a Grade 3/4 infusion-related reaction at Week 2 or subsequent infusions. The median time to onset was 1.5 hours (range: 0 to 73 hours). Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, tachycardia, headache, laryngeal edema, pulmonary edema, and ocular adverse reactions, including choroidal effusion, acute myopia, and acute angle closure glaucoma. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common signs and symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, hypotension and blurred vision.

When DARZALEX dosing was interrupted in the setting of ASCT (CASSIOPEIA) for a median of 3.75 months (range: 2.4 to 6.9 months), upon re-initiation of DARZALEX, the incidence of infusion-related reactions was 11% for the first infusion following ASCT. Infusion-related reactions occurring at re-initiation of DARZALEX following ASCT were consistent in terms of symptoms and severity (Grade 3 or 4: <1%) with those reported in previous studies at Week 2 or subsequent infusions. In EQUULEUS, patients receiving combination treatment (n=97) were administered the first 16 mg/kg dose at Week 1 split over two days, ie, 8 mg/kg on Day 1 and Day 2, respectively. The incidence of any grade infusion-related reactions was 42%, with 36% of patients experiencing infusion-related reactions on Day 1 of Week 1, 4% on Day 2 of Week 1, and 8% with subsequent infusions.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt DARZALEX infusion for reactions of any severity and institute medical management as needed. Permanently discontinue DARZALEX therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion-related reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Ocular adverse reactions, including acute myopia and narrowing of the anterior chamber angle due to ciliochoroidal effusions with potential for increased intraocular pressure or glaucoma, have occurred with DARZALEX infusion. If ocular symptoms occur, interrupt DARZALEX infusion and seek immediate ophthalmologic evaluation prior to restarting DARZALEX.

Interference With Serological Testing

Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive indirect antiglobulin test (indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type is not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia and Thrombocytopenia

DARZALEX may increase neutropenia and thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX until recovery of neutrophils or for recovery of platelets.

Interference With Determination of Complete Response

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Embryo-Fetal Toxicity

Based on the mechanism of action, DARZALEX can cause fetal harm when administered to a pregnant woman. DARZALEX may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX and for 3 months after the last dose.

The combination of DARZALEX with lenalidomide, pomalidomide, or thalidomide is contraindicated in pregnant women because lenalidomide, pomalidomide, and thalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide, pomalidomide, or thalidomide prescribing information on use during pregnancy.

ADVERSE REACTIONS

The most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory infection, neutropenia, infusion related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia. The most common hematologic laboratory abnormalities (≥40%) with DARZALEX are: neutropenia, lymphopenia, thrombocytopenia, leukopenia, and anemia.

On December 8, 2024 Jacobio Pharma (1167.HK), a clinical-stage oncology company dedicated to developing therapies toward undruggable targets, reported preliminary Phase I data of BET inhibitor JAB-8263 to treat myelofibrosis (MF) at the 2024 ASH (Free ASH Whitepaper) (American Society of Hematology) Annual Meeting in San Diego, California (Press release, Jacobio Pharmaceuticals, DEC 8, 2024, View Source [SID1234648879]).

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The data showed that JAB-8263 was well tolerated with Recommended Phase 2 Dose (RP2D) being 0.3mg QD. The preliminary efficacy data for JAB-8263 monotherapy in MF are promising, as most patients demonstrated spleen volume reduction (SVR) and total symptom score (TSS) reduction.

As of the data cutoff date of Oct 17, 2024, 16 patients with intermediate-/high-risk MF have been enrolled, and 13 patients have undergone at least one post-treatment efficacy assessment.

All patients showed a mean SVR-19.95%at week 24 and -26.16% at best response.
Two patients achieved ≥35% SVR, and an SVR of -34.9% was observed in one patient.
Six of ten (60%) patients experienced a ≥50% reduction in TSS at week 24.
The best response of SVR in 2 of 8 patients (JAK inhibitors-treated) was -41.2% and -34.9%, respectively.
At week 24, 3 of 6 (50%) patients (JAK inhibitors-treated) achieved TSS50.
The monotherapy of JAB-8263 expansion in MF and solid tumor is ongoing. Andrea Wang-Gillam M.D., Ph.D., Chief Medical Officer and Global Head of R&D at Jacobio said, "The preliminary data demonstrated the promising clinical value of our potent BET inhibitor in MF. We will continue exploring for broader indications for JAB-8263, hoping to bring hope to more cancer patients."

On December 8, 2024 Abbisko Therapeutics (HKEX: 02256) reported the presentation of preliminary Phase 2 study results for pimicotinib (ABSK021) in patients with chronic Graft-versus-Host Disease (cGvHD) who have either progressed or not responded to one or more prior lines of therapy (Press release, Abbisko Therapeutics, DEC 8, 2024, View Source [SID1234648878]). The presentation took place at the 66th ASH (Free ASH Whitepaper) Annual Conference, held December 7-10, 2024, in San Diego, California. Despite most enrolled patients having not yet completed the 6-month treatment cycle required for cGvHD response evaluation, preliminary data from the subset of patients receiving 20mg QD shows that pimicotinib achieved an ORR of 64%.

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As of November 22, 2024, a preliminary 64% ORR was observed in the subset of patients receiving pimicotinib 20mg QD, with responses observed in all affected organs, including the gastrointestinal tract, oral cavity, eyes, liver, joints and fascia, esophagus, skin, and lungs.

In many patients with cGvHD, pulmonary manifestations, such as shortness of breath and diminished lung function, can occur and finally be diagnosed as cGvHD-associated BOS (Bronchiolitis Obliterans Syndrome), which is one of the major challenges in the treatment of cGvHD urgently requiring new therapies. During the oral presentation, researchers highlighted specific lung response results in six subjects at the latest data cut-off: one subject achieved an 11% increase in FEV1 (forced expiratory volume in the first second), one subject’s FEV1 recovered to more than 75% after treatment thereby returning to normal levels, and the remaining four subjects saw improvements in the NIH Lung score with significant improvements in shortness of breath. Together, data demonstrate the clinical efficacy of pimicotinib for the treatment of cGvHD-associated BOS.

As of the November 22, 2024 data cut-off, the majority of enrolled patients have not yet completed the 6-month treatment cycle to determine the primary endpoint of the study, suggesting the possibility of improved outcomes with longer-term treatment with pimicotinib. The results show that pimicotinib demonstrated robust clinical efficacy and is well tolerated in heavily pre-treated patients with cGvHD. Rapid and durable responses were observed across both inflammation-dominated and fibrosis-dominated organs, accompanied by patient-reported reductions in organ-specific symptom burden. The majority of adverse events were Grade 1 and reversible. Based on latest clinical experience, pimicotinib represents a potentially promising and novel therapeutic option for the management of cGvHD.

About Pimicotinib (ABSK021)

Pimicotinib (ABSK021), which is being independently developed by Abbisko Therapeutics, is a novel, orally administered, highly selective, and potent small-molecule inhibitor of CSF-1R. Pimicotinib has been granted breakthrough therapy designations (BTD) by China National Medical Products Administration (NMPA) and the U.S. Food and Drug Administration (FDA) and priority medicine (PRIME) designation from the European Medicines Agency (EMA) for the treatment of patients with TGCT that are not amenable to surgery. Pimicotinib is also currently being evaluated for the treatment of patients with chronic Graft-versus-Host Disease.

On December 8, 2024 Kite, a Gilead Company (Nasdaq: GILD), reported findings from three new analyses for Yescarta (axicabtagene ciloleucel) that demonstrate improved outcomes for people living with relapsed or refractory (R/R) large B-cell lymphoma (LBCL), which were presented at 66 th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, Gilead Sciences, DEC 8, 2024, View Source [SID1234648877]).

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The data include findings from the largest real-world analysis of patients who received Yescarta as second-line treatment for R/R LBCL during 2022-2023 based on Center for International Blood and Marrow Transplant Research (CIBMTR) registry data (abstract #526). This real-world evidence (RWE) demonstrates high rates of overall survival (OS), overall response rate (ORR), complete response (CR), and other effectiveness measures, consistent with ZUMA-7 outcomes. Further RWE from CIBMTR demonstrate a decreasing trend in incidence, severity and duration of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) in the third-line-plus setting during 2017-2023 (abstract #527). In addition, findings from the Phase 2 ALYCANTE study on health-related quality of life (HRQoL) outcomes following Yescarta treatment (abstract #4505), co-sponsored by the French collaborative group The Lymphoma Study Association/Lymphoma Academic Research Organization (LYSA/LYSARC) and Kite, show either stability or improvement of HRQoL three months following infusion.

"We are pleased that Yescarta’s overall survival benefit for patients with early relapsed/refractory large B-cell lymphoma is confirmed in the largest real-world analysis of a broader patient population," said Dominique Tonelli, VP, Global Head of Medical Affairs, Kite. "By studying outcomes in the real world, we consistently demonstrate that patients treated with Yescarta have the opportunity to live longer."

Detailed Information on Yescarta Abstracts:

Abstract #526
Real-World Early Outcomes of Second-Line Axicabtagene Ciloleucel (Axi-Cel) Therapy in Patients (Pts) With Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL)

The largest real-world analysis of 446 patients from 89 U.S. centers from the CIBMTR Registry with LBCL (diffuse LBCL [DLBCL], 78%; primary mediastinal LBCL [PMBCL], 3%; high-grade B-cell lymphoma, 18%; follicular lymphoma grade IIIB, 1%) who received second-line Yescarta treatment demonstrated outcomes consistent with the ZUMA-7 study across broader patient and disease characteristics than those included in the ZUMA-7 pivotal study or Phase 2 ALYCANTE study, at a median of 12-months of follow-up.

Among all patients, ORR was 79% (95% confidence interval [CI], 75–82), with a CR rate of 64% (95% CI, 60–69). The 12-month rate of duration of response (DOR) was 66% (95% CI, 59–71), progression-free survival (PFS) was 53% (48–58), event-free survival (EFS) was 53% (48–58), and OS was 71% (66–76). Any-grade CRS and ICANS were reported in 87% (Grade ≥ 3, 5%) and 50% (Grade ≥ 3, 22%), respectively.

When assessed by ZUMA-7 eligibility, ORRs in ineligible patients (n=219) versus eligible or unknown patients (n=214) were both 79%, respectively, with CR rates of 63% and 65%, respectively. At 12-months, DOR in ZUMA-7 ineligible and eligible or unknown patients were 60% and 69%, PFS were 48% and 58%, EFS were 48% and 58%, and OS were 62% and 80%, respectively. Incidence of ICANS was 54% in ZUMA-7 ineligible patients and 45% in ZUMA-7 eligible or unknown patients. Among 13 patients with PMBCL, ORR was 69% (95% CI, 39–91), all with CR. The six-month rate (95% CI) of DOR was 100%, PFS was 68%, EFS was 68%, and OS was 100%. Incidence of any-grade CRS was 85% and ICANS was 54%.

"It is reassuring that the largest real-world dataset for axi-cel as a second-line treatment for relapsed/refractory large B-cell lymphoma, across a broader patient population than the ZUMA-7 pivotal study or Phase 2 ALYCANTE study for transplant-ineligible patients, has demonstrated consistent outcomes at 12-months median follow-up as in ZUMA-7," said Dr. Dasom (Caroline) Lee, Lead Investigator on the study and Fellow, Hematology and Medical Oncology, Stanford Medicine. "These data should provide further confidence to physicians that earlier use of axi-cel can provide the best chance for overall survival and possibly a cure for these patients."

Abstract #527
Real-world Trends of Cytokine Release Syndrome and Neurologic Events, and Pattern of Their Management among Patients Receiving Axicabtagene Ciloleucel for Relapsed or Refractory (r/r) Large B-cell Lymphoma (LBCL) in the U.S.: a CIBMTR Report

Real-world data from 1,615 patients with R/R LBCL from 109 U.S. centers from the CIBMTR registry demonstrated a decreasing trend in incidence, severity and duration of CRS and ICANS following treatment with Yescarta for adult patients with R/R LBCL in the third-line-plus setting.

Patients who received Yescarta during 2022–2023 (n=206) and 2020–2021 (n=486) had significantly lower incidences of Grade ≥ 3 CRS compared to those treated during 2017–2019 (n=923, odds ratio [OR] 0.17, 95% CI, 0.07−0.41, and OR 0.63, 95% CI, 0.43−0.94, respectively). Furthermore, patients treated in the later time periods of 2022-2023 and 2020-2021 experienced significantly shorter duration of CRS compared to 2017-2019 (hazard ratio [HR] 1.36, 95% CI, 1.14-1.64, and HR 1.34, 95% CI, 1.18-1.52, respectively).

Patients who received Yescarta during 2022–2023 and 2020–2021 had a significantly lower incidence of any-grade ICANS compared to those treated in 2017–2019 (OR 0.47, 95% CI, 0.34−0.66, and OR 0.63, 95% CI, 0.50−0.80, respectively). The duration of ICANS was also significantly shorter for those treated in 2020-2021 compared to 2017-2019 (HR 1.21, 95% CI, 1.02-1.43)

The rates of use of tocilizumab and corticosteroids for the treatment of CRS/ICANS were consistent for the three periods, although there was an increasing trend of anakinra use (1%, 6%, and 13%, respectively). Concerning other adverse events, rates of prolonged thrombocytopenia and clinically significant infections were consistent.

"Over the past seven years, there has been wider adoption of CAR T-cell therapies as a standard treatment for patients, and the knowledge, skills, and experience needed to administer the therapies safely and effectively has grown," said Dr. Jiasheng Wang, Assistant Professor of Medicine, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. "This real-world analysis reflects a growing understanding in clinical tools such as prophylactic and preemptive management strategies that can help manage axi-cel patients safely and effectively."

Abstract #4505
Health-related quality of life after Axi-cel as a second-line therapy in patients with high-risk relapsed/refractory large B-cell lymphoma who are ineligible for autologous stem cell transplantation: results of the ALYCANTE phase II trial

New HRQoL findings from the Phase 2 ALYCANTE study, led and sponsored by the French collaborative group LYSA/LYSARC, for use of Yescarta in patients with R/R LBCL after one prior line of therapy who were deemed ineligible for high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), demonstrated that after a short initial deterioration at one-month post-infusion, patients reported longer-term stable or improved quality of life across parameters, after up to 12 months of follow-up.

Findings from 61 patients included in the ALYCANTE study reported a lower symptomatic level, noted by lower HRQoL, at three months compared to baseline, with a clinically significant difference for pain (mean=11.9 [95% CI, 5.4-18.4] at three months vs. 25.1 [95% CI, 17.7-32.6] at baseline), emotional impact (mean=12.9 [95% CI, 8.6-17.2] vs. 23.8 [95% CI, 17.9-29.6]) and worries/fears about health and functioning (mean=22.1 [95% CI, 16.8-27.3] vs. 33.0 [95% CI, 27.2-38.8]).

At three months post Yescarta infusion, 45% of patients presented a stable global health condition and 73% stable physical functioning. In the longer-term, at 12 months post-infusion, patients reported stable states, with clinically and statistically significant improvement in 4/22 HRQoL measures. Analyses confirmed findings observed over time for global health status, physical functioning and visual analogue scale (VAS, common valuation method to provide a single-index measure of HRQoL) were consistent between both the ALYCANTE and pivotal ZUMA-7 study.

"ALYCANTE is the first study to assess axi-cel as second-line therapy in transplant-ineligible relapsed/refractory large B-cell lymphoma patients, with previous study findings confirming its efficacy in this patient population," said Prof. Roch Houot, Head of Haematology Department, University Hospital of Rennes, France and coordinator of the ALYCANTE study. "This current study shows that, in this frail and elderly population, axi-cel not only increased the quantity of life but also improved the quality of life which was comparable to that of the transplant-eligible patients, and allowed recovery of a fatigue score close to the general French population."

About LBCL

Globally, LBCL is the most common type of non-Hodgkin lymphoma . In the United States, more than 18,000 people are diagnosed with LBCL each year. About 30-40% of patients with LBCL will need second-line treatment, as their cancer will either relapse (return) or become refractory (not respond) to initial treatment.

About ALYCANTE study

ALYCANTE (NCT04531046) is a phase 2 study evaluating the efficacy and safety of Yescarta in patients with R/R LBCL after one prior line of therapy who were deemed ineligible for high-dose chemotherapy and ASCT, sponsored by the LYSA/LYSARC collaborative group. The primary endpoint was the complete metabolic response at three months from Yescarta infusion. The study was funded by Kite, a Gilead Company, and carried out with Yescarta manufactured by Kite.

About ZUMA-7 Study

Based on the primary efficacy endpoint results of ZUMA-7, the U.S. Food & Drug Administration approved Yescarta as initial treatment of R/R LBCL in April 2022. The EU granted approval in October 2022, followed by approvals in several other countries such as: Australia, Canada, Great Britain, Israel, Japan and Switzerland.

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus standard of care (SOC) for second-line therapy in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. The SOC for initial treatment of R/R LBCL has been a multi-step process involving platinum-based salvage combination chemotherapy regimen, and for responders, HDT and ASCT. In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or SOC second-line treatment. The primary endpoint was EFS as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate and OS. Additional secondary endpoints included patient-reported outcomes (PROs) and safety. Per hierarchical testing of primary and key secondary endpoints and group sequential testing of OS, an interim analysis of OS occurred at the time of the primary EFS.

About Yescarta

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES and SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids, as needed.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including YESCARTA.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL) receiving YESCARTA, including ≥ Grade 3 (Lee grading system1) CRS in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 CRS in 9%. Among patients with LBCL who died after receiving YESCARTA, four had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1 to 10 days) and the median duration was 7 days (range: 2 to 43 days).

CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 CRS in 8%. Among patients with iNHL who died after receiving YESCARTA, one patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1 to 20 days) and the median duration was 6 days (range: 1 to 27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include, cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) .

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in two subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events. CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days).

Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS at which point the patients were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing Grade 3 or higher CRS. The median time to onset of CRS was 5 days (range: 1 to 15 days) and the median duration of CRS was 4 days (range: 1 to 10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life- threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range:1- 133 days) and median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained about the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL. Grade 3 or higher infections occurred in 17% of patients, including ≥ Grade 3 or higher infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL 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.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed. 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 B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA 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 YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Patients treated with YESCARTA may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including YESCARTA. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.

Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA 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 non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with pathogen unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.