On December 11, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported results from one of the largest real-world analyses of patients who received CAR T-cell therapy assessing the impact of time from leukapheresis to infusion ("vein-to-vein" time) for Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (Press release, Kite Pharma, DEC 11, 2022, View Source [SID1234625055]). The analysis reported shorter vein-to-vein times associated with improved outcomes in patients treated with Yescarta, adjusted for key prognostic factors. Data were presented on December 11, during the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Abstract #3345).

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"These real-world data further clarify the positive impact that shorter vein-to-vein time can have on patient outcomes," said Frederick L. Locke, MD, Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center. "Additional studies must be conducted to further understand the impact of vein-to-vein time on treatment outcomes in the context of other prognostic features such as requirement for bridging therapy and tumor burden. It is important for both community oncologists seeking a CAR T consult and cell therapists to understand the potential impact of lost time when seeking the best possible CAR T result for their patients."

In the pivotal clinical trials of the three commercially available CAR T-cell therapies for LBCL, Yescarta has reported shorter median vein-to-vein wait times from leukapheresis to infusion.

"As the leader in cell therapy, it’s important that we understand all of the factors that can contribute to the best possible outcomes for patients," said Chris McDonald, SVP, Global Head of Technical Operations, Kite. "We’re continuing to invest in technical advances to reduce times even further. I am hopeful studies like this will prompt improvements in the health care delivery system to reduce lost time for patients leading up to apheresis."

This new real-world use analysis assessed Yescarta patients between October 2017 and August 2020 using the Center for International Blood and Marrow Transplant Research (CIBMTR) Research Database, the post marketing registry of commercial patients prescribed Yescarta. Among all patients in the analysis (n=1,383 treated across 78 U.S. authorized treatment centers), the overall median vein-to-vein time for Yescarta was 27 days, inclusive of apheresis, both pre- and post-manufacturing transport, manufacturing time, and hospital scheduling and readiness including patient pre-conditioning prior to receiving their CAR T treatment. Kite’s manufacturing time for Yescarta in the U.S. is a median of seven days from start of cell enrichment to harvest, with an overall 16-day turnaround time (Leukapheresis to Product Release).

Shorter vein-to-vein time from the same analysis was associated with a favorable complete response (CR) rate and overall survival (OS). With a median follow-up of 24.2 months, for patients with less than 28 days or 28-39 days of vein-to-vein time, CR rates were 60% or 61%, respectively in contrast to a CR rate of 50% among patients with vein-to-vein time of 40 or more days. OS rate at 24 months was 53% among patients with vein-to-vein time up to 39 days versus 38% among patients with 40 or more days vein-to-vein time.

Similar rates of Grade ≥3 cytokine release syndrome (CRS), Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged neutropenia were observed regardless of vein-to-vein time. Patients with shorter vein-to-vein time had reduced risk of thrombocytopenia. ICANS of any grade may be higher among patients with vein-to-vein time less than 28 days but most were resolved by 21 days from onset regardless of vein-to-vein time.

CAR T-cell therapies are one-time treatments individually made starting from a patient’s own white blood cells, called T-cells. The cells are removed through leukapheresis and sent to Kite’s specialized manufacturing facilities where they are modified with a Chimeric Antigen Receptor (CAR). Once an individual therapy is created for a patient, the cells are carefully checked, preserved, packed and sent back to the hospital to be infused back into the patient. Over 11,000 patients have been treated with Kite’s CAR T-cell therapies globally through more than 300 authorized treatment centers around the world, including 117 of the leading cancer hospitals in the U.S.

About LBCL

In the United States and globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). 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 Yescarta

Please see full US 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 the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

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.
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. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 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: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 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.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 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: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 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 and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 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 YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 the 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 a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of 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 in 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 infections occurred in 17% of patients, including ≥ Grade 3 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

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one 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 an 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 an 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 an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

About the CIBMTR

The Center for International Blood and Marrow Transplant Research is a nonprofit research collaboration between the National Marrow Donor Program (NMDP)/Be The Match, in Minneapolis, and the Medical College of Wisconsin, in Milwaukee. The CIBMTR collaborates with the global scientific community to increase survival and enrich quality of life for patients. The CIBMTR facilitates critical observational and interventional research through scientific and statistical expertise, a large network of centers, and a unique database of long-term clinical data for more than 600,000 people who have received hematopoietic cell transplantation and other cellular therapies. Learn more at cibmtr.org.

On December 11, 2022 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that new and updated data for its first-in-class anti-CD79b antibody-drug conjugate Polivy (polatuzumab vedotin-piiq) were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 10-13 (Press release, Genentech, DEC 11, 2022, View Source [SID1234625054]). Data from the POLARIX study support the potential benefit of Polivy in combination with Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) to improve outcomes for people with previously untreated diffuse large B-cell lymphoma (DLBCL).

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"These updated POLARIX data indicate the potential benefits that this Polivy based-regimen could bring to people living with this aggressive type of lymphoma, and demonstrate our commitment to developing new treatment options."

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"Too many patients with diffuse large B-cell lymphoma see their cancer relapse or progress after initial treatment. This highlights the need to improve on a standard-of-care that has remained unchanged for the last two decades," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "These updated POLARIX data indicate the potential benefits that this Polivy based-regimen could bring to people living with this aggressive type of lymphoma, and demonstrate our commitment to developing new treatment options."

After a median follow up of three years, progression-free survival (PFS) data continued to show a statistically significant reduction in the risk of disease worsening or death with Polivy plus R-CHP compared with Rituxan plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; [hazard ratio (HR) 0.76; 95% confidence interval (CI): 0.60-0.97]). After a median follow-up of 39.7 months, overall survival (OS) data was immature with few events in each arm and remained similar between Polivy plus R-CHP and R-CHOP (HR 0.94; 95% CI: 0.67-1.33; p=0.73). In the longer follow-up analysis, no new safety signals were identified.

Health-related quality of life (HRQoL) data from the POLARIX study were also presented, showing that most patients with previously untreated DLBCL receiving Polivy plus R-CHP or R-CHOP reported clinically meaningful improvements in lymphoma symptoms after the first cycle of treatment across both arms (82.3% and 81.3% of patients, respectively). Improvements in fatigue and physical functioning were similar with Polivy plus R-CHP versus R-CHOP, with 74.8% versus 68.2% of patients reporting improvements in fatigue and 42.4% versus 39.6% of patients reporting clinically meaningful improvements in physical functioning at any time point. Reported improvements were sustained during and after first-line therapy, up to the 24-month follow-up. This HRQoL analysis of the POLARIX study demonstrates that these patient-reported outcomes are not compromised with improved PFS, highlighting the potential of Polivy to help manage the burden of DLBCL.

The need for more effective treatments for patients with previously untreated DLBCL was underscored in an economic analysis of the total cost of care in relapsed or refractory (R/R) DLBCL. The study evaluated healthcare costs and resources in the second-line setting and beyond, and found that total healthcare costs increased with each additional line of treatment. Separately, an analysis of the POLARIX study also presented at ASH (Free ASH Whitepaper) showed that over the next ten years, Polivy plus R-CHP has the potential to reduce the number of patients receiving second-line treatment by 27% compared to R-CHOP, potentially improving the chance of a positive outcome for more patients and significantly reducing the overall treatment burden of DLBCL.

Based on the pivotal data from the POLARIX study, more than 50 countries have approved Polivy in combination with R-CHP for the treatment of adult patients with previously untreated DLBCL, including the EU, Japan and, most recently, Canada. The company’s supplemental Biologics License Application was accepted by the U.S. Food and Drug Administration, and a decision is expected by April 2, 2023. Polivy is currently approved in more than 80 countries and regions worldwide, including in the U.S. and Europe, as a readily available, fixed-duration treatment option for R/R DLBCL in combination with bendamustine and Rituxan, after at least two prior therapies.

Genentech continues to explore areas of unmet need where Polivy has the potential to deliver additional benefit, including in ongoing studies investigating combinations of Polivy with CD20xCD3 T-cell engaging bispecific antibodies, mosunetuzumab and glofitamab, including the Phase III SUNMO study in combination with mosunetuzumab, and with Rituxan in combination with gemcitabine and oxaliplatin in the Phase III POLARGO study.

About the POLARIX Study

POLARIX [NCT03274492] is an international Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Polivy (polatuzumab vedotin-piiq) plus Rituxan (rituximab), cyclophosphamide, doxorubicin and prednisone (R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in people with previously untreated diffuse large B-cell lymphoma (DLBCL). Eight-hundred and seventy-nine patients were randomized 1:1 to receive either Polivy plus R-CHP plus a vincristine placebo for six cycles, followed by rituximab for two cycles; or R-CHOP plus a Polivy placebo for six cycles, followed by two cycles of rituximab. The primary outcome measure is progression-free survival (PFS) as assessed by the investigator using the Lugano Response Criteria for malignant lymphoma. POLARIX is being conducted in collaboration with The Lymphoma Study Association (LYSA) and The Lymphoma Academic Research Organisation (LYSARC). Other clinical investigators from around the world also participated in the trial.

About Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for about one in three cases of NHL. DLBCL is an aggressive (fast-growing) type of NHL. While it is generally responsive to treatment in the frontline, as many as 40% of people will relapse or have refractory disease, at which time salvage therapy options are limited and survival is short. Approximately 150,000 people worldwide are estimated to be diagnosed with DLBCL each year.

About Polivy (polatuzumab vedotin-piiq)

Polivy is a first-in-class anti-CD79b antibody-drug conjugate (ADC). The CD79b protein is expressed specifically in the majority of B cells, an immune cell impacted in some types of non-Hodgkin’s lymphoma (NHL), making it a promising target for the development of new therapies. Polivy is designed to bind to CD79b on B cells and destroys them through the delivery of an anti-cancer agent, which is thought to minimize the effects on normal cells. Polivy is being developed by Genentech using Seagen ADC technology and is currently being investigated for the treatment of several types of NHL.

Polivy U.S. Indication

Polivy is a prescription medicine used with other medicines, bendamustine and a rituximab product, to treat diffuse large B-cell lymphoma in adults who have progressed after at least two prior therapies.

The accelerated approval of Polivy is based on a type of response rate. There are ongoing studies to confirm the clinical benefit of Polivy.

Important Safety Information

Possible serious side effects

Everyone reacts differently to Polivy therapy, so it’s important to know what the side effects are. Some people who have been treated with Polivy have experienced serious to fatal side effects. A patient’s doctor may stop or adjust a patient’s treatment if any serious side effects occur. Patients must contact their healthcare team if there are any signs of these side effects.

Nerve problems in arms and legs: This may happen as early as after the first dose and may worsen with every dose. If a patient already has nerve pain, Polivy may make it worse. The patient’s doctor will monitor for signs and symptoms, such as changes in sense of touch, numbness or tingling in hands or feet, nerve pain, burning sensation, any muscle weakness, or changes to walking patterns
Infusion-related reactions: A patient may experience fever, chills, rash, breathing problems, low blood pressure, or hives within 24 hours of the infusion
Infections: Patients should contact their healthcare team if they experience a fever of 100.4°F or higher, chills, cough, or pain during urination. Also, a patient’s doctor may give medication before giving Polivy, which may prevent some infections, and monitor blood counts throughout treatment with Polivy. Treatment with Polivy can cause severe low blood cell counts
Rare and serious brain infections: A patient’s doctor will monitor the patient closely for signs and symptoms of these types of infections. Patients should contact their doctor if they experience confusion, dizziness or loss of balance, trouble talking or walking, or vision changes
Tumor lysis syndrome: Caused by the fast breakdown of cancer cells. Signs include nausea, vomiting, diarrhea, and lack of energy
Potential harm to liver: Some signs include tiredness, weight loss, pain in the abdomen, dark urine, and yellowing of the skin or the white part of the eyes. Patients may be at higher risk if they already have liver problems or are taking other medication
Side effects seen most often

The most common side effects during treatment were:

Low blood cell counts (platelets, red blood cells, white blood cells)
Nerve problems in arms and legs
Tiredness or lack of energy
Diarrhea
Nausea
Fever
Decreased appetite
Infections
Polivy may not be for everyone. A patient should talk to their doctor if they are:

Pregnant or may be pregnant: Data have shown that Polivy may harm an unborn baby
Planning to become pregnant: Women should avoid getting pregnant while taking Polivy. Women should use effective contraception during treatment and for at least 3 months after their last Polivy treatment. Men taking Polivy should use effective contraception during treatment and for at least 5 months after their last Polivy treatment
Breastfeeding: Women should not breastfeed while taking Polivy and for at least 2 months after the last dose
These may not be all the side effects. Patients should talk to their healthcare provider for more information about the benefits and risks of Polivy treatment.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information for additional Important Safety Information.

On December 11, 2022 Incyte (Nasdaq:INCY) reported that new research detailing the development and mechanism of action of INCA033989, an Incyte-discovered, investigational novel anti-mutant calreticulin (CALR)-targeted monoclonal antibody (Press release, Incyte, DEC 11, 2022, View Source [SID1234625053]). Pre-clinical data indicate that INCA033989 can alter disease course by reducing mutant CALR allele burden and thus may be an efficacious and safe treatment in patients with myelofibrosis (MF) and essential thrombocythemia (ET). This research was featured in the Plenary Scientific Session (Abstract #6. Session: Hematology Disease Topics & Pathways: Research, Diseases, Therapies, Myeloid Malignancies) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held December 10-13, 2022, in New Orleans and virtually1.

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"Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies"

"As a pioneer in the field of myeloproliferative neoplasms (MPNs), having brought the first FDA-approved treatment to patients, we are excited to have the opportunity to share details of our latest research," said Dash Dhanak, Ph.D., Executive Vice President and Chief Scientific Officer, Incyte. "We continue to apply our deep understanding of the complex biology of MPNs to expand treatment options for patients and the work on INCA033989 presented today reflects our progress toward this goal. We look forward to continuing to advance the development of this potential new treatment and to initiating clinical trials for INCA033989 next year."

CALR mutations are responsible for disease development in approximately 25-35%2,3 of patients with MF and ET – two common types of MPNs. INCA033989 binds with high affinity to mutant CALR and inhibits oncogenesis, the process of cells becoming cancerous, in cells expressing this oncoprotein. As described in our presentation, INCA033989 potently antagonizes CALR oncogenic function, resulting in selective inhibition of JAK/STAT signaling only in CALR-mutated cells with no effect on normal, non-oncogenic cells. This selectivity of action with INCA033989 results in the specific killing of tumor cells harboring the mutation and is suggestive of the potential to alter the course of disease in patients with CALR-mutant MF and ET.

"Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies," said Srdan Verstovsek, M.D., Ph.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center. "As a leader in the field, Incyte is uniquely positioned to develop novel medicines for these rare blood cancers, and this research provides strong rationale for the continued investigation and clinical advancement of INCA033989 – a novel treatment approach that targets CALR mutations."

More information regarding the congress and the more than 50 abstracts from Incyte’s oncology portfolio being featured at the meeting is available on the ASH (Free ASH Whitepaper) website: View Source

About Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a closely related group of blood cancers in which the bone marrow functions abnormally. The bone marrow is where the body’s blood cells are made. MPNs are progressive blood cancers that can strike anyone at any age, but they are more common in older adults. Estimates of the prevalence of MPNs vary, but analysis of claims data suggests there may be as many as 200,000 people in the U.S. living with the most prevalent MPNs: myelofibrosis, polycythemia vera or essential thrombocythemia4.

About LIMBER

Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD). The Leadership In MPNs and GVHD BEyond Ruxolitinib (LIMBER) program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs and GVHD. The program currently has three key areas of focus: development of a new, once-daily formulation of ruxolitinib; ruxolitinib-based combinations with new targets such as PI3Kδ, BET and ALK2; and new therapeutic options such as mutant CALR.

On December 11, 2022 Genmab A/S (Nasdaq: GMAB) reported that the results from multiple clinical trials evaluating epcoritamab (DuoBody-CD3xCD20), an investigational subcutaneous bispecific antibody, alone or in combination with other therapies for the treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), R/R follicular lymphoma (FL), previously untreated FL, and Richter’s Syndrome (RS) (Press release, Genmab, DEC 11, 2022, View Source [SID1234625052]). These data, along with additional results from the phase 1/2 EPCORE NHL-1 clinical trial, evaluating the safety and efficacy of epcoritamab in patients with R/R large B-cell lymphoma (LBCL), are being presented at the 64th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper), being held in New Orleans, Louisiana, and virtually, December 10-13, 2022.

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"The breadth of clinical data for epcoritamab presented at ASH (Free ASH Whitepaper) demonstrates Genmab’s commitment to addressing treatment needs for people living with a variety of B-cell lymphomas," said Dr. Judith Klimovsky, Executive Vice President and Chief Development Officer of Genmab. "Together with AbbVie, we continue to evaluate epcoritamab in various treatment settings and patient populations to unlock its potential to become a core therapy for B-cell malignancies."

Notably, results from the phase 1b/2 EPCORE NHL-2 arm (Abstract #443) evaluating 27 patients with R/R DLBCL who were eligible for autologous stem cell transplant, showed an 85 percent (23/27) overall response rate (ORR) and a 67 percent (18/27) complete metabolic response (CMR) rate, following treatment with the combination of subcutaneous epcoritamab plus standard rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C) salvage therapy. The most common treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia (69 percent), anemia (51 percent), neutropenia (44 percent), cytokine release syndrome (CRS) (41 percent), nausea (31 percent), fatigue (28 percent), constipation, diarrhea, headache, pyrexia (all at 24 percent), and increased aspartate aminotransferase (AST) (21 percent). These results were highlighted during an oral presentation on Sunday, December 11, 2022, at 10:30 a.m. CST.

Results from two additional arms of the EPCORE NHL-2 study, evaluating subcutaneous epcoritamab in combination with rituximab and lenalidomide, one arm in patients with R/R FL and the other arm in previously untreated FL, will be presented during an oral session on Sunday, December 11, 2022, beginning at 4:30 p.m. CST.

In the R/R FL arm (Abstract #609), 95 percent (63/66) of efficacy evaluable patients treated with subcutaneous epcoritamab in combination with rituximab and lenalidomide achieved an overall response. Among these patients, 80 percent (53/66) achieved a CMR, and 15 percent (10/66) achieved a partial metabolic response (PMR). The majority of patients achieved a response at the first tumor response assessment and most continued to respond through the latest assessment at the time of data collection. The most common TEAEs of any grade were neutropenia (47 percent), CRS (43 percent), injection-site reactions (32 percent), fatigue (31 percent), constipation, COVID-19, pyrexia (all at 25 percent), and infusion-related reaction (21 percent).

In the previously untreated FL patient arm (Abstract #611), 94 percent (34/36) of efficacy evaluable patients who received subcutaneous epcoritamab in combination with rituximab and lenalidomide achieved an overall response, including 86 percent (31/36) achieving a CMR as their best overall response. The most common TEAEs of any grade were CRS (54 percent), neutropenia (47 percent), pyrexia (44 percent), fatigue (37 percent), injection site reaction (37 percent), headache (34 percent), COVID-19 (33 percent), diarrhea (32 percent), constipation (29 percent), rash (27 percent), increased alanine aminotransferase (ALT) (22 percent), and vomiting (22 percent).

Preliminary results from the phase 1b/2 open-label, multi-center safety and efficacy EPCORE CLL-1 trial (Abstract #348) showed that treatment with investigational subcutaneous epcoritamab monotherapy had promising antitumor activity in 10 patients with Richter’s Syndrome, with a 60 percent ORR and a 50 percent CMR rate. Most responses were observed by the first assessment at week six. The most common related TEAEs of any grade percent were CRS (90 percent), anemia (50 percent), neutropenia (50 percent), injection-site reaction (40 percent), thrombocytopenia (40 percent), and hypophosphatemia, hypokalemia, hyperglycemia, COVID-19, diarrhea, fatigue, and nausea (all at 30 percent). These results were highlighted during an oral session on Saturday, December 10, 2022, at 5:15 p.m. CST.

About Diffuse Large B-cell Lymphoma (DLBCL)
Diffuse large B-cell lymphoma (DLBCL) is a fast-growing type of non-Hodgkin’s lymphoma (NHL) that affects B-cell lymphocytes, a type of white blood cell.1 It is the most common type of NHL worldwide and accounts for approximately 30 percent of all NHL cases.1 DLBCL can arise in lymph nodes, as well as in organs outside of the lymphatic system.1 The disease occurs more commonly in the elderly and is slightly more prevalent in men.1

About Follicular Lymphoma (FL)
Approximately 2.7 per 100,000 people in the U.S. are newly diagnosed with FL every year and the median age of patients at diagnoses with FL is 63.2,3,4 FL is typically an indolent (or slow growing) form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes.5 Although FL is an indolent lymphoma, it is considered incurable with conventional therapy.6,7

About Richter’s Syndrome (RS)
RS, also known as Richter’s Transformation, is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).8,9 RS occurs in approximately 2 to 10 percent of CLL patients during the course of their disease.8

About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response towards target cells. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of CD20+ cells.10 CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.11,12

Genmab recently announced that the Biologics License Application (BLA) for epcoritamab for the treatment or R/R LBCL was accepted for Priority Review by the U.S. Food and Drug Administration (FDA), with an FDA action date of May 21, 2023. Additionally, the European Medicines Agency (EMA) recently validated the Marketing Authorization Application (MAA) for epcoritamab for the treatment of adult patients with R/R DLBCL after two or more lines of systemic therapy.

Epcoritamab is being co-developed by AbbVie and Genmab as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. The companies are committed to evaluating epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes an ongoing Phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma (NCT: 04628494) and a Phase 3, open-label clinical trial evaluating epcoritamab in combination in patients with relapsed/refractory follicular lymphoma (NCT: 05409066).

On December 11, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported findings from two new analyses of the landmark ZUMA-7 trial of Yescarta (axicabtagene ciloleucel), the largest and longest follow-up of a CAR T-cell therapy versus standard of care (SOC) in patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) (Press release, Kite Pharma, DEC 11, 2022, View Source [SID1234625051]). These results include an analysis of outcomes for patients who received subsequent treatment for their lymphoma following second-line Yescarta therapy or SOC therapy, as well as an exploratory analysis of the association between metabolic tumor volume (MTV) and clinical outcomes. The data were presented orally at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition on December 11 and 10, respectively (Abstracts #659 and #259).

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Data from the pivotal ZUMA-7 trial supported the U.S. Food and Drug Administration’s (FDA) expanded approval of Yescarta in April 2022 as initial treatment in adults with r/r LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy, and led to a similar approval by the European Medicines Agency in October 2022. This year marks Yescarta’s 5th anniversary from the initial approval by the FDA in 2017 as the first CAR T-cell therapy for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy.

"These further analyses from the ZUMA-7 study show consistent benefit of Yescarta versus standard of care in the second-line r/r LBCL setting, including for those who require subsequent third-line treatment and even for specific patient subgroups," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. "These results provide physicians additional confidence in utilizing Yescarta as initial treatment of relapsed/refractory large B-cell lymphoma."

Abstract #659

Outcomes of Subsequent Anti-Lymphoma Therapies In Patients With Large B-Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel) or Standard of Care (SOC) in the Second-Line (2L) Zuma-7 Study

In an analysis of patients from the ZUMA-7 trial who required subsequent therapy following second-line treatment, 47% (84 of 180) of patients randomized to receive Yescarta in the second-line (2L) required subsequent therapy compared to 71% (127 of 179) patients randomized to 2L standard of care. For patients who received third-line (3L) chemotherapy following treatment with Yescarta (n=60), overall median progression-free survival (PFS) was 1.7 months (95% CI, 1.4-2.0) and median overall survival (OS) was 8.1 months (95% CI, 5.8-11.5) since 3L treatment initiation, with an objective response rate (ORR) of 25% [complete response (CR) rate: 13%]. Among Yescarta patients who received 3L cellular immunotherapy (n=8), median PFS was 3.5 months (95% CI, 1.1-not evaluable), and six patients went on to receive subsequent stem cell transplant, with all six alive at data cutoff (median follow-up since 3L treatment initiation: 24.4 months). Of the patients who received retreatment with CAR T-cell therapy in 3L, but did not progress on to stem cell transplant (n=2), one had fatal disease progression at 8.7 months following retreatment, and one had a complete response (CR) and was alive at data cutoff (8.4 months following retreatment). Thirty-four of these patients received 3L chemotherapy following initial response to 2L Yescarta. Among those patients, overall median PFS was 1.7 months (95% CI, 1.4-2.4) and median OS was 8.1 months (95% CI, 6.8-11.9), with an ORR of 32% (CR rate: 18%). Among patients randomized to SOC who received 3L cellular immunotherapy (n=68), median PFS was 6.3 months (95% CI, 3.4-16.3) and median OS was 16.3 months (95% CI, 8.7-not evaluable).

"These findings showed that patients who received CAR T-cell therapy as second-line treatment for r/r LBCL do better than those who wait and receive it as third-line," said Armin Ghobadi, MD, ZUMA-7 investigator and Associate Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri. "These findings support the earlier use of CAR T, and can help inform subsequent treatment choices after second-line treatment, including stem cell transplant."

Abstract #259

Association of Metabolic Tumor Volume (MTV) and Clinical Outcomes in Second-Line (2L) Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Following Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care (SOC) Therapy in ZUMA-7

In an analysis from ZUMA-7 of the association of metabolic tumor volume (MTV) and clinical outcomes, event-free survival (EFS) was superior for Yescarta compared to SOC for patients with high and low MTV (HR, 0.417 and 0.423, respectively; descriptive P<0.05 for both). EFS trended shorter in Yescarta patients with high MTV (HR, 1.441 [95% CI, 0.978-2.124]) and EFS was shorter in SOC patients with high MTV (HR, 1.486 [95% CI, 1.055-2.093]). Similarly, PFS with Yescarta was superior to SOC for both low and high MTV (HR, 0.504 [95% CI, 0.328-0.776] and HR, 0.523 [95% CI, 0.357-0.765], respectively). In the Yescarta arm, median MTV was higher in patients who experienced Grade ≥3 neurologic events or Grade ≥3 cytokine release syndrome (CRS) compared with patients who experienced Grade 1-2 or no neurologic events or Grade 1-2 or no CRS, respectively.

"ZUMA-7 demonstrated that axi-cel is superior to standard of care across common prognostic subgroups, including tumor burden," said Frederick L. Locke, MD, ZUMA-7 principal investigator and Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center. "These findings are further supported by this analysis which is the first-ever report to examine metabolic tumor volume in a large, randomized, prospective relapsed/refractory large B-cell lymphoma study."

The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

About Large B-Cell Lymphoma (LBCL)

Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). 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 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 AND NEUROLOGIC TOXICITIES

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.
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. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 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: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and median duration was 6 days (range: 1-27 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.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 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: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 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 and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 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 YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. 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 infections occurred in 17% of patients, including ≥ Grade 3 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

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one 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.