On December 11, 2021 Novartis reported that Kymriah (tisagenlecleucel) demonstrated strong efficacy in high-risk patients with relapsed or refractory (r/r) follicular lymphoma (FL) based on a subgroup analysis from an approximately 17-month median follow-up of the pivotal Phase II ELARA study1 (Press release, Novartis, DEC 11, 2021, View Source [SID1234596842]). These results were presented in an oral session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) (Abstract #131).

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In the subgroup analysis, results showed high rates of durable responses were induced by Kymriah in patients for the majority of high-risk disease subgroups, who typically have a poor prognosis. Complete response rate (CRR), overall response rate (ORR), and durability of response (DOR) were maintained in most patients in the high-risk subgroups, with the exception of those in three of the nine subgroups analyzed: those with progression-of-disease within two years (POD24), high total metabolic tumor volume (TMTV) and patients who had received five or more prior lines of therapy1.

"It’s truly exciting to see that after treatment with Kymriah in patients with difficult-to-treat, high-risk follicular lymphoma, patients are experiencing long-lasting responses with a low risk of severe adverse events," said Catherine Thieblemont, MD, PhD, Professor of Hematology in the Paris VII- University, France and Head of the Hemato-Oncology Unit of St-Louis Hospital in Paris.

High and durable responses were seen in the overall population of the ELARA study in which 94 patients were evaluable for efficacy with a median follow-up of approximately 17 months. The CRR was 69% (95% CI, 60-78), ORR was 86% (95% CI, 78-92), 12-month progression-free survival (PFS) was 67% (95% CI, 56-76) and nine-month DOR was 76% (95% CI, 65-84). For patients who had a complete response (CR), 12-month PFS was 86% (95% CI, 74-92) and the estimated DOR rate was 87% (95% CI, 75-93). In the safety analysis (n=97), the safety profile of Kymriah continued to reflect the remarkable results seen in earlier ELARA analyses. Within eight weeks of infusion, 48% of patients experienced cytokine release syndrome (CRS), with no patients experiencing CRS of grade 3 or higher as defined by the Lee scale, 37% had neurological events (3% were greater than or equal to grade 3) and there were no treatment-related deaths1.

A separate analysis of hospitalization and intensive care unit patterns for patients treated in the inpatient and outpatient settings in the ELARA trial suggest Kymriah may reduce healthcare resource utilization for patients with r/r FL treated in the outpatient setting (Abstract #3533). Among patients treated in the outpatient setting (n=17), 35% did not require hospitalization during the first two months of the post-infusion period; those who did had a lower median average length of stay than the patients infused in an inpatient setting (4 days [n=17] vs 12 days [n=80]). Additionally, the mean hospitalization costs in the post-infusion period were substantially lower in the outpatient versus inpatient setting2.

"The ability to administer Kymriah, a potentially definitive treatment, in the outpatient setting may reduce the burden of therapy for patients and their care teams," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development, Novartis. "The breadth of follicular lymphoma data presented at this year’s ASH (Free ASH Whitepaper) demonstrate the potential for Kymriah to provide transformative results and a positive impact on health systems overall."

Novartis is committed to bringing the benefits of Kymriah to more patients with advanced blood cancers worldwide, with regulatory submissions for follicular lymphoma in the US and EU complete in October 2021. If approved in this indication, Novartis will look to confirm these results of the ELARA trial and related analyses in the real-world setting.

About follicular lymphoma
Follicular lymphoma (FL), the second most common form of non-Hodgkin lymphoma (NHL), is an indolent lymphoma, and represents approximately 22% of NHL cases3,4. It is often an unrelenting malignancy with a relapsing and remitting pattern5,6. Throughout the lifetime of a patient with relapsing FL, he or she may be exposed to a median of five lines of prior treatment, with an upper range of 13 lines7,8. Although patients in third or later line treatment for FL have multiple systemic therapies available, the efficacy of these regimens drops off rapidly in later lines5. Additionally, because of this relapsing and remitting pattern, patients who are refractory to treatment or relapse may exhaust available treatment options5.

About the ELARA trial
ELARA is a Phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of Kymriah in adult patients with r/r FL after at least two prior therapies. This international trial has enrolled patients from over 30 sites in 12 countries worldwide. The primary endpoint is complete response rate (CRR) based on best response by central review (Lugano 2014 criteria). Patients evaluable for efficacy had measurable disease at infusion and more than six months of follow-up from infusion or discontinued early. After infusion, disease assessments were performed every three months. In a high-risk subgroup analysis, patients evaluated included those with prior hematopoietic stem cell transplant, double-refractory disease, high Follicular Lymphoma International Prognostic Index at study entry, high lactate dehydrogenase at baseline, high C-reactive protein prior to infusion, radiological bulky disease, progression-of-disease within two years (POD24), high total metabolic tumor volume (TMTV), and patients who had received five or more prior lines of therapy1. Secondary endpoints include overall response rate, duration of response, progression-free survival, overall survival and safety. Primary analysis data announced at ASCO (Free ASCO Whitepaper) 2021 showed Kymriah led to responses for the majority of patients treated, with 66% achieving a complete response (95% CI, 56-75). The overall response rate was 86% (95% CI, 78-92)9. Importantly, no patients in ELARA trial experienced grade 3 or higher cytokine release syndrome related to Kymriah within the first 8 weeks following infusion, the most common side effect associated with CAR-T therapy9.

About Novartis commitment to Oncology Cell Therapy
Novartis has a mission to reimagine medicine by bringing curative cell therapies to patients worldwide. Novartis has a deep CAR-T pipeline and ongoing investment in manufacturing and supply chain process improvements. With active research underway to broaden the impact of cell and gene therapy in oncology, Novartis is going deeper in hematological malignancies, reaching patients with other cancer types and evaluating next-generation CAR-T cell therapies that focus on new targets and utilize new technologies.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of Novartis’ commitment to CAR-T cell therapy.

Kymriah is currently approved for use in at least one indication in 30 countries and at more than 350 certified treatment centers, with the ambition for further expansion to help fulfill the ultimate goal of bringing CAR-T cell therapy to every patient in need.

Novartis has a global CAR-T manufacturing footprint that includes both Novartis-owned and contract manufacturing sites. This comprehensive, integrated footprint strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain.

US FDA approved indications for Kymriah
Kymriah (tisagenlecleucel) is a CD19-directed genetically modified autologous T cell immunotherapy, which is indicated for:

The treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
The treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma (FL). Limitations of Use: Kymriah is not indicated for treatment of patients with primary central nervous system lymphoma.
Kymriah (tisagenlecleucel) US Important Safety Information
KYMRIAH may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or neurological toxicities. Patients with CRS may experience symptoms including difficulty breathing, fever (100.4◦F/38◦C or higher), chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their healthcare provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, KYMRIAH is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.

Serious allergic reactions, including anaphylaxis, may occur after KYMRIAH infusion. KYMRIAH can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their healthcare provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s healthcare provider will do blood tests to check all their blood cell counts after treatment with KYMRIAH. Patients should be advised to tell their healthcare provider right away if they get a fever, are feeling tired, weak, or short of breath, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with KYMRIAH and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with KYMRIAH. Patients should tell their healthcare provider about their treatment with KYMRIAH before receiving a live vaccine.

After treatment with KYMRIAH, patients will be monitored lifelong by their healthcare provider, as they may develop secondary cancers or recurrence of their cancer.

Patients should not drive, operate heavy machinery, or do other dangerous activities for eight weeks after receiving KYMRIAH because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of KYMRIAH are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, dizziness/lightheadedness, and headache. However, these are not all the possible side effects of KYMRIAH. Patients should talk to their healthcare provider for medical advice about side effects.

Prior to a female patient starting treatment with KYMRIAH, their healthcare provider may do a pregnancy test. No information is available for KYMRIAH use in pregnant or breast-feeding women. Therefore, KYMRIAH is not recommended for women who are pregnant or breast feeding. Patients should talk to their healthcare provider about birth control and pregnancy.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving KYMRIAH, patients should be advised that some commercial HIV tests may cause a false-positive test result. Patients should also be advised not to donate blood, organs, tissues, sperm, oocytes, and other cells after receiving KYMRIAH.

On December 11, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported updated two-year results from ZUMA-5, a global, multicenter, single-arm, open-label Phase 2 study evaluating Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL) after at least two prior lines of therapy (Press release, Kite Pharma, DEC 11, 2021, View Source [SID1234596841]). The data were presented in an oral session during the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Abstract #93).

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At the time of data cut-off, 110 patients (86 with follicular lymphoma (FL); 24 with marginal zone lymphoma (MZL)) were eligible for efficacy analyses. FL patients had at least two years of follow-up time, and the minimum requirement for MZL was four weeks. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). The objective response rate (ORR) in FL was 94%, with a complete response (CR) rate of 79%. Fifty-seven percent of eligible FL patients had ongoing responses. The estimated median duration of response (DOR) and progression-free survival (PFS) was 38.6 months and 39.6 months, respectively. Among eligible FL patients, median time to next treatment was 39.6 months. Median overall survival (OS) was not reached, with an estimated 24-month OS rate of 81%.

Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). Eighty-three percent of patients achieved ORR, including 63% with a CR. Fifty percent of patients were in ongoing response at the time of data cut-off. Median DOR and time to next treatment were not yet reached among eligible patients, and median PFS was 17.3 months. Median OS was not yet reached, with an estimated 24-month OS rate of 70%.

"When treating patients with indolent non-Hodgkin lymphomas including follicular lymphoma, we try to reduce the frequency of relapses and slow progression to more aggressive disease," said Sattva S. Neelapu, MD, Professor, Department of Lymphoma-Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Relapse among these patients is most likely to take place within two years of treatment, so to see high rates of response, an estimated median PFS of almost 40 months, and no evidence of progressive events after the two-year mark is highly encouraging of the potential for axicabtagene ciloluecel to redefine treatment for these patients."

Among all evaluable patients (n=149), safety observations were consistent with the known safety profile for Yescarta. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 7% (6% FL; 8% MZL) and 19% (15% FL; 36% MZL) of patients, respectively. Most CRS cases (120/121) and neurologic events (82/87) of any grade resolved by the time of data cut-off.

"The continued durable response to a single infusion of Yescarta in a patient population that tends to experience frequent relapses is impressive," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "With these longer-term data, we believe Yescarta is truly practice-changing for patients with indolent NHLs like follicular lymphoma, and we’re working diligently to bring this therapy to patients across the globe who may benefit."

Yescarta received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy in March 2021. 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.

Yescarta is currently under review in the European Union for the treatment of adult patients with relapsed or refractory FL. Yescarta has not been approved by any regulatory agency for the treatment of MZL.

About ZUMA-5
ZUMA-5 is an ongoing, single-arm, open-label, multicenter trial evaluating 146 patients (≥18 years old) with relapsed or refractory iNHL including FL, who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was established on the basis of objective response rate (ORR) and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification.

About Indolent Non-Hodgkin Lymphoma and Follicular Lymphoma
Follicular lymphoma (FL) is a form of indolent non-Hodgkin lymphoma (iNHL) in which malignant tumours slowly grow but can become more aggressive over time. FL is the most common form of indolent non-Hodgkin lymphoma and the second most common type of lymphoma globally. It accounts for approximately 22% of all lymphomas diagnosed worldwide. Currently, there are limited options for the treatment of relapsed or refractory indolent FL after two or more lines of therapy.

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 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), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving Yescarta, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). 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 (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing 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). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following 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 that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. 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 for patients with iNHL. 98% 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 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing 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). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, 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 47% (119/254) of all patients with NHL. Grade ≥3 infections occurred in 19% of patients, Grade ≥3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, 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 anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% 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. 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 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% 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 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 adverse reactions (incidence ≥20%) in patients with LBCL 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 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.

On December 11, 2021 BeiGene (NASDAQ: BGNE; HKEX: 06160), a global, science-driven biotechnology company focused on developing innovative and affordable medicines, reported that additional safety and efficacy results from an ongoing Phase 2 trial evaluating BRUKINSA (zanubrutinib) in patients with previously treated B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib (Press release, BeiGene, DEC 11, 2021, View Source [SID1234596839]). These data were reported in a mini-oral presentation today at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"We are highly encouraged by these results, providing further evidence of BRUKINSA’s potential to benefit patients with a variety of advanced B-cell malignancies who experience intolerable adverse events on other BTK inhibitors," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "BRUKINSA was purposefully designed by BeiGene scientists to deliver sustained inhibition of the BTK protein and address certain tolerability concerns by optimizing kinase selectivity to reduce off-target effects. The updated results from this trial in patients who discontinued treatment with other BTK inhibitors due to adverse events complements previously reported findings from our two Phase 3 head-to-head trials comparing BRUKINSA to ibrutinib, where BRUKINSA demonstrated certain safety advantages over ibrutinib."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

Phase 2 Trial of BRUKINSA in BTK Inhibitor-Intolerant Patients with R/R B-cell Malignancies

Mini Oral Presentation; Abstract #1410

This single-arm, open-label, multicenter Phase 2 trial in the U.S. (NCT04116437) evaluated the safety and efficacy of BRUKINSA in patients with previously treated B-cell malignancies who were intolerant to prior BTK inhibitor therapy, with preliminary results presented at the 62nd ASH (Free ASH Whitepaper) Annual Meeting in December 2020. The primary endpoint of safety was assessed by the recurrence and the change in severity of adverse events (AEs) compared to patients’ intolerance AE profile to ibrutinib and/or acalabrutinib. Secondary endpoints included investigator-assessed disease control rate (DCR), overall response rate (ORR), investigator-assessed progression-free survival (PFS) and patient-reported outcomes.

A total of 67 patients were enrolled in the trial, with 57 patients intolerant to ibrutinib (Cohort 1) and 10 patients intolerant to acalabrutinib and/or ibrutinib (Cohort 2), including 43 patients with chronic lymphocytic leukemia (CLL; 38 in Cohort 1 and five in Cohort 2), 11 patients with Waldenström’s Macroglobulinemia (WM; nine in Cohort 1 and two in Cohort 2), seven patients with small lymphocytic lymphoma (SLL; six in Cohort 1 and one in Cohort 2), three patients with mantle cell lymphoma (MCL; two in Cohort 1 and one in Cohort 2), and three patients with marginal zone lymphoma (MZL; two in Cohort 1 and one in Cohort 2). Patients were considered intolerant if they developed significant or persistent toxicities while on ibrutinib and/or acalabrutinib despite optimal care.

"Tolerability of BTK inhibitors continues to be a significant challenge for patients and their physicians, as treatment disruption or discontinuation may impact clinical outcomes. These data demonstrated that treatment with BRUKINSA was well-tolerated and unlikely to lead to recurrence of intolerant AEs experienced with prior BTK inhibitor therapy," commented Mazyar Shadman, M.D., MPH, Associate Professor of Clinical Research Division at Fred Hutchinson Cancer Research Center and Assistant Professor of Oncology at University of Washington, and a principal investigator of the trial. "Additionally, BRUKINSA was effective in at least maintaining or improving treatment responses from baseline, suggesting BRUKINSA may be a treatment option for patients intolerant to other BTK inhibitor therapy across hematologic malignancies."

At the data cutoff on September 8, 2021, with a median BRUKINSA exposure of 11.1 months (11.6 months in Cohort 1 and 9.8 months in Cohort 2), more than a majority of the ibrutinib and acalabrutinib intolerance events did not recur with BRUKINSA treatment and none of the intolerance events recurred at a higher severity. Safety results included:

34 out of 57 patients (59.6%) who took ibrutinib and seven out of 10 patients (70.0%) who took acalabrutinib did not have recurrence of any intolerance event with BRUKINSA treatment;
Of the 115 ibrutinib intolerance events, 81 (70.4%) did not recur on BRUKINSA; of the 34 recurrent events, 26 (76.5%) recurred at a lower severity, and eight (23.5%) recurred at the same severity;
Of the 18 acalabrutinib intolerance events, 15 (83.3%) did not recur on BRUKINSA; of the three recurrent events, one (33.3%) recurred at a lower severity, and two (66.6%) recurred at the same severity;
Of the 38 Grade 3 ibrutinib intolerance events, 25 (65.8%) did not recur on BRUKINSA, 12 (31.6%) recurred at a lower severity, and one (2.6%) recurred at the same severity;
Of the four Grade 3 acalabrutinib intolerance events, three (75.0%) did not recur on BRUKINSA and one (25.0%) recurred at a lower severity;
All four Grade 4 intolerance events (neutropenia [n=2], ALT increase [n=1], AST increase [n=1]) did not recur on BRUKINSA; and
One patient (1.5%) discontinued BRUKINSA due to recurrence of a prior intolerant event (myalgia; acalabrutinib).
In 67 patients across both cohorts, BRUKINSA was tolerable with additional safety results including:

AEs leading to BRUKINSA treatment discontinuation occurred in five patients (7.5%), including four in Cohort 1 and one in Cohort 2);
64 patients (95.5%) experienced at least one AE of any grade with BRUKINSA treatment, including 54 in Cohort 1 and 10 in Cohort 2, with the most common (≥10%) being confusion or bruising (22.4%), fatigue (20.9%), myalgia (14.9%), arthralgia (13.4%), diarrhea (13.4%), hypertension (11.9%), dizziness (10.4%), and nausea (10.4%);
20 patients (29.9%) experienced at least one Grade ≥3 AE with BRUKINSA treatment, including 17 in Cohort 1 and three in Cohort 2, with the most common (in more than one patient) being neutropenia (7.5%) and decreased neutrophil count (4.5%);
Eight patients (11.9%) experienced at least one serious AE with BRUKINSA treatment, including six in Cohort 1 and two in Cohort 2; and
AEs leading to dose interruption, reduction, and death with BRUKINSA treatment occurred in 20 patients (29.9%; 16 in Cohort 1 and four in Cohort 2), six patients (9.0%; five in Cohort 1 and one in Cohort 2), and one patient (1.5%; Cohort 1), respectively.
Efficacy results were assessed by investigators in patients who were on treatment for more than 90 days across both cohorts. BRUKINSA was effective in at least maintaining response in 60 patients (93.8% in all patients, with 94.7% in Cohort 1 and 85.7% in Cohort 2) or improving response from baseline in 41 patients (64.1% in all patients, with 63.2% in Cohort 1 and 71.4% in Cohort 2); the median time to first response was 2.96 months in all patients, with 2.92 months in Cohort 1 and 3.02 months in Cohort 2.

About BRUKINSA

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA has received 12 approvals covering 40 countries and regions:

For the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy (United States, November 2019)*;
For the treatment of MCL in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have received at least one prior therapy (China, June 2020)**;
For the treatment of relapsed or refractory MCL (United Arab Emirates, February 2021);
For the treatment of Waldenström’s macroglobulinemia (WM) in adult patients (Canada, March 2021);
For the treatment of adult patients with WM who have received at least one prior therapy (China, June 2021)**;
For the treatment of MCL in adult patients who have received at least one prior therapy (Canada, July 2021);
For the treatment of MCL in adult patients who have received at least one prior therapy (Chile, July 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Brazil, August 2021);
For the treatment of adult patients with WM (United States, August 2021);
For the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen (United States, September 2021)*;
For the treatment of adult patients with MCL who have received at least one previous therapy (Singapore, October 2021);
For the treatment of MCL in patients who have received at least one prior therapy (Israel, October 2021);
For the treatment of adult patients with WM who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one prior therapy (Australia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Russia, October 2021);
For the treatment of adult patients with MCL who have received at least one previous therapy (Saudi Arabia, November 2021); and
For the treatment of adult patients with WM who have received at least one prior therapy or first-line treatment of patients unsuitable for chemo-immunotherapy (European Union plus Iceland and Norway, November 2021).
To date, more than 20 marketing authorization applications have been submitted for BRUKINSA for various indications.

* This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

** This indication was approved under conditional approval. Complete approval for this indication may be contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.4% of patients treated with BRUKINSA monotherapy. Hemorrhage events of any grade occurred in 35% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 27% of patients, most commonly pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (26%), thrombocytopenia (11%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia occurred in 3.6% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer, reported in 8% of patients. Other second primary malignancies included malignant solid tumors (4.0%), melanoma (1.7%) and hematologic malignancies (1.2%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter were reported in 3.2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 1.1% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse reactions

The most common adverse reactions, including laboratory abnormalities, in ≥ 30% of patients who received BRUKINSA (N = 847) included decreased neutrophil count (54%), upper respiratory tract infection (47%), decreased platelet count (41%), hemorrhage (35%), decreased lymphocyte count (31%), rash (31%) and musculoskeletal pain (30%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

Please see full U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf.

BeiGene Oncology

BeiGene is committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D team of approximately 2,750 colleagues dedicated to advancing more than 90 ongoing or planned clinical trials that have involved more than 14,000 patients and healthy volunteers. Our expansive portfolio is directed predominantly by our internal colleagues supporting clinical trials in more than 45 countries and regions. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. BeiGene currently has three approved medicines discovered and developed in our own labs: BTK inhibitor BRUKINSA in the United States, China, the EU, Canada, Australia and additional international markets; and the non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab as well as the PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On December 11, 2021 Harpoon Therapeutics, Inc. (NASDAQ: HARP), a clinical-stage immunotherapy company developing novel T cell engagers, reported a poster with interim data from the ongoing dose-escalation portion of the Phase 1/2 trial for HPN217 in patients with relapsed/refractory multiple myeloma (R/R MM) at the 63rd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Harpoon Therapeutics, DEC 11, 2021, View Source [SID1234596838]). HPN217 targets B-cell maturation antigen (BCMA) and is based on Harpoon’s proprietary Tri-specific T cell Activating Construct (TriTAC) platform designed to recruit a patient’s own immune cells to kill tumor cells.

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As of November 10, 2021, the data cutoff date for the interim clinical data presentation, 37 patients have been dosed across 10 cohorts at fixed doses of 5 to 2860 µg/week and in step dosing cohorts up to 3240 µg/week administered as an intravenous infusion. These interim data demonstrated:

HPN217 is generally well tolerated with one dose limiting toxicity (DLT) reported of Grade 4 AST elevation that resolved, MTD has not been reached
HPN217 is clinically active at higher dose levels with clinical benefit, disease control rate (DCR) of 88%, demonstrated in 7 of 8 disease evaluable patients in the 2150 µg/week cohort
2 stringent complete responses (SCRs) have been observed, one in each of the higher dose 2150 and 2860 µg/week cohorts
Transient and manageable cytokine release syndrome (CRS) reported in 9 of 37 patients (24%) were all Grade 1 or 2
Introduction of step dose regimens has allowed for the administration of higher target doses, currently at 3240 µg/week
"These encouraging data for HPN217 demonstrate robust clinical activity at higher doses, strong target engagement, and a manageable safety profile in this heavily refractory patient population," said Natalie Sacks, M.D., Chief Medical Officer of Harpoon Therapeutics. "Dose escalation is ongoing to determine the RP2D for advancement into the expansion phase of the trial."

Interim Results from the Ongoing HPN217 Phase 1/2 Trial Presented at ASH (Free ASH Whitepaper)

This Phase 1/2 trial is a multicenter, open-label study designed to evaluate safety, tolerability, pharmacokinetics and clinical activity in patients with R/R MM who have had at least three prior systemic treatments including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody. The initial ongoing phase of the trial is dose escalation, with the goal of determining a recommended dose for the expansion phase. The escalation phase began with single patient cohorts and transitioned to a 3+3 design when Grade 2 toxicity was observed. HPN217 is being administered to patients once weekly by intravenous infusion and the primary outcome measures are an assessment of safety and tolerability, pharmacokinetics and pharmacodynamics. Secondary endpoints include duration of response, progression free and overall survival. Tumor assessment is based on International Myeloma Working Group (IMWG) Response Criteria.

As of the November 10, 2021 data cut-off date, 37 patients have been treated in 10 cohorts with fixed doses ranging from 5 to 2860 µg/week or a step dosing regimen of 1620 µg priming dose followed by a 3240 µg/week target dose. Premedication to minimize CRS includes dexamethasone and other standard therapies. Enrolled patients had a median of 7 prior therapies. The most frequent treatment-emergent adverse events (TEAEs) occurring in greater than 20% were anemia, 17 patients (46%), fatigue, 12 patients (32%), and transient CRS, 9 patients (24%), No grade 3 or higher CRS was reported and one dose limiting toxicity (DLT) was reported, grade 4 AST, which resolved. Maximum tolerated dose has not been reached.

Clinical benefit was observed in the patients receiving higher doses. In 8 disease evaluable patients enrolled at 2150 µg/week an ORR of 63% was reported (5/8 patients) consisting of 1 stringent CR, 1 VGPR, and 3 PRs. including 1 patient with prior BCMA-targeting therapy exposure. The disease control rate, (DCR), was 88% based on 7/8 patients. For the 2860 µg/week cohort consisting of 5 evaluable patients, the ORR was 2/5 (40%) including a second stringent CR, with a DCR of 60%. As of the data cutoff, all responders remained on study treatment.

HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 – 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increase in serum cytokines and chemokines (IL-6, IL-8, IL-10, TNFα).

Patients continue to be enrolled in the escalation phase of the trial, with a goal to identify a recommended Phase 2 dose for an expansion phase. The expansion phase of the trial will further evaluate the safety and activity of HPN217 in patients with R/R MM. This trial is titled, "A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and PK of HPN217 in Patients With R/R MM". For additional information about the trial, please visit www.clinicaltrials.gov using the identifier NCT04184050.

Preclinical Data for HPN217 Presented at ASH (Free ASH Whitepaper)

The poster titled "The Effects of BCMA Expression, Soluble BCMA, and Combination Therapeutics on the Anti-Tumor Activity of HPN217, a BCMA-Targeting Tri-Specific T Cell Engager Against Multiple Myeloma" showcased translational studies to examine factors that may impact the therapeutic efficacy of HPN217. These factors include the target BCMA, in membrane-bound or soluble form, and concomitant or combination therapeutics such as gamma secretase inhibitor (GSI) and dexamethasone.

Preclinical data from this presentation for HPN217 demonstrated:

In a patient derived cell culture system, HPN217 was able to mediate multiple myeloma cell killing by autologous T cells in 80% of the cultures
Presence of dexamethasone appeared to have limited effect on the anti-tumor activity of HPN217-redirected T cells
GSI increased the expression of BCMA on multiple myeloma cells and enhanced the effect of HPN217
Preclinical evaluation of HPN217 in combination with approved and experimental multiple myeloma therapeutics is ongoing

Conference Call and Webcast Details

Harpoon’s management will host a webcast and conference call on Monday, December 13, 2021 at time 4:30 p.m. ET / 1:30 p.m. PT to review the data presented at ASH (Free ASH Whitepaper) and provide an update on other pipeline programs. The live call may be accessed by dialing 866-951-6894 for domestic callers or 409-216-0624 for international callers using conference ID # 2760075.

A live webcast of the call will be available from the Events and Presentations section of the company’s website here and will be archived there shortly after the live event.

On December 11, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported results from the primary analysis of ZUMA-7, a global Phase 3 study evaluating Yescarta (axicabtagene ciloleucel) as a one-time infusion, in a head-to-head study against standard of care (SOC) for adults with large B-cell lymphoma (LBCL) who relapsed or were refractory to first-line treatment (Press release, Gilead Sciences, DEC 11, 2021, View Source [SID1234596837]). Yescarta was evaluated against the current SOC which is a multi-step process intended to culminate in a stem cell transplant. ZUMA-7 was initiated in 2017 and is the first and largest Phase 3 randomized study of any CAR T-cell therapy in the second-line setting, enrolling 359 patients in 77 centers around the world. ZUMA-7 is considered a landmark trial for being the only study to reach the clinically meaningful two-year follow-up milestone. The findings were featured in the American Society of Hematology (ASH) (Free ASH Whitepaper) press briefing today at their 63rd ASH (Free ASH Whitepaper) Annual Meeting & Exposition and in a simultaneous publication in the New England Journal of Medicine (NEJM). The data will also be presented in full at the ASH (Free ASH Whitepaper) plenary session on Sunday, December 12 (Abstract #2).

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With a median follow-up of over two years, the study met the primary endpoint of event-free survival (EFS; hazard ratio 0.398; 95% CI: 0.308-0.514, P<0.0001). Yescarta demonstrated a 2.5 fold increase in patients who were alive at two years and did not require the need for additional cancer treatment or experienced cancer progression (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 mo. vs. 2.0 mo.) compared to SOC. These statistically significant and clinically meaningful results were not confounded by any bridging chemotherapy. Improvements in EFS with Yescarta were consistent across key patient subgroups, including the elderly (HR: 0.276 [95% CI: 0.164-0.465]), primary refractory disease (HR: 0.426 [95% CI: 0.319-0.570]), high-grade B-cell lymphoma including double-hit and triple-hit lymphoma (HGBL; HR: 0.285 [95% CI: 0.137-0.593]), and double expressor lymphoma (HR: 0.424 [95% CI: 0.268-0.671]).

"The majority of patients with relapsed/refractory LBCL do not achieve long-term remission with currently available treatments and as we saw in this trial, are often not able to complete the multi-step process that culminates in a transplant," said Frederick L. Locke, MD, ZUMA-7 Lead Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida. "The results of ZUMA-7 are remarkable and represent a paradigm shift in the way that we should treat patients with LBCL in the second-line setting."

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. SOC therapy with curative intent for this patient population is a multi-step process intended to lead to a stem cell transplant as definitive treatment. The process starts with chemoimmunotherapy, and if a patient responds and can tolerate further treatment, they move on to high-dose chemotherapy (HDT) followed by a stem cell transplant (ASCT). Unfortunately, many patients do not advance through this lengthy process for a variety of reasons including lack of response to second-line chemotherapy, treatment complications or further disease progression.

In ZUMA-7, nearly three times as many patients randomized to Yescarta ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (36%) who received HDT+ASCT. Among randomized patients, overall response (ORR) and complete response (CR) rates were also higher with Yescarta (ORR: 83% vs. 50%, odds ratio: 5.31 [95% CI: 3.1-8.9; P<0.0001]; CR rate: 65% vs. 32%). Median overall survival (OS), evaluated as a preplanned interim analysis, favored Yescarta compared to SOC (not reached vs. 35.1 months, respectively). The primary analysis of OS will occur at approximately 210 deaths.

In a separate ZUMA-7 analysis of patient-reported outcomes (PROs) which will also be shared in an ASH (Free ASH Whitepaper) oral presentation on December 12 (Abstract #430), patients receiving Yescarta and eligible for the PROs portion of the study (n=165) showed significant and clinically meaningful improvements in quality of life (QoL) at Day 100 compared with those who received SOC (n=131) using a prespecified analysis for three PRO domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QOL, and EQ-5D-5L visual analog scale [VAS]). The data also suggest faster recovery to pretreatment QoL for patients treated with Yescarta versus SOC.

"Beyond the poor prognosis, patients with relapsed or refractory LBCL also face substantially decreased quality of life with chemotherapy and stem cell transplant treatments," said Mahmoud Elsawy, MD, MSc, ZUMA-7 Investigator and Medical Director of Immune Effector Cell Therapy Program at Queen Elizabeth II Health Sciences Centre and Assistant Professor at Dalhouse University, Halifax, NS, Canada. "With the primary results of ZUMA-7, we see that axicabtagene ciloleucel offers superior clinical outcomes, and with the PRO analysis we also have support that it provides a better quality of life for these patients. Giving patients not just more but also better quality time is always our goal."

In the ZUMA-7 trial, Yescarta had a manageable safety profile that was consistent with previous studies. Among the 170 Yescarta-treated patients evaluable for safety, Grade ≥3 cytokine release syndrome (CRS) and neurologic events were observed in 6% and 21% of patients, respectively. No Grade 5 CRS or neurologic events occurred. In the SOC arm, 83% of patients had high grade events, mostly cytopenias (low blood counts).

Global regulatory filings to expand the indication for Yescarta to include second-line relapsed or refractory LBCL based on the ZUMA-7 data are currently underway. The U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review designation to Yescarta for this patient population with a target action date under the Prescription Drug User Fee Act (PDUFA) of April 1, 2022. Regulatory submissions have also been filed with other global health authorities, including the European Medicines Agency (EMA).

"The ZUMA-7 trial demonstrates the power of CAR T-cell therapy when used earlier in the course of treatment and for the first time shows the promise of CAR T to replace a standard of care that has been in place for decades," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "Kite is the world’s leading company dedicated exclusively to cell therapy, and we are committed to continuing to conduct groundbreaking research like the ZUMA-7 study to bring the hope of survival to more patients through this technology."

About ZUMA-7 Study Design

ZUMA-7 is a randomized, open-label, global, multicenter, Phase 3 study evaluating the safety and efficacy of Yescarta versus current standard of care (SOC) for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and autologous stem cell transplant [ASCT] in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy. In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of Yescarta or current SOC second-line therapy. The primary endpoint is event free survival (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 (ORR) and overall survival (OS). Additional secondary endpoints include patient reported outcomes (PROs) and safety.

About Yescarta

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

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

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), including fatal or life-threatening reactions, occurred. CRS occurred in 88% (224/254) of all patients with non-Hodgkin lymphoma (NHL), including Grade ≥3 in 10%. CRS occurred in 94% (101/108) of patients with large B-cell lymphoma (LBCL), including Grade ≥3 in 13%. Among patients with LBCL who died after receiving Yescarta, 4 had ongoing CRS events at the time of death. The median time to onset of CRS was 2 days (range: 1-12 days) and the median duration was 7 days (range: 2-58 days) for patients with LBCL. CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL), including Grade ≥3 in 8% (11/146). 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 (80%), hypotension (38%), tachycardia (29%), hypoxia (21%), chills (21%), and headache (13%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, multi-organ failure and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. In a subsequent cohort of LBCL patients, tocilizumab and/or corticosteroids were administered for ongoing Grade 1 events. CRS occurred in 93% (38/41) of these patients and 2% (1/41) had Grade 3 CRS, with no patients experiencing 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). Key manifestations of CRS (>5%) included pyrexia, hypotension, chills, headache, nausea, tachycardia, C-reactive protein increased, fatigue, hypoxia, and vomiting. Ensure that 2 doses of tocilizumab are available prior to Yescarta infusion. Following 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 that were fatal or life-threatening occurred. Neurologic toxicities occurred in 81% (206/254) of all patients with NHL receiving Yescarta, including Grade ≥3 in 26%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL, including Grade ≥3 in 31%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL. 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 for patients with iNHL. 98% 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 89% of affected patients with LBCL and 74% of affected patients with iNHL. The most common neurologic toxicities (≥10%) in all patients combined included encephalopathy (53%), headache (45%), tremor (31%), dizziness (20%), delirium (16%), aphasia (15%), and insomnia (11%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including leukoencephalopathy and seizures, as well as fatal and serious cases of cerebral edema, have occurred. In a subsequent cohort of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41) of these patients and 20% (8/41) had Grade 3 neurologic toxicities with no patients experiencing 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). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta. Following Yescarta infusion, 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 47% (119/254) of all patients with NHL. Grade ≥3 infections occurred in 19% of patients, Grade ≥3 infections with an unspecified pathogen occurred in 15%, bacterial infections in 5%, viral infections in 2%, 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 anti-microbials according to local guidelines. Febrile neutropenia was observed in 40% 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. 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 30% of all patients with NHL and included neutropenia (22%), thrombocytopenia (13%), and anemia (5%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA and B-cell aplasia can occur. Hypogammaglobulinemia occurred in 17% 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 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 adverse reactions (incidence ≥20%) in patients with LBCL 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 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.