On June 4, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported longer-term follow-up results from two pivotal studies of the CAR T-cell therapy Tecartus (brexucabtagene autoleucel) (Press release, Kite Pharma, JUN 4, 2022, View Source [SID1234615569]). The three-year follow-up of ZUMA-2, a Phase 2 global, multi-center study evaluating the efficacy of Tecartus in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), and two-year follow-up of ZUMA-3, a global, multi-center, single-arm, open-label Phase 1/2 study evaluating Tecartus in adult patients (≥18 years old) with R/R B-cell acute lymphoblastic leukemia (B-ALL) were both presented today during a poster session at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstracts #7518 and #7010). Three-year follow-up data from ZUMA-2 were also simultaneously published in ASCO (Free ASCO Whitepaper)’s Journal of Clinical Oncology.

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"We are very encouraged by the totality of these data, which suggest a significant and sustained response with Tecartus for people living with difficult-to-treat blood cancers like MCL and B-ALL," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. "These longer-term results add to the growing maturity of data on Kite’s CAR T-cell therapies."

At nearly three years of follow-up (median 35.6 months) in the ZUMA-2 trial, the overall response rate (ORR) was 91%, with 68% of treated patients achieving a complete response (CR; 95% CI, 55.2–78.5). The median duration of response (DOR) was 28.2 months, with 37% of treated patients in ongoing response at data cut-off. Median overall survival (OS) among treated patients was 46.6 months. Among those patients who achieved a CR, the median OS has not yet been reached (30-month OS rate was 60.3%). Late relapse, classified as more than 24 months post-infusion, was infrequent (n=3).

"There remains a significant need among patients living with MCL for therapies that provide a long-term response, as many patients have high-risk disease that is more likely to relapse or progress following multiple lines of treatment," said Michael Wang, MD, ZUMA-2 Lead Investigator and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "The three-year data from ZUMA-2 represent the longest follow-up for a CAR T-cell therapy in MCL patients to date and are impressive in their demonstration of brexu-cel to elicit durable long-term responses."

In the ZUMA-3 trial, longer follow-up of the pivotal analysis and outcomes of a newly-conducted larger pooled analysis of Phase 1 and 2 patients by independent review who received the pivotal dose of Tecartus were reported. Most patients in the analysis were heavily pre-treated, with a median of two prior therapies, and 47% had received three or more prior therapies. At a median follow-up of 29.7 months for pooled Phase 1 and 2 patients, 73.1% of treated patients achieved a CR or CR with incomplete hematological recovery (CRi). Median OS was 25.4 months for both Phase 2 treated patients and pooled Phase 1 and 2 treated patients. At data cutoff, median OS had not yet been reached in Phase 2 patients who achieved a CR. Similar outcomes among Phase 2 treated patients (n=55) and the pooled analysis of Phase 1 and 2 patients (n=78) were observed.

"With two years of follow-up and an expanded data set in ZUMA-3 in a heavily pre-treated patient population, we’ve observed a high durable response rate, with the majority of the responses associated with undetectable minimal residual disease following treatment with brexu-cel," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Florida. "For adult patients with B-ALL, this is a marked improvement relative to historical standards of care, so these treatment results are particularly important."

Across both trials, no new safety signal has been observed in this extended follow-up period. In ZUMA-2, 3% of treatment-emergent adverse events (AEs) of interest occurred since the primary report. The most frequent Grade ≥3 AE was neutropenia (1 [1%] Grade 3; 7 [10%] Grade 4). Two patients had treatment-related Grade 3 serious infections, pneumonia and upper respiratory tract infection (n=1) and influenza (n=1). There were no new cytokine release syndrome (CRS) AEs. In ZUMA-3, no new-onset CRS, neurological events, infections, or hypogammaglobulinemia of any grade have occurred since the Phase 2 primary analysis. One new Grade 5 AE has occurred since the primary analysis (graft-versus-host disease; deemed not treatment-related).

Tecartus is currently approved for the treatment of relapsed or refractory MCL, as the first and only CAR T-cell therapy to receive accelerated approval from the U.S. Food and Drug Administration (FDA) in this indication. Tecartus is also approved for relapsed or refractory B-cell ALL, as the first and only CAR T-cell therapy approved for adults (≥18 years old) with ALL. The Tecartus U.S. Prescribing Information has a Boxed Warning in its product label regarding the risks of CRS and neurologic toxicities, and Tecartus is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Indication and Important Safety Information.

About MCL

MCL is a rare form of non-Hodgkin lymphoma (NHL) that arises from cells originating in the "mantle zone" of the lymph node and predominantly affects men over the age of 60. Approximately 33,000 people worldwide are diagnosed with MCL each year. MCL is highly aggressive following relapse, with many patients progressing following therapy.

About B-ALL

ALL is an aggressive type of blood cancer that can also involve the lymph nodes, spleen, liver, central nervous system and other organs. Globally, approximately 64,200 people are diagnosed with ALL each year. Of those, 60% of cases occur in those under age 20. Approximately 1,000 adults in the U.S. are treated annually for relapsed or refractory ALL. B-cell precursor ALL is the most common form, accounting for approximately 75% of cases, and treatment is typically associated with inferior outcomes compared with other types of ALL. Survival rates remain very poor in adult patients with relapsed or refractory ALL, with median OS at less than eight months.

About Tecartus

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

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

Adult patients with relapsed or refractory mantle cell lymphoma (MCL).
This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.
Tecartus 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 life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including ≥ Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, the key manifestations (>10%) were similar in MCL and ALL and included fever (93%), hypotension (62%), tachycardia (59%), chills (32%), hypoxia (31%), headache (21%), fatigue (20%), and nausea (13%). Serious events associated with CRS included hypotension, fever, hypoxia, tachycardia, and dyspnea.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility, and for four 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 Events, including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 81% (66/82) of patients with MCL, including ≥ Grade 3 in 37% of patients. The median time to onset for neurologic events was six days (range: 1 to 32 days) with a median duration of 21 days (range: 2 to 454 days) in patients with MCL. Neurologic events occurred in 87% (68/78) of patients with ALL, including ≥ Grade 3 in 35% of patients. The median time to onset for neurologic events was seven days (range: 1 to 51 days) with a median duration of 15 days (range: 1 to 397 days) in patients with ALL. For patients with MCL, 54 (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Neurologic events resolved for 119 out of 134 (89%) patients treated with Tecartus. Nine patients (three patients with MCL and six patients with ALL) had ongoing neurologic events at the time of death. For patients with ALL, neurologic events occurred before, during, and after CRS in 4 (5%), 57 (73%), and 8 (10%) of patients; respectively. Three patients (4%) had neurologic events without CRS. The onset of neurologic events can be concurrent with CRS, following resolution of CRS or in the absence of CRS.

The most common neurologic events (>10%) were similar in MCL and ALL and included encephalopathy (57%), headache (37%), tremor (34%), confusional state (26%), aphasia (23%), delirium (17%), dizziness (15%), anxiety (14%), and agitation (12%). Serious events including encephalopathy, aphasia, confusional state, and seizures occurred after treatment with Tecartus.

Monitor patients daily for at least seven days for patients with MCL and at least 14 days for patients with ALL at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Healthcare facilities that dispense and administer Tecartus must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after Tecartus infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Tecartus 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: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections (all grades) occurred in 56% (46/82) of patients with MCL and 44% (34/78) of patients with ALL. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients with ALL and MCL. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients with MCL and 35% of patients with ALL after Tecartus infusion and may be concurrent with CRS. The febrile neutropenia in 27 (35%) of patients with ALL includes events of "febrile neutropenia" (11 (14%)) plus the concurrent events of "fever" and "neutropenia" (16 (21%)). 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, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g., fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in 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 Tecartus infusion. In patients with MCL, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% (45/82) of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). In patients with ALL who were responders to Tecartus treatment, Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion occurred in 20% (7/35) of the patients and included neutropenia (12%) and thrombocytopenia (12%); Grade 3 or higher cytopenias not resolved by Day 60 following Tecartus infusion occurred in 11% (4/35) of the patients and included neutropenia (9%) and thrombocytopenia (6%). Monitor blood counts after Tecartus infusion.

Hypogammaglobulinemia: B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia was reported in 16% (13/82) of patients with MCL and 9% (7/78) of patients with ALL. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment with Tecartus.

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 Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common non-laboratory adverse reactions (≥ 20%) were fever, cytokine release syndrome, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting. The most common serious adverse reactions (≥ 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

On June 4, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported findings from two pre-planned, subgroup analyses of the landmark ZUMA-7 trial of Yescarta (axicabtagene ciloleucel), which led to the U.S. Food and Drug Administration’s (FDA) recent expanded approval of Yescarta as initial treatment in adults with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy (Press release, Kite Pharma, JUN 4, 2022, View Source [SID1234615568]). These results include an analysis of clinical and patient-reported outcomes (PROs) in patients aged 65 or older, as well as an exploratory analysis of the association of pre-treatment tumor characteristics with clinical outcomes in patients with both low and high tumor burden and elevated and non-elevated lactate dehydrogenase (LDH). The data were presented today at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstracts #7548 and #7565).

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"Patients with large B-cell lymphoma aged 65 and above are at higher risk of not being eligible for or able to tolerate the standard of care, which can lead to poorer outcomes and health-related quality of life," said Jason Westin, MD, MS, FACP, ZUMA-7 Principal Investigator, Director, Lymphoma Clinical Research, and Associate Professor, Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "These data demonstrate that older patients, who are frequently considered transplant-ineligible based on age, can safely receive second-line CAR T-cell therapy with curative intent."

In the ZUMA-7 sub-analysis of patients aged 65 and older, the primary endpoint of event-free survival (EFS) demonstrated that Yescarta (n=51) was superior to SOC (salvage chemoimmunotherapy followed by high-dose chemotherapy and stem cell transplant in those who respond; n=58; Hazard Ratio [HR], 0.276; descriptive P<0.0001), with over eight-fold greater median EFS (21.5 months vs 2.5 months) and over three-fold greater estimated 24-month EFS rate (47.8% vs 15.1%). Objective response rate (ORR) was higher with Yescarta vs. SOC (88% vs 52%; Odds Ratio: 8.81; descriptive P<0.0001). Complete response (CR) rates in the Yescarta group were over double that of the SOC group (75% vs 33%). Overall survival (OS), evaluated as a preplanned interim analysis, was prolonged in the Yescarta arm compared with the SOC arm (HR, 0.517). Fifty-seven percent of patients in the SOC arm received subsequent cellular immunotherapy (off protocol).

Yescarta also showed meaningful improvement in quality of life (QoL) over SOC with faster recovery to pre-treatment quality of life among patients 65 years of age or older. Among those evaluable for the PRO portion of the study, Yescarta (n=46) showed clinically meaningful differences in QoL at Day 100 compared to patients receiving SOC (n=42) for three prespecified PRO domains (European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-C30 Global Health Status/QOL, EORTC QLQ-C30 Physical Functioning, and EQ-5D-5L visual analog scale [VAS]). For all three domains, scores continued to favor Yescarta over SOC at Day 150 (descriptive P<0.05).

The safety profile of Yescarta was consistent with previous studies and real-world data in patients of all ages. Rates of cytokine release syndrome (CRS) and neurologic events (NE) for patients 65 and older were slightly higher than those observed in the overall patient population. Notably, compared with SOC patients, more Yescarta patients had high-risk features at baseline, including second-line age-adjusted International Prognostic Index (IPI) 2-3 (53% vs 31%), elevated LDH (61% vs 41%), and high grade B‑cell lymphoma (including double/triple-hit‑ lymphoma (33% vs 14%)).

"The consistent benefit of Yescarta over standard of care in the second-line setting in higher-risk patients, such as those aged 65+ and those with high tumor burden or LDH, can provide additional confidence to physicians that Yescarta should be considered the new standard of care as initial treatment for relapsed/refractory LBCL," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite.

In a separate exploratory analysis of pre-treatment tumor characteristics including tumor burden and LDH, EFS was superior for Yescarta compared to SOC for patients with high and low pre-treatment tumor burden (HR, 0.29 and 0.49, respectively; descriptive P<0.001 for both) and elevated and non-elevated LDH (HR, 0.32 and 0.5, respectively; descriptive P<0.001 for both). EFS in Yescarta patients was not significantly different for patients with high or low pre-treatment tumor burden (HR, 0.92; descriptive P=0.68) or elevated and non-elevated LDH (HR, 1.11; descriptive P=0.61), but was worse in patients who received SOC with high pre-treatment tumor burden (HR, 1.51; descriptive P=0.02) or elevated LDH (HR, 1.56; descriptive P=0.01). Durable responses with Yescarta were greatest in tumors with prominent B-cell features, but were superior to SOC regardless of these features.

"High tumor burden and elevated LDH levels are typically associated with poorer outcomes, especially when patients have exhausted treatment options," said Frederick L. Locke, MD, ZUMA-7 Principal Investigator and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida. "These are factors that clinicians take into consideration when determining eligibility for standard of care in the second-line setting as well as CAR T-cell therapy in the third-line setting. In this analysis, response rates to axi-cel in the second-line setting were consistent regardless of level of tumor burden or LDH, which reaffirms that axi-cel should be considered the new standard of care in this earlier setting."

Yescarta was the first CAR T-cell therapy to be approved by the FDA for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy. Yescarta was also approved by the FDA in April 2022 as the first CAR T-cell therapy for adult patients with LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. 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 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.

On June 4, 2022 Gilead Sciences, Inc. (Nasdaq: GILD) reported positive results from the primary analysis of the Phase 3 TROPiCS-02 study of Trodelvy (sacituzumab govitecan-hziy) versus physicians’ choice of chemotherapy (TPC) in heavily pre-treated HR+/HER2- metastatic breast cancer patients who received prior endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy (Press release, Gilead Sciences, JUN 4, 2022, View Source [SID1234615567]). The study met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful 34% reduction in the risk of disease progression or death (median PFS 5.5 vs. 4 months; HR: 0.66; 95% CI: 0.53-0.83; P<0.0003). The first interim analysis of the key secondary endpoint of overall survival (OS) demonstrated a trend in improvement. These data are immature, and patients will be followed for subsequent OS analysis. These findings will be featured in both a press briefing and an oral session (Abstract #LBA1001) on Saturday, June 4, during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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

The study demonstrated that at the one-year mark, three times as many patients were progression-free when treated with Trodelvy compared to those who received TPC (21% versus 7%). Improvements in PFS with Trodelvy were also consistent across key patient subgroups, including patients who had previously received three or more chemotherapy regimens for metastatic disease (HR: 0.70; CI: 0.52-0.95), patients with visceral metastasis (HR: 0.66; CI: 0.53-0.83), and the elderly (≥65 years of age; HR: 0.59; CI: 0.38-0.93).

"For patients with HR+/HER2- metastatic breast cancer, resistance to endocrine therapy is inevitable in almost all cases. The standard of care is then limited to sequential single agent chemotherapy, with declining response rates, disease control and quality of life," said Dr. Hope Rugo, Professor of Medicine and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, U.S. "In TROPiCS-02, we enrolled heavily pre-treated patients with metastatic breast cancer who had disease progression following multiple lines of chemotherapy. To observe a clinically meaningful reduction in the risk of disease progression or death in these patients with limited treatment options is remarkable. Sacituzumab govitecan-hziy will be an important potential future treatment option for these patients."

A prespecified quality of life (QoL) analysis, one of the secondary endpoints using the EORTC QLQ-C30 instrument, also favored Trodelvy over TPC demonstrating meaningful benefit. In the evaluable population, improvements in global health status and fatigue with Trodelvy (n=234) compared with those who received TPC (n=207) were also observed.

"With Trodelvy, our bold ambition is that it will help transform care for people living with cancer, including in pre-treated HR+/HER2- metastatic breast cancer, where more options are needed," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We look forward to continuing discussions with regulatory agencies to further understand how Trodelvy can impact this patient population with a high unmet need."

The safety profile for Trodelvy was consistent with prior studies, with no new safety concerns identified in this patient population. The most frequent Grade ≥3 treatment-related adverse reactions for Trodelvy compared to TPC were neutropenia (51% versus 38%), diarrhea (9% versus 1%), leukopenia (9% versus 5%), anemia (6% versus 3%), fatigue (6% versus 2%) and febrile neutropenia (5% versus 4%).

Trodelvy has not been approved by any regulatory agency for the treatment of HR+/HER2- metastatic breast cancer. Its safety and efficacy have not been established for this indication. Trodelvy has a Boxed Warning for severe or life-threatening neutropenia and severe diarrhea; please see below for additional Important Safety Information.

About HR+/HER2- Metastatic Breast Cancer

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common type of breast cancer and accounts for approximately 70% of all new cases, or nearly 400,000 diagnoses worldwide each year. Almost one in three cases of early-stage breast cancer eventually become metastatic, and among patients with HR+/HER2- metastatic disease, the five-year relative survival rate is 30%. As patients with HR+/HER2- metastatic breast cancer become resistant to endocrine-based therapy, their primary treatment option is limited to single-agent chemotherapy. In this setting, it is common to receive multiple lines of chemotherapy regimens over the course of treatment, and the prognosis remains poor.

About the TROPiCS-02 Study

The TROPiCS-02 study is a global, multicenter, open-label, Phase 3 study, randomized 1:1 to evaluate Trodelvy versus physicians’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in 543 patients with HR+/HER2- metastatic breast cancer who were previously treated with endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy for metastatic disease. The primary endpoint is progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by blinded independent central review (BICR) for participants treated with Trodelvy compared to those treated with chemotherapy. Secondary endpoints include overall survival, overall response rate, clinical benefit rate and duration of response, as well as assessment of safety and tolerability and quality of life measures. In the study, HER2 negativity was defined per American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the College of American Pathologists (CAP) criteria as immunohistochemistry (IHC) score of 0, IHC 1+ or IHC 2+ with a negative in-situ hybridization (ISH) test. More information about TROPiCS-02 is available at View Source

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class Trop-2 directed antibody-drug conjugate. Trop-2 is a cell surface antigen highly expressed in multiple tumor types, including in more than 90% of breast and bladder cancers. Trodelvy is intentionally designed with a proprietary hydrolyzable linker attached to SN-38, a topoisomerase I inhibitor payload. This unique combination delivers potent activity to both Trop-2 expressing cells and the microenvironment.

Trodelvy is approved in more than 35 countries, with multiple additional regulatory reviews underway worldwide, for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. Trodelvy is also approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with locally advanced or metastatic urothelial cancer (UC) who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

Trodelvy is also being developed for potential investigational use in other TNBC and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer, metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.

U.S. Indication for Trodelvy

In the United States, Trodelvy is indicated for the treatment of:

Adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Adult patients with locally advanced or metastatic UC who have previously received a platinum-containing chemotherapy and either programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
U.S. Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

Severe or life-threatening neutropenia may occur. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patients with febrile neutropenia without delay.
Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold Trodelvy until resolved to ≤Grade 1 and reduce subsequent doses.
CONTRAINDICATIONS

Severe hypersensitivity reaction to Trodelvy.
WARNINGS AND PRECAUTIONS

Neutropenia: Severe, life-threatening, or fatal neutropenia can occur and may require dose modification. Neutropenia occurred in 61% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 7%. Withhold Trodelvy for absolute neutrophil count below 1500/mm3 on Day 1 of any cycle or neutrophil count below 1000/mm3 on Day 8 of any cycle. Withhold Trodelvy for neutropenic fever.

Diarrhea: Diarrhea occurred in 65% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 12% of patients. One patient had intestinal perforation following diarrhea. Neutropenic colitis occurred in 0.5% of patients. Withhold Trodelvy for Grade 3-4 diarrhea and resume when resolved to ≤Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: Serious hypersensitivity reactions including life-threatening anaphylactic reactions have occurred with Trodelvy. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.3%. The incidence of anaphylactic reactions was 0.3%. Pre-infusion medication is recommended. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.

Nausea and Vomiting: Nausea occurred in 66% of all patients treated with Trodelvy and Grade 3 nausea occurred in 4% of these patients. Vomiting occurred in 39% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold Trodelvy doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with Trodelvy. The incidence of Grade 3-4 neutropenia was 67% in patients homozygous for the UGT1A1*28, 46% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 25% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 11% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue Trodelvy based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, Trodelvy can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. Trodelvy contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Trodelvy and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Trodelvy and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were fatigue, neutropenia, diarrhea, nausea, alopecia, anemia, constipation, vomiting, abdominal pain, and decreased appetite. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced neutrophils, leukocytes, and lymphocytes.

In the TROPHY study (IMMU-132-06), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, neutropenia, nausea, any infection, alopecia, anemia, decreased appetite, constipation, vomiting, abdominal pain, and rash. The most frequent serious adverse reactions (SAR) (≥5%) were infection (18%), neutropenia (12%, including febrile neutropenia in 10%), acute kidney injury (6%), urinary tract infection (6%), and sepsis or bacteremia (5%). SAR were reported in 44% of patients, and 10% discontinued due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPHY study were reduced neutrophils, leukocytes, and lymphocytes.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of Trodelvy with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with Trodelvy.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.

On June 4, 2022 MEI Pharma, Inc. (NASDAQ: MEIP), a latestage pharmaceutical company focused on advancing new therapies for cancer, and Kyowa Kirin Co., Ltd. (Kyowa Kirin, TSE: 4151), a global specialty pharmaceutical company creating innovative medical solutions utilizing the latest biotechnology, reported data from the ongoing Phase 2 TIDAL study evaluating the intermittent dosing of zandelisib, an orally administered investigational phosphatidylinositol 3-kinase delta ("PI3Kδ") inhibitor in clinical development for the treatment of B-cell malignancies, is highlighted in a poster and oral discussion session at the of American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2022 Annual Meeting(Press release, Kyowa Hakko Kirin, JUN 4, 2022, View Source [SID1234615564]).

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"The Phase 2 TIDAL data generated to date continue to highlight zandelisib’s therapeutic profile and the potential to benefit patients, supporting our commitment to advancing the program and our already ongoing randomized Phase 3 COASTAL study with our partner, Kyowa Kirin," said Richard Ghalie, M.D., chief medical officer of MEI Pharma. "In light of the promising results from TIDAL to date, we remain committed to the zandelisib program with our primary focus being on COASTAL, our ongoing Phase 3, randomized, study evaluating zandelisib in combination with rituximab in follicular and marginal zone lymphoma patients with at least one prior line of therapy."

"We are very pleased to present data from Phase 2 TIDAL study in ASCO (Free ASCO Whitepaper) meeting," said Yoshifumi Torii, Ph.D., Executive Officer, Vice President, Head of R&D Division of Kyowa Kirin. We continue to see favorable profile of zandelisib that balances efficacy and safety. We remain committed to maximizing the value of zandelisib in B-cell malignancies with our partner MEI Pharma."

Clinical Data from the Phase 2 TIDAL Study Evaluating Zandelisib in Patients with Relapsed or Refractory Follicular Lymphoma
• Presentation Title: Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the global phase 2 study TIDAL
• Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
• Presenter: Andrew David Zelenetz, Ph.D., M.D.
• Date and Time: Saturday, June 4, 2022, at 3:00 Central Time
• Poster ID: 7511 / 165

Study Details The ongoing TIDAL study (NCT03768505) is a global, open-label Phase 2 trial evaluating zandelisib as a single agent in two disease cohorts: one in relapsed or refractory (r/r) follicular lymphoma (FL) and one for r/r marginal zone lymphoma (MZL), in both cases after failure of at least two prior systemic therapies, including chemotherapy and an anti-CD20 antibody. Patients were administered zandelisib once daily for two 28-day cycles as response induction therapy, followed thereafter by once daily dosing for the first seven days of each subsequent 28-day cycle, a schedule called Intermittent Dosing (ID). Enrollment in the FL cohort is complete; enrollment in the MZL cohort is ongoing.

The FL cohort enrolled a total of 121 patients, with the first 91 consisting of the primary efficacy population (PEP) for the evaluation of overall response rate (ORR) and duration of response (DOR).

The median age of patients enrolled with FL was 64 years old. Enrolled patients were generally heavily pretreated; the median number of prior therapies was 3 (range 2-8) and 96% of patients had received prior chemoimmunotherapy. Further, 28 patients (23%) received prior stem cell transplant, 50 patients (41%) were refractory to last therapy, 41 patients (34%) had tumors ≥5 cm, and 68 patients (56%) were POD24 (progression of disease within 24 months of prior chemoimmunotherapy). The primary efficacy endpoint is ORR as assessed by independent review committee (IRC) using a modified Lugano criteria. The data cutoff date is September 30, 2021, approximately 6 months after the last patient in the PEP received their first dose of zandelisib. Data from the enrolling MZL cohort is not reported.

Efficacy The primary endpoint of ORR of zandelisib as a single agent in the PEP was 70.3% (N=64), 95% CI=59.8, 79.5, as assessed by IRC; the complete response rate was 35.2% (N=32), 95% CI=25.4, 45.9. Responses across sub-groups (i.e. response to last treatment, number of prior therapies and POD24) were all >63%. Response Rates by Independent Review Committee in All PEP Patients and by Subgroup Response to Last Treatment Number of Prior Therapies POD24 n(%) Efficacy Population (n=91) Relapsed (n=49) Refractory (n=42) 2 (n=42) >2 (n=49) Yes (n=51) No (n=40) ORR (CR or PR) 64 (70.3) 37 (75.5) 27 (64.3) 33 (78.6) 31 (63.3) 34 (66.7) 30 (75.0) CR 32 (35.2) 20 (40.8) 12 (28.6) 18 (42.9) 14 (28.6) 16 (31.4) 16 (40.0) CR, complete response; PEP, primary efficacy population; POD24 progression of disease within 24 months; PR, partial response. Responses were first observed in the first two cycles of therapy in 87.5% of all responses (N=56) and 75% of all CRs (N=24) were observed in the first four cycles. As of the data cutoff date, the data are not sufficiently mature to accurately estimate the final DOR in the PEP.

Safety and Tolerability With a median follow-up of 9.4 months (range 0.8-24) in the safety population of 121 patients, 9.9% (N=12) of patients had discontinued therapy due to any drug-related adverse event. Grade 3 adverse events of special interest (AESI) were diarrhea in 5% (N=6), colitis in 1.7% (N=2), cutaneous rash in 3.3% (N=4), stomatitis in 2.5% (N=3), and 0.8% (N=1) each for AST and ALT elevation, and non-infectious pneumonitis. Grade 3 AESIs primarily (83%, 15 of 18) occurred in cycles 1-3, with only 3 cases reported on ID in Cycles ≥4. No Grade 4 or Grade 5 AESI were recorded. Cumulative Incidence of Time to First Occurrence of Grade 3 AESI Treatment-emergent COVID-19 infections were reported in 8.3% (N=10) of patients, and 8.3% (N=10) of patients reported other Grade 3 infections. Four COVID infections were fatal, as were 1 case each of pneumonia and Tumor Lysis Syndrome About Zandelisib Zandelisib, a selective PI3Kδ inhibitor, is an investigational cancer treatment being developed as an oral, once-daily, treatment for patients with B-cell malignancies. Clinical trials are investigating the efficacy and safety of zandelisib as a single agent and in combination with other modalities while administered on an Intermittent Dosing Regimen (ID) and in a timelimited manner when dosed in combination. The ID leverages molecular and biologic properties specific to zandelisib. In November 2021, MEI Pharma and Kyowa Kirin announced topline data from ongoing Phase 2 TIDAL study (NCT03768505) evaluating zandelisib as a single agent for follicular lymphoma (FL) patients who received at least two prior systemic therapies. Zandelisib demonstrated a 70.3% objective response rate (ORR) as determined by an Independent Review Committee (IRC) assessment in the primary efficacy population (n=91). In addition, 35.2% of patients achieved a complete response. At the time of the data cutoff, the data were insufficiently mature to accurately estimate duration of response (DOR). In line with previously reported data from the Phase 1B study, zandelisib was generally well tolerated. With 9.4 months (range: 0.8-24) median duration of follow-up in the total study population (n=121), interim data demonstrated a discontinuation rate due to any drug related adverse event of 9.9%.

Patients enrolled in the study will continue to be followed for safety and DOR. Ongoing zandelisib studies include the cohort in TIDAL evaluating patients with r/r marginal zone lymphoma (MZL) and continuing evaluation of the cohort of patients in the study with r/r FL. Also ongoing is the Phase 3 COASTAL study (NCT04745832), comparing zandelisib plus rituximab to standard of care chemotherapy plus rituximab in patients with r/r FL or MZL who received more than one prior line of therapy, which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide. COASTAL, which is also evaluating timelimited intermittent administration of zandelisib, is intended to support marketing applications in the U.S. and globally. Other ongoing studies include a Phase 2 pivotal study in Japan (NCT04533581) in patients with indolent B-cell non-Hodgkin’s lymphoma (iB-NHL) without small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and Waldenström’s macroglobulinemia (WM) conducted by Kyowa Kirin. In March 2020, the FDA granted zandelisib Fast Track designation for the treatment of adult patients with r/r follicular lymphoma who have received at least two prior systemic therapies. In November 2021, the FDA granted zandelisib Orphan Drug designation for the treatment of patients with follicular lymphoma. In April 2020, MEI and Kyowa Kirin entered a global license, development, and commercialization agreement to further develop and commercialize zandelisib. MEI and Kyowa Kirin will co-develop and co-promote zandelisib in the U.S., with MEI booking all revenue from the U.S. sales. Kyowa Kirin has exclusive commercialization rights outside of the U.S. About Follicular Lymphoma Follicular lymphoma (FL) is the most common indolent lymphoma, comprising about 20-30% of all non-Hodgkin lymphomas (NHL).

The disease also develops in B lymphocytes, is chronic in most cases and tends to progress slowly. Most people diagnosed with FL are over 65 years of age. Sometimes follicular lymphomas can transform into a more aggressive form of large B-cell lymphoma, a fast-growing (aggressive) type of NHL.

On June 4, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported the presentation of encouraging clinical data from both the TakeAim Lymphoma and TakeAim Leukemia studies at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting currently taking place in Chicago and online until June 7, 2022 (Press release, Curis, JUN 4, 2022, View Source [SID1234615562]).

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"We are excited to share data with the oncology community from our TakeAim Lymphoma and TakeAim Leukemia studies at ASCO (Free ASCO Whitepaper), including the first release of clinical data investigating the use of emavusertib in combination with ibrutinib in patients with Non-Hodgkin’s Lymphoma," said James Dentzer, President and Chief Executive Officer of Curis. "These data demonstrate encouraging signs of anti-cancer activity, including a complete response in a primary CNS lymphoma patient who had prior treatment with ibrutinib. We also presented a poster with data from the TakeAim Leukemia study, previously disclosed in a January 2022 press release, demonstrating emavusertib’s encouraging monotherapy activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS)."

"In addition to the data from Curis’s studies, there are presentations at the meeting this year by our collaborators at Washington University and the University of Florida, which help more fully explore emavusertib’s use in tumor types outside of the company’s current focus in hematologic malignancies," said Robert Martell, M.D., Ph.D., Head of Research and Development.

TakeAim Lymphoma:
The TakeAim Lymphoma study is a Phase 1/2 open-label, dose escalation, dose expansion clinical trial investigating emavusertib as monotherapy and in combination with ibrutinib in patients with R/R hematologic malignancies, such as non-Hodgkins’s lymphoma and other B cell malignancies. The poster presentation (#7575) made by Dr. Grzegorz Nowakowski, Division of Hematology, Mayo Clinic-Minnesota, today at ASCO (Free ASCO Whitepaper) includes clinical data from a May 6, 2022 data cutoff, on 13 patients who received the combination, 9 of whom had post-baseline response assessments and were evaluable for response.

Key findings in patients treated with the combination included:

The combination appeared to be well tolerated
No dose-limiting toxicities (DLTs) at 200mg of emavusertib; 2 DLTs observed at 300mg (stomatitis and syncope)
8 of 9 evaluable patients experienced reduction in tumor burden, including:
2 complete responses (CR) (primary CNS lymphoma and mantle cell lymphoma)
2 partial responses (PR) (chronic lymphocytic leukemia and mantle cell lymphoma)
One of the CRs was in a patient who had received prior treatment with ibrutinib, suggesting that the combination may be able to overcome ibrutinib resistance
Next steps for the TakeAim Lymphoma study include further dose expansion in order to determine the Recommended Phase 2 Dose for the combination.

TakeAim Leukemia:
The TakeAim Leukemia study is a Phase 1/2 dose escalation and dose expansion study examining emavusertib use as both monotherapy and in combination with azacitidine or venetoclax in patients with R/R AML or high risk MDS. The poster presentation (#7016) made by Dr. Guillermo Garcia-Manero, Chief of the Section of Myelodysplastic Syndromes within the Department of Leukemia at The University of Texas MD Anderson Cancer Center, today at ASCO (Free ASCO Whitepaper), include clinical data from a December 16, 2021 data cutoff for the 49 patients who had been treated with emavusertib in monotherapy as of that date.

Key safety findings included:

Emavusertib was well-tolerated across multiple dose levels, including at the Recommended Phase 2 Dose of 300 mg BID
No dose-limiting myelosuppression observed
No cumulative toxicities observed
These attributes of emavusertib’s emerging safety profile may provide an advantage compared to current standard of care therapies in monotherapy and may also make emavusertib an attractive candidate for addition to combination therapy regimens.

Key tumor assessment findings included:

Collaborator Studies:
In patients with spliceosome-mutated R/R AML:
CR/CRh rate of 40% (2 out of 5 patients) (CRh=complete response with partial hematologic recovery)
Both patients who achieved CR/CRh have been on study > 6 months and achieved negative MRD (minimal residual disease) status
Consistent tumor burden reduction observed, 4 out of 5 patients achieved blast reduction, 3 of whom by ≥ 50%
In patients with spliceosome-mutated R/R MDS:
Objective response rate of 57% (4 out of 7 patients)
One of the patients who achieved a marrow CR (mCR) proceeded to stem cell transplant after 1 cycle
Consistent tumor burden reduction observed, with 4 out of 6 patients with elevated baseline blast counts achieving ≥ 50% reduction in blast counts
In patients with FLT3-mutated R/R AML:
CR rate of 33% (1 out of 3 patients)
2 out of 3 patients showed eradication of FLT3 mutation following treatment, indicating potential for disease modification with emavusertib
Consistent tumor burden reduction observed with 2 out of 3 patients with elevated blast counts achieving ≥ 50% reduction in blast counts
Being presented today (#TPS4168) is work in gastric cancer by Dr. Kian-Huat Lim’s team at Washington University School of Medicine. Based on compelling preclinical work, Dr. Lim and his team have developed a clinical study exploring combination of emavusertib (CA-4948) in combination with FOLFOX chemotherapy plus nivolumab or pembrolizumab. Preclinically, it has been established that chemotherapy resistance can be driven by TLR9 activation and IRAK4 dependent activation of pro-survival NF-kB signaling. Inhibition of IRAK4 has been shown to block this signaling, and to reduce tumor desmoplasia along with revitalization of intratumoral T-cells, setting the stage for combination with immune checkpoint inhibitors. This study is active, but not yet recruiting.

Being presented tomorrow (#2011), June 5, is preclinical work from Dr. Duane Mitchell’s team at the University of Florida, which investigated emavusertib (CA-4948) in melanoma brain metastasis where IRAK4-dependent signaling is known to be high. Emavusertib exposure in the brain and in brain tumors achieved therapeutically relevant levels, resulted in substantial reduction of B16.F10 tumor volume and prolonged survival of the mice.

About Emavusertib (CA-4948)
Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Additionally, third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutation such as SF3B1 and U2AF1. In addition to inhibiting IRAK4, emavusertib was also designed to inhibit FLT3, a known oncologic driver, which may provide additional benefit in patients with AML and MDS.