On December 11, 2023 Kite, a Gilead Company (Nasdaq: GILD), reported the results of four new analyses supporting the use of Tecartus (brexucabtagene autoleucel) in relapsed/refractory mantle cell lymphoma (R/R MCL) and relapsed/refractory adult B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) (Press release, Gilead Sciences, DEC 11, 2023, View Source [SID1234638444]). These results include four-year overall survival (OS) data from the pivotal ZUMA-2 study and primary results from ZUMA-18, an expanded access study, evaluating the CAR T-cell therapy Tecartus in patients with R/R MCL that were presented orally (Abstract #106) at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition.

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An analysis from ZUMA-2 showing that patients who received early versus late intervention for management of cytokine release syndrome (CRS) and neurological events experienced improved safety outcomes was also presented in a poster session (Abstract #2120).

In addition, real-world findings on effectiveness and safety outcomes from the Center for International Blood and Marrow Transplant Research (CIBMTR) observational database of U.S. patients who received Tecartus for R/R MCL (Abstract #107) were highlighted in an oral session; CIBMTR data from adult patients with R/R B-ALL (Abstract #1029) were also presented orally today.

"The clinical results and real-world evidence presented at ASH (Free ASH Whitepaper) clearly support the potential for long-term response and safety of Tecartus in aggressive blood cancers for which patients have limited treatment options," said Frank Neumann, MD, PhD, Senior Vice President, Global Head of Clinical Development, Kite. "We are particularly encouraged that the real-world evidence demonstrates consistent outcomes for Tecartus among a broader range of patients."

Detailed Information on Tecartus Abstracts:

(Abstract #106)

Outcomes of Patients with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Treated with Brexucabtagene Autoleucel (Brexu-cel) in ZUMA-2 and ZUMA-18, an Expanded Access Study

At a median follow-up of 47.5 months in all 68 patients with R/R MCL who had previously received anthracycline or bendamustine-containing chemotherapy; an anti CD20 antibody; and a Bruton’s tyrosine kinase inhibitor (BTKi; ibrutinib or acalabrutinib); and were treated with Tecartus in the pivotal ZUMA-2 study, median OS was 46.4 months with 30 patients (44%) still alive at data cutoff. The median OS for patients with complete response (CR) (n=46) was 58.7 months.

Efficacy and safety outcomes for 23 patients with R/R MCL enrolled in ZUMA-18, a multicenter, open-label, expanded-access study of Tecartus, were also presented. With a median follow-up of 33.5 months, the investigator-assessed objective response rate (ORR) was 87% (95% Confidence Interval [CI], 66.4-97.2); 57% had a CR (95% CI, 34.5-76.8), 30% had a partial response (95% CI, 13.2-52.9), and 9% had progressive disease (95% CI, 1.1-28.0) as their best response to Tecartus. The median OS was not reached (95% CI, 10.4-not estimable) at data cutoff with a 58% OS rate at 24 months.

At data cutoff, 61% of patients were still alive. All 23 patients who received Tecartus in ZUMA-18 experienced at least one Grade ≥3 adverse event (AE); Grade ≥3 CRS and neurological events occurred in one patient (4%) and eight patients (35%), respectively. Five Grade 5 AEs occurred, one that was deemed related to Tecartus therapy (multiple organ dysfunction syndrome on Day 20) and four that were deemed unrelated to Tecartus therapy (sepsis [2, Days 123 and 219], aspiration [1, on Day 49], and encephalopathy [1, on Day 68]).

"Consistent with ZUMA-2 findings, which showed a median overall survival of 46.4 months in patients with a complete response, brexu-cel demonstrated a high level of efficacy in relapsed/refractory mantle cell lymphoma patients in the ZUMA-18 expanded-access study, with less serious cytokine release syndrome," said Andre Goy, MD, ZUMA-2 investigator and Lymphoma Division Chief, John Theurer Cancer Center, Hackensack University Medical Center. "Together, the results of these two studies provide strong support for the continued use of brexu-cel in the relapsed/refractory mantle cell lymphoma setting."

(Abstract #107)

Real-world Outcomes of Brexucabtagene Autoleucel (Brexu-cel) for Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL): A CIBMTR Subgroup Analysis of High-Risk Characteristics

Patients with R/R MCL and TP53 mutation/deletion or high Ki-67 proliferation index (PI) have historically had limited treatment options with dismal outcomes. In a previously presented three-year follow-up of ZUMA-2, outcomes were comparable across various high-risk subgroups, including in patients with TP53 mutation or Ki-67 PI ≥ 30% or ≥ 50%.

An analysis of a CIBMTR observational database of R/R MCL patients receiving Tecartus from 84 U.S. centers was presented. With a median follow-up of 12.2 months, CR rates were high among these challenging-to-treat sub-populations:

For patients with deletion of TP53/17p (n=44), CR was 84% compared to 81% in those without (n=183)
For patients with Ki-67 PI ≥ 50% (n=146), CR was 83% vs 84% in those with Ki-67 PI < 50% (n=111).
Safety endpoints were largely consistent among all subgroups. Prolonged neutropenia and thrombocytopenia occurred more frequently in patients with vs without deletion of TP53/17p (25% vs 13% and 28% vs 16%, respectively). Grade ≥ 3 CRS occurred more frequently in ZUMA-2-ineligible vs eligible patients (13% vs 7%). After multivariable adjustment, all effectiveness and most safety outcomes were consistent regardless of deletion of TP53/17p and Ki-67 >+50%.

"These real-world findings suggest that outcomes of brexu-cel treatment, including a high complete response rate, are largely consistent, regardless of ZUMA-2 eligibility or the high-risk feature subgroups analyzed. Although patients without deletion of TP53/17p appeared to have longer overall survival than patients with, the data further demonstrate the safety and durability of response of brexu-cel for patients with relapsed/refractory mantle cell lymphoma, who typically face poor prognoses and have limited treatment options," said Swetha Kambhampati, MD, lead investigator, City of Hope assistant professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation.

(Abstract #1029)

Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) adult B-cell acute lymphoblastic leukemia (B-cell ALL): Evidence from the CIBMTR registry

This real-world evidence study of Tecartus in adult patients with B-ALL examined a CIBMTR registry database of 150 patients across 67 centers in the United States.

The assessment found the overall complete remission or complete remission with incomplete hematological recovery (CR/CRi) rate by Day 100 post-infusion was 76%, and 70% were still in remission at 6 months post-initial response (95% CI: 55-80). For those who were not in response prior to lymphodepletion (LD), 63% of these patients converted to a CR/CRi post-infusion.

The OS rate at six months was 78% (95% CI: 69-84); primary causes of death were primary disease (n=13/32, 41%) and infection (n=7/32, 22%). About one-third (31%) of responders received a subsequent allogeneic stem cell transplant (allo SCT). High response rates were observed in all patients regardless of age, prior exposure to blinatumomab, prior allo SCT, or the presence of extramedullary disease prior to LD. Grade ≥3 CRS and immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT consensus) occurred in 9% and 24% of patients, respectively. Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%). Most of these AEs were resolved within three weeks of infusion (CRS, 94%; ICANS, 80%). Prolonged cytopenia and neutropenia 30 days post-infusion were experienced by 42% and 33% of patients, respectively.

"It is encouraging to see that the efficacy and safety outcomes of the largest real-world evidence study of brexu-cel in B-ALL are consistent with the results of the ZUMA-3 study, with high response rates in a broad, actual patient population," said Evandro Bezerra, MD, lead investigator, hematology specialist, Ohio State University Comprehensive Cancer Center. "These findings further build our confidence in the role of brexu-cel in treating adult patients with B-ALL, including those living with high-risk comorbidities and other factors that make treatment particularly challenging."

About ZUMA-2

ZUMA-2 is a single-arm, international multicenter (US and Europe), open-label Phase 2 study involving 74 enrolled/leukapheresed adult patients (≥18 years old) with MCL whose disease is refractory to or has relapsed following up to five prior lines of therapy, including anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy and the BTK inhibitors ibrutinib or acalabrutinib. The objectives of the study are to evaluate the efficacy and safety after a single infusion of KTE-X19 in this patient population. The primary endpoint for the study is objective response rate and is defined as the combined rate of complete responses and partial responses as assessed by an Independent Radiology Review Committee. Secondary endpoints include duration of response, best objective response, progression-free survival, OS, incidence of AEs, incidence of anti-CD19 CAR antibodies, levels of anti-CD19 CAR T cells in blood, levels of cytokines in serum, and changes over time in the EQ-5D scale score and visual analogue scale score. The study is ongoing.

About ZUMA-18

The U.S. expanded-access ZUMA-18 trial consists of two cohorts of 27 patients per total. The primary objectives were to provide access to Tecartus for patients with R/R MCL until it was commercially available (Cohort 1) and patients with R/R MCL whose manufactured product did not meet commercial release specifications (Cohort 2). In Cohort 1, adults (≥18 years) with R/R MCL with ≥1 prior regimen underwent leukapheresis and conditioning chemotherapy followed by a single infusion of Tecartus at a target dose of 2×106 cells/kg (or fixed dose of 2×108 anti-CD19 CAR T cells for patients who are ≥100 kg). In Cohort 2, patients received Cohort 1 treatment without leukapheresis (initial leukapheresis product used). Key endpoints were safety, ORR, and OS.

About Mantle Cell Lymphoma

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’ disease progressing following therapy.

About Acute Lymphoblastic Leukemia

ALL is an aggressive and rare type of blood cancer that can also involve the lymph nodes, spleen, liver, central nervous system and other organs, and is very challenging to treat. In adults, B-ALL is the most common form, accounting for 75% of cases. Survival rates in adults with R/R B-ALL are poor, with a median OS of less than eight months.

About Tecartus

Please see full FDA 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. CRS occurred in 92% (72/78) of patients with ALL, including ≥ Grade 3 (Lee grading system) CRS in 26% of patients. Three patients with ALL had ongoing CRS events at the time of death. The median time to onset of CRS was five days (range: 1 to 12 days) and the median duration of CRS was eight days (range: 2 to 63 days) for patients with ALL.
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 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 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.

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