On July 26, 2020 TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage immunotherapy company with a pipeline of novel T cell therapies for patients suffering from cancer, reported positive interim data from the first five patients treated in the Phase 1 portion of the TC-210 Phase 1/2 clinical trial for mesothelin-expressing solid tumors (Press release, TCR2 Therapeutics, JUL 26, 2020, View Source [SID1234562396]). All five patients showed tumor regression including two RECIST unconfirmed partial responses (one of which remains subject to independent central review) and two patients with stable disease through six months. Translational data further demonstrated TRuC-T cell expansion and activation. A manageable toxicity profile was observed with only one patient exhibiting TC-210-related non-hematologic grade >2 toxicity and no evidence of neurotoxicity or on-target, off-tumor toxicity.

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"We are delighted that our very first dose of TC-210 induced consistent tumor regression and clinical benefit in heavily pre-treated cancer patients," said Garry Menzel, Ph.D., President and Chief Executive Officer of TCR2 Therapeutics. "There are very few options for patients with solid tumors and those expressing mesothelin represent a significant frontier of unmet medical need. While these are early data requiring further study, we are encouraged by the potential of our TRuC-T cells as we continue to enroll and treat patients with the goal of quickly finding a recommended Phase 2 dose for TC-210."

"Based on my prior experience working with both TCR-T and CAR-T cells, including the FDA approval of Kymriah, observing consistent clinical benefit in patients at presumably suboptimal T cell doses is quite meaningful," said Alfonso Quintás-Cardama, M.D., Chief Medical Officer of TCR2 Therapeutics. "These early TC-210 data suggest our approach may overcome the challenges faced by many T cell therapies in the hostile solid tumor microenvironment. Our enrolled patients have failed multiple lines of therapy, including standard chemotherapy, checkpoint inhibitors and in some cases other mesothelin-directed approaches, in indications where survival has been historically shorter than six months."

The primary objectives of the Phase 1 portion of the study are to define the safety profile of TC-210 in patients whose tumors overexpress mesothelin and to determine the recommended Phase 2 dose (RP2D). Secondary objectives include overall response rate (ORR) and disease control rate (DCR). Exploratory objectives include the assessment of expansion, tumor infiltration, and persistence of TC-210 T cells.

Summary of trial conduct, baseline characteristics and TC-210 dose:

Screening: Forty-eight percent of patients met the mesothelin expression cut-off as defined per protocol.

Manufacturing: TC-210 T cell products meeting protocol defined specifications have been manufactured successfully for each patient enrolled in the clinical trial.

Patient Characteristics: TC-210 treated patients included four with mesothelioma and one with ovarian cancer with a median age of 61 years (range, 36-74 years). The median number of prior therapies was five (range, 3-9), including immune checkpoint inhibitor therapy (n=3) and the anti-mesothelin ADC anetumab ravtansine (n=1).

TC-210 Dose: All patients received the same TC-210 dose either with or without lymphodepletion. One patient with mesothelioma was enrolled to dose level (DL) 0 (5×107 TC-210 T cells/m2 without lymphodepletion) whereas four patients (three with mesothelioma and one with ovarian cancer) were enrolled to DL1 (5×107 TC-210 T cells/m2 following lymphodepletion with fludarabine 30 mg/m2/day x4 and cyclophosphamide 600 mg/m2/day x3).

Key clinical findings from the first five patients treated with TRuC-T cells include:

Safety: TC-210 was generally well tolerated, with no patients experiencing neurotoxicity or on-target, off-tumor toxicities. Three (60%) patients experienced Cytokine Release Syndrome (CRS), which was Grade 1 in two patients and Grade 3 in one patient. The patient experiencing Grade 3 CRS also developed Grade 3 pneumonitis during the first week post infusion that responded to tocilizumab and steroid therapy. This patient died 34 days post treatment due to fungal sepsis, which was deemed unrelated to TC-210. Because of the earlier pneumonitis event, however, the Safety Review Team recommended the expansion of the cohort from three to six patients. None of the subsequent three patients treated at DL1 developed pneumonitis or CRS above Grade 1.

Clinical Activity: All five patients treated with TC-210 T cells have had at least one disease response assessment. The DCR was 100%, with all patients experiencing tumor regression. The median change in the sum of diameters of target lesions was -42% (range, -17% to -67%). The ORR was 40% (2 unconfirmed PRs) according to RECIST v1.1. TC-210 therapy induced a significant reduction in FDG uptake by PET imaging in two evaluable patients, including one patient who achieved a complete metabolic response (PR by RECIST v1.1).

Translational Data: Peak TC-210 expansion (Cmax) occurred between days 7 and 22. The median peak TC-210 expansion was 821 copies/µg of genomic DNA (range, 520 to 5,901 copies/µg). Cmax increased when TC-210 was administered following lymphodepletion. Cytokine induction post-TC-210 infusion was observed in all evaluable patients suggesting target engagement.

About the Phase 1/2 Clinical Trial in Advanced Mesothelin-Expressing Solid Tumors

The Phase 1/2 clinical trial (NCT03907852) is evaluating the safety and efficacy of TC-210, TCR2’s T-cell receptor fusion construct directed against mesothelin. The trial is enrolling patients with mesothelin expressing NSCLC, ovarian cancer, cholangiocarcinoma, and malignant pleural/peritoneal mesothelioma. The Phase 1 dose escalation portion of the clinical trial utilizes a modified 3+3 design with four increasing TC-210 T cell doses. At each dose, TC-210 will be tested in two separate dose levels: first without lymphodepletion and then following lymphodepleting chemotherapy. The Phase 1 portion of the clinical trial is ongoing.

In the Phase 2 portion of the clinical trial, approximately 50 patients are planned to receive TC-210 at the RP2D in four distinct cohorts according to their cancer diagnosis: NSCLC, ovarian cancer, malignant pleural/peritoneal mesothelioma and cholangiocarcinoma. Each cohort will include ten patients, except the NSCLC cohort which will include 20 patients with eight patients to receive TC-210 as single agent and 12 patients to receive TC-210 in combination with a programmed cell death 1 (PD-1) blocking antibody.

About Mesothelin-Expressing Solid Tumors

Mesothelin is a cell-surface glycoprotein highly expressed in a wide range of solid tumors, including malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, breast cancer, pancreatic cancer and others. Overexpression of mesothelin is associated with poorer prognosis in some cancers due to its active role in both malignant transformation and tumor aggressiveness by promoting cancer cell proliferation, invasion, and metastasis. Of the wide range of solid tumors expressing mesothelin, non-small cell lung cancer, ovarian cancer, mesothelioma and cholangiocarcinoma represent a significant patient population up to 80,000 in the United States alone.

TCR2 Therapeutics Conference Call and Webcast

TCR2 Therapeutics will host a conference call and webcast on Monday, July 27th at 8:00am E.T. The webcast and presentation will be made available on the TCR2 Therapeutics website in the Investors section under Eventsat View Source Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.

On July 24, 2020 Researchers at Children’s Hospital of Philadelphia (CHOP) reported that have developed a new computational algorithm that has, for the first time, identified a spectrum of mutations in the noncoding portion of the human genome across five major pediatric cancers (Press release, Children’s Hospital of Philadelphia, JUL 24, 2020, View Source [SID1234562375]). The study, which was published today in Science Advances, used the algorithm to analyze more than 500 pediatric cancer patients’ mutations and gene expression profiles to develop a comprehensive list of potentially cancer-causing mutations.

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"Noncoding mutations are very important because the noncoding portion of the genome typically regulates how genes are turned on and off, much like a control switch, which has implications for the uncontrolled growth that occurs in cancer," said Kai Tan, PhD, Professor of Pediatrics at CHOP and senior author of the study. "However, these regions are also challenging to study, and our knowledge about them not as developed as that of coding regions. Our computational model has identified a set of targets in pediatric cancers that we hope to study further and eventually move to clinical practice."

The researchers developed a computation tool called PANGEA (predictive analysis of noncoding genomic enhancer/promoter alterations) to analyze noncoding mutations and their impact on gene expression in more than 500 pediatric cancer patients who had five major types of pediatric cancer: B cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), neuroblastoma, Wilms tumor, and osteosarcoma. PANGEA identified all types of mutations that are associated with gene expression changes, including single nucleotide variants, small indels, copy number variations, and structural variants.

Previous studies on noncoding mutations have focused on single nucleotide variants and small indels, which are insertions or deletions of bases in the genome that are relatively short in length. However, structural variants are regions of DNA much larger in size – 1 kilobase or larger – a quality that makes them more difficult to identify but also more likely to contribute to changes in gene regulation that lead to cancer.

Using PANGEA, the researchers found that structural variants are indeed the most frequent cause of potentially cancer-causing mutations and identified 1,137 structural variants that affect the expression of more than 2,000 genes across the five pediatric cancer types.

In analyzing the data, the researchers found that coding and noncoding mutations affect distinct sets of genes and pathways, which is likely due to the different genomic locations of these two types of genes. The researchers found that genes involved in metabolism – the rewiring of which is a hallmark of cancer – are more frequently affected by noncoding mutations. However, it is unclear to what degree noncoding mutations facilitate metabolism rewiring in the five cancer types the researchers studied.

"Our results highlight the need for comparative analysis of both coding and noncoding mutations, which might reveal novel cancer-related genes and pathways," said Tan. "Identifying putative mutations is a starting point that will facilitate experimental work to validates these predictions."

This work was supported by grants from the National Institutes of Health, including the National Cancer Institute and the National Institute of General Medical Sciences.

B. He et al. "Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers," Science Advances, July 24, 2020. DOI: 10.1126/sciadv.aba3064

On July 24, 2020 Tvardi Therapeutics Inc. ("Tvardi"), a privately held, clinical-stage biopharmaceutical company focused on the development of STAT3 inhibitors, reported over $5 million in non-dilutive grants to support the ongoing validation and clinical development of Tvardi’s lead compound, TTI-101 (Press release, Tvardi Therapeutics, JUL 24, 2020, View Source [SID1234562350]). The three National Cancer Institute (NCI) funding awards are two Specialized Programs of Research Excellence (SPORE) grants to support clinical trials of TTI-101 in hepatocellular carcinoma (HCC) and gastrointestinal cancer as well as funding from the PREVENT program to support translational work of TTI-101 in HCC prevention.

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The new funding brings the total non-dilutive support of TTI-101 to approximately $20 million from multiple sources including the National Institutes of Health (NIH), V Foundation and the Cancer Prevention & Research Institute of Texas (CPRIT).

"These grants are rigorously peer-reviewed and validate the scientific foundation of Tvardi’s STAT3 inhibitor program. Our ability to serve our patients’ needs has been greatly enhanced by strong collaborations with the academic community and private sector. TTI-101 has the potential to help millions of patients suffering from STAT3-related diseases," said Ronald DePinho, M.D., Tvardi’s Co-Founder and Director.

"Our success to date stems from a strong team effort of dedicated, innovative scientists coming together to solve a major unmet need. To date, TTI-101 has demonstrated an excellent safety profile and, importantly, the ability to shrink tumors in patients who have no other options," shared Imran Alibhai, Ph.D., CEO of Tvardi.

On July 24, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a Positive Opinion recommending marketing authorisation for IMBRUVICA (ibrutinib) to include the combination with rituximab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, Janssen Pharmaceuticals, JUL 24, 2020, View Source [SID1234562349]).

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The Positive Opinion is based on data from the Phase 3 E1912 study, designed and conducted in the United States (U.S.) by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the U.S. National Institutes of Health. The study evaluated 529 patients with previously untreated CLL aged 70 years or younger (median age 58) who were randomly assigned in a 2:1 ratio to receive ibrutinib plus rituximab (n=354) or the standard of care chemo-immunotherapy fludarabine, cyclophosphamide and rituximab (FCR) (n=175). The primary study results were published in The New England Journal of Medicine, and the extended four-year median follow-up results were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.1,2

"Ibrutinib in combination with rituximab represents an important new targeted and non-chemotherapy option for patients with CLL," said John Gribben, MD DSc, Professor of Medical Oncology at St Bartholomew’s Hospital, Barts Cancer Institute, Queen Mary, University of London. "For people living with CLL, relapse is often inevitable. Using this combination in the frontline setting has the potential to not only extend life, but also offer a tolerability profile with less of the known chemotherapy-related events."

The CHMP Positive Opinion comes after the U.S. Food and Drug Administration’s (FDA) approval of this expanded indication for ibrutinib in April 2020. The application will now be reviewed by the European Commission (EC).

"Ibrutinib has been used to treat more than 200,000 people globally, and this latest milestone further highlights its potential for patients diagnosed with CLL," said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. "We look forward to working with the European Commission to bring this new, ibrutinib-based, non-chemotherapy frontline treatment option to adult patients with CLL."

"This landmark head-to-head study, conducted by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute has generated important, practice changing results which challenge FCR, the gold standard of chemotherapy-based treatment regimens for younger, fit patients with previously untreated CLL for over a decade," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development. "We are pleased to build upon the robust body of data supporting the most widely studied BTK inhibitor as we continue to study further ibrutinib-based regimens in our mission to improve the lives of patients with complex blood cancers, like CLL."

About ibrutinib
Ibrutinib is a once-a-day, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally.3 Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.4 By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.5

Ibrutinib is currently approved in Europe for:3

Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL
Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients
Ibrutinib is approved in more than 99 countries for at least one indication, and to date, has been used to treat more than 200,000 patients worldwide across its approved indications.6

The most common adverse reactions seen with ibrutinib include diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia.3

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.7 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.8 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.9

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.

On July 24, 2020 Kite, a Gilead Company (Nasdaq: GILD), reported that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to Tecartus (brexucabtagene autoleucel, formerly KTE-X19), the first and only approved chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) (Press release, Kite Pharma, JUL 24, 2020, View Source [SID1234562347]). The approval of this one-time therapy follows a priority review and FDA Breakthrough Therapy Designation and is based on results of ZUMA-2, a single-arm, open-label study in which 87 percent of patients responded to a single infusion of Tecartus, including 62 percent of patients achieving a complete response (CR). Among patients evaluable for safety, 18 percent experienced Grade 3 or higher cytokine release syndrome (CRS) and 37 percent experienced Grade 3 or higher neurologic toxicities.

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"Despite promising advances, there are still major gaps in treatment for patients with MCL who progress following initial therapy," said Michael Wang, MD, ZUMA-2 Lead Investigator and Professor, Department of Lymphoma and Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Many patients have high-risk disease and are more likely to keep progressing, even after subsequent treatments. The availability of Tecartus as the first-ever cell therapy for patients with relapsed/refractory MCL provides an important option with a response rate of nearly 90 percent and early clinical evidence suggesting durable remissions in later lines of therapy."

"Kite is committed to bringing the promise of CAR T therapy to patients with hematological cancers, and as such, we are proud to launch our second cell therapy," said Christi Shaw, Chief Executive Officer of Kite. "I extend my thanks to the patient study participants, caregivers, clinical researchers, regulators and dedicated colleagues at Kite who helped make this approval possible, and we look forward to partnering with the lymphoma community to deliver this potentially transformative therapy to patients with relapsed or refractory MCL."

Tecartus has a Boxed Warning in its product label regarding the risks of CRS and neurologic toxicities. A Risk Evaluation and Mitigation Strategy (REMS) has been approved by the FDA for Tecartus and has been combined with the Yescarta (axicabtagene ciloleucel) REMS. The REMS program will inform and educate healthcare professionals about the risks associated with Tecartus therapy, and training and certification on the REMS program will be an integral part of the final authorization for centers offering Tecartus. Additional information about the REMS program can be found at www.YescartaTecartusREMS.com. Please see below for Important Safety Information.

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. MCL is highly aggressive following relapse, with many patients progressing following therapy.

"This approval marks the first CAR T cell therapy approved for mantle cell lymphoma patients and represents a new frontier in the treatment of this disease," said Meghan Gutierrez, Chief Executive Officer at the Lymphoma Research Foundation. "In the past decade, researchers have made significant progress in our understanding of this disease and we have seen an increase in clinical trials for patients, which we hope will continue to improve treatment strategies and the options available to people with mantle cell lymphoma. Today’s news builds upon this progress and provides hope to mantle cell patients and their loved ones."

Tecartus will be manufactured in Kite’s commercial manufacturing facility in El Segundo, California. In the ZUMA-2 trial, Kite demonstrated a 96 percent manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery. Manufacturing speed is especially critical for patients with advanced disease, who are very ill and at risk for quick progression.

Patients whose healthcare professionals have prescribed Tecartus therapy can work with Kite Konnect, an integrated technology platform that provides information and assistance throughout the therapy process for Kite’s commercialized CAR T therapies, including courier tracking for shipments and manufacturing status updates. Kite Konnect provides support for eligible patients receiving Yescarta and Tecartus, and it provides information for the healthcare teams supporting their patients. Healthcare providers and patients can reach Kite Konnect at www.KiteKonnect.com or 1-844-454-KITE (1-844-454-5483).

KTE-X19 is currently under review in the European Union and has been granted Priority Medicines (PRIME) designation by the European Medicines Agency for relapsed or refractory MCL.

Tecartus Trial Results
The approval of Tecartus is supported by data from the ongoing, single arm, open-label ZUMA-2 pivotal trial. The study enrolled 74 adult patients with relapsed or refractory MCL who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody therapy and a Bruton tyrosine kinase inhibitor (ibrutinib or acalabrutinib). The primary endpoint was objective response rate (ORR) per the Lugano Classification (2014), defined as the combined rate of CR and partial responses as assessed by an Independent Radiologic Review Committee (IRRC).

In the study, 87 percent of patients (n=60 evaluable for efficacy analysis) responded to a single infusion of Tecartus, including 62 percent of patients who achieved a CR. Among all patients, follow-up was at least six months after their first objective disease response. Median duration of response has not yet been reached.

In the trial, 18 percent of patients (n=82 evaluable for safety) experienced Grade 3 or higher CRS and 37 percent experienced neurologic events. The most common (≥ 10 percent) Grade 3 or higher adverse reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia and lymphopenia. The FDA approved Tecartus with a Risk Evaluation and Mitigation Strategy (REMS). The Tecartus REMS has been combined with the Yescarta REMS and is now called the "Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel) REMS Program" (www.YescartaTecartusREMS.com).

About Tecartus
Tecartus is an autologous, anti-CD19 CAR T cell therapy. Tecartus uses the XLP manufacturing process that includes T cell enrichment, a necessary step in certain B-cell malignancies in which circulating lymphoblasts are a common feature. In addition to MCL, Tecartus is also currently in Phase 1/2 trials in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). The use of Tecartus in ALL and CLL is investigational, and its safety and efficacy have not been established in these cancer types.

Tecartus Indication
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.

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, key manifestations (>10%) included fever (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (37%), headache (24%), fatigue (19%), nausea (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (12%), and diarrhea (11%). Serious events associated with CRS included hypotension, fever, hypoxia, acute kidney injury, and tachycardia.

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 Toxicities, including those that were life-threatening, occurred following treatment with Tecartus. In ZUMA-2, neurologic events occurred in 81% of patients, 37% of whom experienced Grade ≥3 adverse reactions. The median time to onset for neurologic events was six days (range: 1 to 32 days). Neurologic events resolved for 52 out of 66 (79%) patients with a median duration of 21 days (range: 2 to 454 days). Three patients had ongoing neurologic events at the time of death, including one patient with serious encephalopathy. The remaining unresolved neurologic events were either Grade 1 or Grade 2. Fifty-four (66%) patients experienced CRS by 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. 85% of all treated patients experienced the first CRS or neurological event within the first seven days after Tecartus infusion.

The most common neurologic events (>10%) included encephalopathy (51%), headache (35%), tremor (38%), aphasia (23%), and delirium (16%). Serious events including encephalopathy, aphasia, and seizures occurred.

Monitor patients daily for at least seven days 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. In ZUMA-2, infections (all grades) occurred in 56% of patients. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients. Tecartus 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 6% of patients after Tecartus infusion 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.

Viral Reactivation
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 ZUMA-2, Grade ≥3 cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). Monitor blood counts after infusion.

Hypogammaglobulinemia and B-cell aplasia can occur in patients receiving treatment with Tecartus. In ZUMA-2, hypogammaglobulinemia occurred in 16% of patients. 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 treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that it 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 adverse reactions (incidence ≥ 20%) were pyrexia, CRS, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection – pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia. Serious adverse reactions occurred in 66% of patients. The most common serious adverse reactions (> 2%) were encephalopathy, pyrexia, infection – pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections.