On May 17, 2023 Gilead Sciences, Inc. (Nasdaq: GILD) and Kite, a Gilead Company, reported that it will present 30 abstracts during the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Gilead Sciences, MAY 17, 2023, View Source [SID1234631819]). These data reinforce the strength of Gilead and Kite Oncology’s transformative science in hard-to-treat cancers.
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"The breadth of data being presented at ASCO (Free ASCO Whitepaper) is a testament to our commitment in helping to bring more life to people with cancer," said Bill Grossman, MD, PhD, Senior Vice President, Therapeutic Area Head, Gilead Oncology. "We are determined to deliver the best outcomes for patients and are proud to highlight the pan-tumor efficacy of Trodelvy as well as our growing presence across lung cancer and many other tumor types."
New Data Reinforce Pan-Tumor Efficacy of Trodelvy
Final overall survival (OS) results from the Phase 3 TROPiCS-02 study for Trodelvy (sacituzumab govitecan-hziy) in HR+/HER2- metastatic breast cancer (mBC) will be presented in an oral session. Gilead will also share data evaluating Trodelvy in metastatic urothelial cancer (UC); in the U.S., Trodelvy currently has an accelerated approval for the treatment of certain patients with second-line metastatic UC. Additionally, Gilead will present the first Phase 2 data evaluating Trodelvy as a potential therapy in advanced endometrial cancer.
Kite Therapies Continue to Advance the Standard of Care in Leukemia and Lymphoma
A late-breaking oral presentation from the landmark Phase 3 ZUMA-7 study will highlight OS results for Yescarta (axicabtagene ciloleucel) versus standard of care for initial treatment of adult patients with relapsed/refractory large B-cell lymphoma (LBCL) within 12 months of completion of first-line therapy. Further analysis of the pivotal ZUMA-3 study in adult B-cell acute lymphoblastic leukemia, in addition to real-world evidence in follicular lymphoma and mantle cell lymphoma, will also be presented.
"The data that will be presented at ASCO (Free ASCO Whitepaper) represent another significant step forward in our goal of bringing the hope of survival to more patients through our innovative cell therapies," said Frank Neumann, MD, PhD, SVP, Kite’s Global Head of Clinical Development. "We are particularly excited to share our overall survival data from the pivotal ZUMA-7 study for Yescarta for initial treatment of relapsed/refractory large B-cell lymphoma, the first and only treatment in 30 years to demonstrate a statistically significant improvement in overall survival versus historical standard of care in this patient population."
Gilead Highlights Emerging Lung Cancer Pipeline, Progress in Solid Tumors
Beyond our ongoing late-stage development program evaluating the investigational use of Trodelvy in non-small cell lung cancer (NSCLC), Gilead will highlight clinical data and trial updates from several other lung cancer trials. This includes an oral presentation with our partner Arcus Biosciences, on the updated interim analysis of ARC-7, which will detail updated efficacy and safety results for domvanalimab, an Fc-silent anti-TIGIT monoclonal antibody, in first-line NSCLC with PD-L1 tumor proportion score (TPS) ≥50% without epidermal growth factor receptor or anaplastic lymphoma kinase (EGFR/ALK) mutations. ARC-7 is an approximately 150-patient randomized Phase 2 study evaluating domvanalimab plus anti-PD-1 antibody zimberelimab (doublet) and domvanalimab plus zimberelimab and etrumadenant, an A2a/b adenosine receptor antagonist (triplet), versus zimberelimab alone.
Further highlighting progress being made across Gilead’s oncology pipeline, trial updates will be shared from ongoing studies in lung cancer, triple-negative breast cancer, UC and several other solid tumors.
Summary of Presentations
Accepted abstracts at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting include (all times CDT):
Tumor Types
Abstract Title
Breast Cancer
Abstract #1003 (Oral Session)
Monday, June 5
12:30 PM
Final Overall Survival (OS) Analysis from the Phase 3 TROPiCS-02 Study of Sacituzumab Govitecan (SG) in Patients (Pts) with Hormone Receptor–Positive/HER2-Negative (HR+/HER2–) Metastatic Breast Cancer (mBC)
Abstract #1082
Sunday, June 4
8:00-11:00 AM
Trop-2 mRNA Expression and Association with Clinical Outcomes with Sacituzumab Govitecan (SG) in Patients with HR+/HER2– Metastatic Breast Cancer (mBC): Biomarker Results from the Phase 3 TROPiCS-02 Study
Abstract #TPS619 (TiP)
Sunday, June 4
8:00-11:00 AM
ASCENT-05/Optimice-RD (AFT-65): Phase 3, Randomized, Open-Label Study of Adjuvant Sacituzumab Govitecan (SG) + Pembrolizumab (Pembro) vs. Pembro ± Capecitabine (Cape) in Patients (Pts) with Triple-Negative Breast Cancer (TNBC) and Residual Disease after Neoadjuvant Therapy (NAT) and Surgery
Abstract #TPS1130 (TiP)
Sunday, June 4
8:00-11:00 AM
A Phase 2 Randomized Study of Magrolimab Combination Therapy in Adult Patients with Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer (mTNBC): ELEVATE TNBC
ePublication
#e18871
Real-World Clinical Outcomes in Patients (Pts) with HR+/HER2- Metastatic Breast Cancer (mBC) Treated with Chemotherapy (CT) in the U.S.
ePublication
e18879
Real-World Outcomes in Patients (Pts) with Metastatic Triple-Negative Breast Cancer (mTNBC) Treated with Sacituzumab Govitecan (SG) in 2L+ in the U.S.
ePublication
e18798
Canadian (CAN) Real-World Outcomes for Relapsed/Recurrent (R/R) Metastatic Triple-Negative Breast Cancer (mTNBC) in the First-Line or Later (1L+) Setting By Early or Late Recurrence Status
B-cell Lymphomas
Abstract #LBA107 (Oral Session)
Monday, June 5
10:09 AM
Primary Overall Survival Analysis of the Phase 3 Randomized ZUMA-7 Study of Axicabtagene Ciloleucel versus Standard-of-Care Therapy in Relapsed/Refractory Large B-Cell Lymphoma
Abstract #7547
Monday, June 5
8:00-11:00 AM
Circulating Tumor DNA (ctDNA) by ClonoSEQ to Monitor Residual Disease after Axicabtagene Ciloleucel (Axi-Cel) in Large B-Cell Lymphoma (LBCL)
Abstract #TPS7578 (TiP)
Monday, June 5
8:00-11:00 AM
ZUMA-23: A Global, Phase 3, Randomized Controlled Study of Axicabtagene Ciloleucel versus Standard of Care as First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma
Mantle Cell Lymphoma
Abstract #7507 (Oral Session)
Tuesday, June 6
11:57 AM
Real-World Outcomes of Brexucabtagene Autoleucel (Brexu-cel) for Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL): A CIBMTR Subgroup Analysis by Prior Treatment
Lung Cancer
Abstract #397600 (Oral Session)
Saturday, June 3
12:48 PM
ARC-7: Randomized Phase 2 Study of Domvanalimab + Zimberelimab +/- Etrumadenant vs Zimberelimab in First-Line, Metastatic, PD-L1-High Non-Small Cell Lung Cancer (NSCLC)
Abstract #9034
Sunday, June 4
8:00-11:00 AM
Molecular Characterization of Resistance to Immune Checkpoint Inhibitor and Chemotherapy Treatment in Advanced Non-Small Cell Lung Cancer
Abstract #TPS9155 (TiP)
Sunday, June 4
8:00-11:00 AM
VELOCITY-Lung: A Phase (Ph) 2 Study Evaluating Safety and Efficacy of Domvanalimab (Dom) + Zimberelimab (Zim) + Sacituzumab Govitecan (SG), or Etrumadenant (Etruma) + Dom + Zim, or Etruma + Zim in Patients (Pts) with Treatment-Naïve Metastatic Non-Small Cell Lung Cancer (mNSCLC)
Abstract #TPS9141 (TiP)
Sunday, June 4
8:00-11:00 AM
STAR-121: A Phase 3, Randomized Study of Domvanalimab (DOM) and Zimberelimab (ZIM) in Combination with Chemotherapy vs. Pembrolizumab (Pembro) and Chemotherapy in Patients with Untreated Metastatic Non-Small Cell Lung Cancer (mNSCLC) with No Actionable Gene Alterations
Abstract #TPS9148 (TiP)
Sunday, June 4
8:00-11:00 AM
ARC-10: A phase 3 Study to Evaluate Zimberelimab + Domvanalimab vs. Pembrolizumab in Front-Line, PD-L1-High, Locally Advanced or Metastatic Non–Small Cell Lung Cancer
Abstract #TPS8609 (TiP)
Sunday, June 4
8:00-11:00 AM
Phase 3 Trial of Durvalumab Combined with Domvanalimab Following Concurrent Chemoradiotherapy (cCRT) in Patients with Unresectable Stage III NSCLC (PACIFIC-8)
Myelodysplastic Syndromes & Acute Myeloid Leukemia
ePublication
Abstract #e19072
Incidence of Drug-Induced Myelosuppression and Associated Adverse Events (AEs), Quality of Life (QoL), and Medical Resource Use (MRU) in Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
Acute Lymphoblastic Leukemia
Abstract #7023
Monday, June 5
8:00-11:00 AM
Impact of Age, Prior Therapies, and Subsequent Transplant on Long-Term Outcomes of Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL) Treated with Brexucabtagene Autoleucel (Brexu-Cel) In ZUMA-3
Endometrial Cancer
Abstract #5610
Monday, June 5
1:15-4:15 PM
TROPiCS-03, A Phase 2 Basket Study of Sacituzumab Govitecan (SG) in Patients (Pts) with Metastatic Solid Tumors: Early Analysis in Pts with Advanced/Metastatic Endometrial Cancer (EC)
Follicular Lymphoma
Abstract #7509
Monday, June 5
8:00-11:00 AM
1:15-2:45 PM (Poster Discussion)
Real-World Early Outcomes of Axicabtagene Ciloleucel for Relapsed or Refractory (R/R) Follicular Lymphoma (FL)
Abstract #TPS7579 (TiP)
Monday, June 5
8:00-11:00 AM
ZUMA-22: A Phase 3, Randomized Controlled Study of Axicabtagene Ciloleucel (Axi-Cel) versus Standard-Of-Care Therapy in Patients with Relapsed or Refractory (R/R) Follicular Lymphoma (FL)
Urothelial Cancer
Abstract #4514
Saturday, June 3
8:00-11:00AM
3:00-4:30 PM (Poster Discussion)
Safety Analysis by UGT1A1 Status of TROPHY-U-01 Cohort 1, a Phase 2 Study of Sacituzumab Govitecan (SG) in Patients (pts) With Metastatic Urothelial Cancer (mUC) who Progressed after Platinum (PT)-Based Chemotherapy and a Checkpoint Inhibitor (CPI)
Abstract #4579
Saturday, June 3
8:00-11:00 AM
Efficacy of Sacituzumab Govitecan (SG) in Locally Advanced (LA) or Metastatic Urothelial Cancer (mUC) By Trophoblast Cell Surface Antigen 2 (Trop-2) Expression
Abstract #TPS4611 (TiP)
Saturday, June 3
8:00-11:00 AM
TROPHY-U-01 Cohort 4 (C4): Sacituzumab Govitecan (SG) in Combination with Cisplatin (Cis) as First-Line (1L) Therapy, Followed by Maintenance Avelumab Plus (+) SG or Zimberelimab (Zim) + SG in Patients (Pts) with Treatment (Tx)-Naïve Metastatic Urothelial Cancer (mUC)
Gastrointestinal Cancers
Abstract #TPS4206 (TiP)
Monday, June 5
8:00-11:00 AM
STAR-221: A Randomized, Open-Label, Multicenter, Phase 3 Trial of Domvanalimab, Zimberelimab, and Chemotherapy vs. Nivolumab and Chemotherapy in Previously Untreated, Locally Advanced, Unresectable or Metastatic Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma
Head And Neck Cancer
Abstract #TPS6102 (TiP)
Monday, June 5
1:15-4:15 PM
A Phase 2 Study of Magrolimab Combination Therapy in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ELEVATE HNSCC)
Advanced Solid Tumors
Abstract #2524
Saturday, June 3
8:00-11:00 AM
3:00-4:30 PM (Poster Discussion)
A Phase 1 Study of AGEN2373, a CD137 Agonist Antibody Designed to Avoid Hepatoxicity, in Patients with Advanced Solid Tumors
Abstract #TPS4602 (TiP)
Saturday, June 3
8:00-11:00 AM
ARC-20: A Phase 1 Dose-Escalation and Dose-Expansion Study to Investigate the Safety, Tolerability, and Pharmacology of HIF-2α Inhibitor AB521 Monotherapy in Patients with Clear Cell Renal Cell Carcinoma and Other Solid Tumors
Abstract #TPS9142 (TiP)
Sunday, June 4
8:00-11:00 AM
A Phase 2 Multi-Arm Study of Magrolimab in Combination with Docetaxel in Patients with Locally Advanced or Metastatic Solid Tumors (ELEVATE Lung and UC)
Domvanalimab, etrumadenant, magrolimab, zimberelimab and Trodelvy for NSCLC and endometrial cancer are investigational and are not approved by the U.S. Food and Drug Administration or any other regulatory authority. Their safety and efficacy have not been established.
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 40 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. to treat certain patients with pre-treated HR+/HER2- metastatic breast cancer and has an accelerated approval for treatment of certain patients with second-line metastatic urothelial cancer; see below for full indication statements.
Trodelvy is also being developed for potential investigational use in other TNBC, HR+/HER2- and metastatic UC populations, as well as a range of tumor types where Trop-2 is highly expressed, including metastatic non-small cell lung cancer (NSCLC), metastatic small cell lung cancer (SCLC), head and neck cancer, and endometrial cancer.
U.S. Indications for Trodelvy
In the United States, Trodelvy is indicated for the treatment of adult patients with:
Unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
Unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
Locally advanced or metastatic urothelial cancer (mUC) 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 confirmatory trials.
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. At the onset of 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 64% of patients treated with Trodelvy. Grade 3-4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6%. Neutropenic colitis occurred in 1.4%. 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. Administer G-CSF as clinically indicated or indicated in Table 1 of USPI.
Diarrhea: Diarrhea occurred in 64% of all patients treated with Trodelvy. Grade 3-4 diarrhea occurred in 11% of patients. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all 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 35% of patients. Grade 3-4 hypersensitivity occurred in 2% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of Trodelvy was 0.2%. The incidence of anaphylactic reactions was 0.2%. Pre-infusion medication is recommended. Have medications and emergency equipment to treat such reactions available for immediate use. Observe patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Permanently discontinue Trodelvy for Grade 4 infusion-related reactions.
Nausea and Vomiting: Nausea occurred in 64% of all patients treated with Trodelvy and Grade 3-4 nausea occurred in 3% of these patients. Vomiting occurred in 35% of patients and Grade 3-4 vomiting occurred in 2% 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 58% in patients homozygous for the UGT1A1*28, 49% in patients heterozygous for the UGT1A1*28 allele, and 43% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia was 21% in patients homozygous for the UGT1A1*28 allele, 10% in patients heterozygous for the UGT1A1*28 allele, and 9% 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 pooled safety population, the most common (≥ 25%) adverse reactions including laboratory abnormalities were decreased leukocyte count (84%), decreased neutrophil count (75%), decreased hemoglobin (69%), diarrhea (64%), nausea (64%), decreased lymphocyte count (63%), fatigue (51%), alopecia (45%), constipation (37%), increased glucose (37%), decreased albumin (35%), vomiting (35%), decreased appetite (30%), decreased creatinine clearance (28%), increased alkaline phosphatase (28%), decreased magnesium (27%), decreased potassium (26%), and decreased sodium (26%).
In the ASCENT study (locally advanced or metastatic triple-negative breast cancer), the most common adverse reactions (incidence ≥25%) were fatigue, diarrhea, nausea, alopecia, 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 TROPiCS-02 study (locally advanced or metastatic HR-positive, HER2-negative breast cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, alopecia, and constipation. The most frequent serious adverse reactions (SAR) (>1%) were diarrhea (5%), febrile neutropenia (4%), neutropenia (3%), abdominal pain, colitis, neutropenic colitis, pneumonia, and vomiting (each 2%). SAR were reported in 28% of patients, and 6% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the TROPiCS-02 study were reduced neutrophils and leukocytes.
In the TROPHY study (locally advanced or metastatic urothelial cancer), the most common adverse reactions (incidence ≥25%) were diarrhea, fatigue, nausea, any infection, alopecia, decreased appetite, constipation, vomiting, rash, and abdominal pain. 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 reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with Trodelvy.
Please see full Prescribing Information , including BOXED WARNING.
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.