The following clinically significant adverse reactions are described elsewhere in the labeling: Effusion and Edema [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2)] Infections [see Warnings and Precautions (5.3) ] Hepatotoxicity, including DILI [see Warnings and Precautions(5.4) ] Cutaneous Reactions [see Warnings and Precautions (5.5) ] Most common (≥20%) adverse reactions, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ADC Therapeutics at 1-855-690-0340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to ZYNLONTA as a single agent at an initial dose of 0.15 mg/kg in 215 patients with DLBCL in studies ADCT-402-201 (LOTIS-2) and ADCT-402-101, which includes 145 patients from LOTIS-2 treated with 0.15 mg/kg × 2 cycles followed by 0.075 mg/kg for subsequent cycles.
Among 215 patients who received ZYNLONTA, the median number of cycles was 3 (range 1 to 15) with 58% receiving three or more cycles and 30% receiving five or more cycles. In this pooled safety population of 215 patients, the most common (>20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.
Relapsed or Refractory Diffuse Large B-Cell Lymphoma LOTIS-2 The safety of ZYNLONTA was evaluated in LOTIS-2, an open-label, single-arm clinical trial that enrolled 145 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including high-grade B-cell lymphoma, after at least two prior systemic therapies [see Clinical Studies (14.1) ] . The trial required hepatic transaminases, including gamma-glutamyltransferase (GGT), ≤2.5 times upper limit of normal (ULN), total bilirubin ≤1.5 times ULN, and creatinine clearance ≥60 mL/min.
Patients received ZYNLONTA 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles and received treatment until progressive disease or unacceptable toxicity. Among the 145 patients, the median number of cycles received was 3, with 34% receiving 5 or more cycles. The median age was 66 years (range 23 to 94), 59% were male, and 94% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Race was reported in 97% of patients; of these patients, 90% were White, 3% were Black, and 2% were Asian. Serious adverse reactions occurred in 28% of patients receiving ZYNLONTA. The most common serious adverse reactions that occurred in ≥2% receiving ZYNLONTA were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection. Permanent treatment discontinuation due to an adverse reaction of ZYNLONTA occurred in 19% of patients.
Adverse reactions resulting in permanent discontinuation of ZYNLONTA in ≥2% were gamma-glutamyltransferase increased, edema, and effusion. Dose reductions due to an adverse reaction of ZYNLONTA occurred in 8% of patients. Adverse reactions resulting in dose reduction of ZYNLONTA in ≥4% was gamma-glutamyltransferase increased. Dosage interruptions due to an adverse reaction occurred in 49% of patients receiving ZYNLONTA.
Adverse reactions leading to interruption of ZYNLONTA in ≥5% were gamma-glutamyltransferase increased, neutropenia, thrombocytopenia, and edema. Table 2 summarizes the adverse reactions in LOTIS-2. Table 2: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory DLBCL who received ZYNLONTA in LOTIS-2 Adverse Reaction ZYNLONTA (N=145) All Grades (%) Grades 3 or 4 (%) General Disorders and Administration Site Conditions Fatigue Fatigue includes fatigue, asthenia, and lethargy 38 1 No Grade 4 adverse reactions occurred Edema Edema includes edema, face edema, generalized edema, peripheral edema, ascites, fluid overload, peripheral swelling, swelling, and swelling face 28 3 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, rash erythematous, rash maculopapular, rash pruritic, rash pustular, erythema, generalized erythema, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, and palmar-plantar erythrodysesthesia syndrome 30 2 Pruritus 12 0 Photosensitivity reaction 10 2 Gastrointestinal Disorders Nausea 23 0 Diarrhea 17 2 Abdominal pain Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, and abdominal pain upper 14 3 Vomiting 13 0 Constipation 12 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, back pain, limb discomfort, myalgia, neck pain, non-cardiac chest pain, and pain in extremity 23 1 Metabolism and Nutrition Disorders Decreased appetite 15 0 Respiratory Disorders Dyspnea Dyspnea includes dyspnea, and dyspnea exertional 13 1 Pleural effusion 10 2 Infection Upper respiratory tract infection Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract congestion, nasopharyngitis, rhinitis, rhinovirus infection, and sinusitis 10 <1 Clinically relevant adverse reactions in <10% of patients (all grades) who received ZYNLONTA included: Blood and lymphatic system disorders: Febrile neutropenia (3%) Cardiac disorders: Pericardial effusion (3%) Infections: Pneumonia Pneumonia includes pneumonia and lung infection (5%), sepsis Sepsis includes sepsis, escherichia sepsis, and septic shock (2%) Skin and subcutaneous disorders: Hyperpigmentation (4%) General disorders: Infusion site extravasation (<1%) Selected Other Adverse Reactions Inflammatory-related conditions were reported in 3% of patients in LOTIS-2, including pericarditis, pneumonitis, pleuritis, and dermatitis.
Table 3 summarizes the laboratory abnormalities in LOTIS-2. Table 3: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with Relapsed or Refractory DLBCL Who Received ZYNLONTA in LOTIS-2 Laboratory Abnormality ZYNLONTA The denominator used to calculate the rate varied from 143 to 145 based on the number of patients with a baseline value and at least one post-treatment value All Grades (%) Grade 3 or 4 (%) Hematologic Platelets decreased 58 17 Neutrophils decreased 52 30 Hemoglobin decreased 51 10 No Grade 4 adverse reactions occurred Chemistry GGT increased 57 21 Glucose increased 48 8 AST increased 41 <1 Albumin decreased 37 <1 ALT increased 34 3 Other Clinical Trials Experience The following adverse reactions have been reported following administration of ZYNLONTA: Hepatotoxicity, including drug- induced liver injury (DILI).
