6 ADVERSE REACTIONS

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)]

Cutaneous Reactions [see Warnings and Precautions (5.4)]

6.1 Clinical 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 1 summarizes the adverse reactions in LOTIS-2.

Table 1: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory DLBCL who received ZYNLONTA in LOTIS-2
Adverse Reaction	ZYNLONTA (N=145)
Adverse Reaction	All Grades (%)	Grades 3 or 4 (%)
* Fatigue includes fatigue, asthenia, and lethargy † No Grade 4 adverse reactions occurred ‡ Edema includes edema, face edema, generalized edema, peripheral edema, ascites, fluid overload, peripheral swelling, swelling, and swelling face § 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 ¶ Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, and abdominal pain upper # 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 Þ Dyspnea includes dyspnea, and dyspnea exertional ß Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract congestion, nasopharyngitis, rhinitis, rhinovirus infection, and sinusitis
General Disorders and Administration Site Conditions
Fatigue*	38	1†
Edema‡	28	3†
Skin and Subcutaneous Tissue Disorders
Rash§	30	2†
Pruritus	12	0
Photosensitivity reaction	10	2†
Gastrointestinal Disorders
Nausea	23	0
Diarrhea	17	2†
Abdominal pain¶	14	3
Vomiting	13	0
Constipation	12	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain#	23	1†
Metabolism and Nutrition Disorders
Decreased appetite	15	0
Respiratory Disorders
DyspneaÞ	13	1†
Pleural effusion	10	2†
Infection
Upper respiratory tract infectionß	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: Pneumonia1 (5%), sepsis2 (2%)
Skin and subcutaneous disorders: Hyperpigmentation (4%)
General disorders: Infusion site extravasation (<1%)

1: Pneumonia includes pneumonia and lung infection
2: Sepsis includes sepsis, escherichia sepsis, and septic shock

Selected Other Adverse Reactions

Inflammatory-related conditions were reported in 3% of patients in LOTIS-2, including pericarditis, pneumonitis, pleuritis, and dermatitis.

Table 2 summarizes the laboratory abnormalities in LOTIS-2.

Table 2: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with Relapsed or Refractory DLBCL Who Received ZYNLONTA in LOTIS-2
Laboratory Abnormality	ZYNLONTA*
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
* 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 † No Grade 4 adverse reactions occurred
Hematologic
Platelets decreased	58	17
Neutrophils decreased	52	30
Hemoglobin decreased	51	10†
Chemistry
GGT increased	57	21
Glucose increased	48	8
AST increased	41	<1†
Albumin decreased	37	<1†
ALT increased	34	3

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of ZYNLONTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: telangiectasia, blister, rash vesicular