Safety

ZYNLONTA® safety profile1

Most adverse reactions were mild to moderate (Grade 1-2)1

Pooled safety analysis: Phase 1 and LOTIS-2 studies of patients who received ZYNLONTA® at an initial dose of 0.15 mg/kg (N=215)

The most common (>20%) adverse reactions, including laboratory abnormalities, were thrombocytopenia, increased GGT, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.1

LOTIS-2 study (N=145)

Serious adverse reactions occurred in 28% of patients. The most common serious adverse reactions that occurred in ≥2% of patients were febrile neutropenia, pneumonia, edema, pleural effusion, and sepsis. Fatal adverse reactions occurred in 1%, due to infection.1 Incidence of peripheral neuropathy was rare (3%) and most were mild to moderate (Grades 1-2).2

Permanent treatment discontinuation due to an adverse reaction occurred in 19% of patients1

Adverse reactions resulting in permanent discontinuation in ≥2% were GGT increased (10.3%), edema (2.8%), and effusion (2.8%).1,3

Dose reductions due to an adverse reaction of ZYNLONTA® occurred in 8% of patients1

Adverse reactions resulting in dose reduction in ≥4% was increased GGT.1

Dosage interruptions due to an adverse reaction occurred in 49% of patients1

Adverse reactions leading to dose interruption in ≥5% were GGT increased, neutropenia, thrombocytopenia, and edema.1

Specific populations

In LOTIS-2, 55% of patients were ≥65 years of age. No overall differences in safety or effectiveness were observed between older (>65 years) and younger patients.1

GGT = gamma-glutamyltransferase.

Adverse reactions (≥10%) in 145 patients who received ZYNLONTA® in LOTIS-21

Adverse Reaction All Grades (%) Grade 3 or 4 (%)
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
Dyspnea 13 1
Pleural effusion 10 2
Infection
Upper respiratory tract infection 10 <1

Select laboratory abnormalities in ≥10% of patients1,a

Laboratory Abnormality All Grades (%) Grade 3 or 4 (%)
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

No new safety concerns were reported in the 2-year follow-up analysis4

aThe 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.1

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

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Indication and Usage

ZYNLONTA® is indicated for the treatment of 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, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important Safety Information

WARNINGS AND PRECAUTIONS

Effusion and Edema, Including Capillary Leak Syndrome

Serious effusion and edema, including capillary leak syndrome, occurred in patients treated with ZYNLONTA®. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites) and Grade 3 pleural effusion occurred in 3% and Grade 3 or 4 pericardial effusion occurred in 1%. Rare cases of cardiac tamponade have been reported in patients with Grade 3 or 4 pericardial effusion. Grade 3 or higher capillary leak syndrome occurred in 0.6%.

Monitor patients for new or worsening edema or effusions. Consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating. Institute appropriate medical management for edema or effusions.

Evaluate and institute appropriate medical management for capillary leak syndrome in patients experiencing worsening effusion or edema with signs and symptoms of weight gain, severe hypotension, hypoalbuminemia, and/or hemoconcentration (by elevated hemoglobin/hematocrit, etc.). Withhold or discontinue ZYNLONTA® based on severity.

Myelosuppression

Treatment with ZYNLONTA® can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. Grade 3 or 4 neutropenia occurred in 32%, thrombocytopenia in 20%, and anemia in 12% of patients. Grade 4 neutropenia occurred in 21% and thrombocytopenia in 7% of patients. Febrile neutropenia occurred in 3%.

Monitor complete blood counts throughout treatment. Cytopenias may require interruption, dose reduction, or discontinuation of ZYNLONTA®. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Infections

Fatal and serious infections, including opportunistic infections, occurred in patients treated with ZYNLONTA®. Grade 3 or higher infections occurred in 10% of patients, with fatal infections occurring in 2%. The most frequent Grade ≥3 infections included sepsis and pneumonia.

Monitor for any new or worsening signs or symptoms consistent with infection. For Grade 3 or 4 infection, withhold ZYNLONTA® until infection has resolved.

Hepatotoxicity, Including Drug-Induced Liver Injury

Cholestatic and hepatocellular liver injury, including severe, life-threatening, and fatal cases of drug-induced liver injury (DILI), have occurred in patients treated with ZYNLONTA®.

Monitor liver function tests at baseline and throughout treatment with ZYNLONTA®. In the event of suspected DILI or Grade ≥3 increase in ALT or AST, withhold ZYNLONTA® until toxicity resolves to Grade 1 or lower. Upon confirmation of DILI, discontinue ZYNLONTA®.

ZYNLONTA® should be avoided in patients with severe hepatic impairment.

Cutaneous Reactions

Serious cutaneous reactions occurred in patients treated with ZYNLONTA®. Grade 3 cutaneous reactions occurred in 4% and included photosensitivity reaction, rash (including exfoliative and maculo-papular), and erythema.

Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions. Withhold ZYNLONTA® for severe (Grade 3) cutaneous reactions until resolution. Advise patients to minimize or avoid exposure to direct natural or artificial sunlight including exposure through glass windows. Instruct patients to protect skin from exposure to sunlight by wearing sun-protective clothing and/or the use of sunscreen products. If a skin reaction or rash develops, dermatologic consultation should be considered.

Embryo-Fetal Toxicity

Based on its mechanism of action, ZYNLONTA® can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (SG3199) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZYNLONTA® and for 10 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZYNLONTA®, and for 7 months after the last dose.

ADVERSE REACTIONS

In a pooled safety population of 215 patients (Phase 1 and LOTIS-2), 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.

In LOTIS-2, 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.

USE IN SPECIFIC POPULATIONS

Pregnancy: ZYNLONTA® can cause embryo-fetal harm. Advise pregnant women of the potential risk to a fetus.

Lactation: Advise women not to breastfeed during treatment with ZYNLONTA® and for 3 months after the last dose.

Hepatic Impairment: ZYNLONTA® should be avoided in patients with severe hepatic impairment.

DOSAGE MODIFICATIONS AND DELAYS

Recommended Dosage Modifications for Adverse Reactions

For neutropenia: if absolute neutrophil count is <1 x 109/L, withhold ZYNLONTA® until the neutrophil count returns to ≥1 x 109/L. For thrombocytopenia: if platelet count is <50,000/mcL, withhold ZYNLONTA® until the platelet count returns to ≥50,000/mcL.

For edema or effusion Grade ≥2, withhold ZYNLONTA® until the toxicity resolves to Grade ≤1. For pericardial effusion Grade 2, withhold ZYNLONTA® until the toxicity resolves. Discontinue ZYNLONTA® if effusion recurs. For pericardial effusion Grade ≥3, discontinue ZYNLONTA®. For hepatotoxicity Grade ≥3, increase in ALT or AST, or suspected DILI, withhold ZYNLONTA® until toxicity resolves to Grade ≤1; discontinue for confirmed DILI. For all other Grade ≥3 nonhematologic toxicity not previously mentioned, withhold ZYNLONTA® until toxicity resolves to Grade ≤1.

Recommendations for Dosage Delays

If dosing is delayed by more than 3 weeks due to toxicity related to ZYNLONTA®, reduce subsequent doses by 50%. If toxicity reoccurs following dose reduction, consider discontinuation. Note: If toxicity requires dose reduction following the second dose of 0.15 mg/kg (C2D1), the patient should receive the dose of 0.075 mg/kg for Cycle 3.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to ADC Therapeutics at 1-855-690-0340.

Please see the full Prescribing Information for additional Important Safety Information.

References: 1. ZYNLONTA [package insert]. Murray Hill, New Jersey: ADC Therapeutics SA; 2026. 2. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS 2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. 3. Data on file. ADC Therapeutics SA. 4. Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study. Haematologica. 2024;109(4):1184-1193.