ZYNLONTA

5 WARNINGS AND PRECAUTIONS Effusion and Edema, Including Capillary Leak Syndrome : Monitor for the development of pleural effusion, pericardial effusion, ascites, peripheral edema, and general edema. Consider diagnostic imaging when symptoms develop or worsen. ( 5.1 ) Myelosuppression: Monitor blood cell counts. Withhold, reduce, or discontinue ZYNLONTA based on severity. ( 5.2 ) Infections : Monitor for infection and treat promptly. ( 5.3 ) Hepatotoxicity, Including Drug-Induced Liver Injury : Monitor liver function tests during treatment. Withhold or permanently discontinue ZYNLONTA based on severity. ( 5.4 ) Cutaneous Reaction s: Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions. Dermatologic consultation should be considered. ( 5.5 ) Embryo-Fetal Toxic ity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 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% [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.3) ] . 5.2 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% [see Adverse Reactions (6.1) ]. 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 [see Dosage and Administration (2.3) ]. 5.3 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 [see Adverse Reactions (6.1) ] . Monitor for any new or worsening signs or symptoms consistent with infection. For Grade 3 or 4 infection, withhold ZYNLONTA until infection has resolved [see Dosage and Administration (2.3) ] . 5.4 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. [see Dosage and Administration (2.3) ] . ZYNLONTA should be avoided in patients with severe hepatic impairment [see Clinical Pharmacology (8.6 , 12.3) ] . 5.5 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 [see Adverse Reactions (6.1) ]. Monitor patients for new or worsening cutaneous reactions, including photosensitivity reactions. Withhold ZYNLONTA for severe (Grade 3) cutaneous reactions until resolution [see Dosage and Administration (2.3) ] . 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 [see Nonclinical Toxicology (13) ]. 5.6 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 [see Use in Specific Populations (8.1 , 8.3) ] .

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) ] 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 . 6.1 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 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). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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, including cutaneous collagenous vasculopathy, blister, rash vesicular.

<table width="90%"><caption>Table 2: Adverse Reactions (&#x2265;10%) in Patients with Relapsed or Refractory DLBCL who received ZYNLONTA in LOTIS-2</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Adverse Reaction</th><th styleCode="Rrule" colspan="2">ZYNLONTA (N=145)</th></tr><tr><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grades 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">General Disorders and Administration Site Conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue<footnote>Fatigue includes fatigue, asthenia, and lethargy</footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">1<footnote ID="tb1ft1">No Grade 4 adverse reactions occurred</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema<footnote>Edema includes edema, face edema, generalized edema, peripheral edema, ascites, fluid overload, peripheral swelling, swelling, and swelling face</footnote></td><td styleCode="Rrule">28</td><td styleCode="Rrule">3<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash<footnote>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</footnote></td><td styleCode="Rrule">30</td><td styleCode="Rrule">2<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Photosensitivity reaction</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">17</td><td styleCode="Rrule">2<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnote>Abdominal pain includes abdominal pain, abdominal discomfort, abdominal pain lower, and abdominal pain upper</footnote></td><td styleCode="Rrule">14</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">12</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain<footnote>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</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">1<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Respiratory Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea<footnote>Dyspnea includes dyspnea, and dyspnea exertional</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">1<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pleural effusion</td><td styleCode="Rrule">10</td><td styleCode="Rrule">2<footnoteRef IDREF="tb1ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold italics">Infection</content></td></tr><tr><td styleCode="Lrule Rrule">Upper respiratory tract infection<footnote>Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract congestion, nasopharyngitis, rhinitis, rhinovirus infection, and sinusitis</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">&lt;1<footnoteRef IDREF="tb1ft1"/></td></tr></tbody></table>

<table width="70%"><caption>Table 3: Select Laboratory Abnormalities (&#x2265;10%) That Worsened from Baseline in Patients with Relapsed or Refractory DLBCL Who Received ZYNLONTA in LOTIS-2</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2">ZYNLONTA<footnote>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</footnote></th></tr><tr><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematologic</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Platelets decreased</td><td styleCode="Rrule">58</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils decreased</td><td styleCode="Rrule">52</td><td styleCode="Rrule">30</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemoglobin decreased</td><td styleCode="Rrule">51</td><td styleCode="Rrule">10<footnote ID="tb2ft1">No Grade 4 adverse reactions occurred</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">GGT increased</td><td styleCode="Rrule">57</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Glucose increased</td><td styleCode="Rrule">48</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">AST increased</td><td styleCode="Rrule">41</td><td styleCode="Rrule">&lt;1<footnoteRef IDREF="tb2ft1"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Albumin decreased</td><td styleCode="Rrule">37</td><td styleCode="Rrule">&lt;1<footnoteRef IDREF="tb2ft1"/></td></tr><tr><td styleCode="Lrule Rrule">ALT increased</td><td styleCode="Rrule">34</td><td styleCode="Rrule">3</td></tr></tbody></table>