LONCASTUXIMAB TESIRINE: 86 Adverse Event Reports & Safety Profile

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valine-alanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine. Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis. ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0.

Chemical

Structure

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 [see Clinical Studies (14.1) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ZYNLONTA is a CD19-directed antibody and alkylating agent conjugate 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. ( 1 ) 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). ( 1 )

AND ADMINISTRATION ZYNLONTA is an intravenous infusion over 30 minutes on Day 1 of each cycle (every 3 weeks). The recommended dosage is: 0.15 mg/kg every 3 weeks for 2 cycles. 0.075 mg/kg every 3 weeks for subsequent cycles. ( 2.1 ) Premedicate with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before ZYNLONTA. ( 2.2 )

See Full Prescribing

Information for instructions on preparation and administration. ( 2.4 )

2.1 Recommended Dosage ZYNLONTA as an intravenous infusion administered over 30 minutes on Day 1 of each cycle (every 3 weeks). Administer intravenous infusion as follows: 0.15 mg/kg every 3 weeks for 2 cycles. 0.075 mg/kg every 3 weeks for subsequent cycles.

2.2 Recommended Premedication Unless contraindicated, administer dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before administering ZYNLONTA. If dexamethasone administration does not begin the day before ZYNLONTA, dexamethasone should begin at least 2 hours prior to administration of ZYNLONTA.

2.3 Dosage Modifications and Delays Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reactions Severity Dosage Modification Hematologic Adverse Reactions Neutropenia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> Absolute neutrophil count less than 1 × 10 9 /L Withhold ZYNLONTA until neutrophil counts returns to 1 × 10 9 /L or higher Thrombocytopenia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> Platelet count less than 50,000/mcL Withhold ZYNLONTA until platelet count returns to 50,000/mcL or higher Nonhematologic Adverse Reactions Edema or Effusion <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>

Grade

2 National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 or higher Withhold ZYNLONTA until the toxicity resolves to Grade 1 or less Hepatotoxicity [ see Warnings and Precautions (5.4) ]

Grade

3 or higher increase in AST or ALT or suspected DILI Withhold ZYNLONTA until toxicity resolves to Grade 1 or less, discontinue for confirmed DILI Other Adverse Reactions [see Warnings and Precautions (5.3) , (5.5) , Adverse Reactions (6.1) ]

Grade

3 or higher Withhold ZYNLONTA until the toxicity resolves to Grade 1 or less 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 (Cycle 2), the patient should receive the dose of 0.075 mg/kg for Cycle 3.

2.4 Reconstitution and Administration Instructions Reconstitute and further dilute ZYNLONTA prior to intravenous infusion. Use appropriate aseptic technique. ZYNLONTA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Dose calculation Calculate the total dose (mg) required based on the patient&apos;s weight and prescribed dose <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . For patients with a body mass index (BMI) ≥35 kg/m 2 , calculate the dose based on an adjusted body weight (ABW) as follows: ABW in kg = 35 kg/m 2 × (height in meters) 2 More than one vial may be needed to achieve the calculated dose. Convert the calculated dose (mg) to volume using 5 mg/mL, which is the concentration of ZYNLONTA after reconstitution. Reconstitution of lyophilized ZYNLONTA Reconstitute each ZYNLONTA vial using 2.2 mL of Sterile Water for Injection, USP with the stream directed toward the inside wall of the vial to obtain a final concentration of 5 mg/mL. Swirl the vial gently until the powder is completely dissolved. Do not shake . Do not expose to direct sunlight. Inspect the reconstituted solution for particulate matter and discoloration. The solution should appear clear to slightly opalescent, colorless to slightly yellow. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Use reconstituted ZYNLONTA immediately. If not used immediately, store the reconstituted solution in the vial for up to 4 hours refrigerated at 2°C to 8°C (36°F to 46°F) or room temperature 20°C to 25°C (68°F to 77°F). Do not freeze . The product does not contain a preservative. Discard unused vial after reconstitution if the recommended storage time is exceeded. Dilution in infusion bag Withdraw the required volume of reconstituted solution from the ZYNLONTA vial using a sterile syringe. Discard any unused portion left in the vial. Add the calculated dose volume of ZYNLONTA solution into a 50 mL infusion bag of 5% Dextrose Injection, USP . Gently mix the intravenous bag by slowly inverting the bag. Do not shake . If not used immediately, store the diluted ZYNLONTA infusion solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Discard diluted infusion bag if storage time exceeds these limits. Do not freeze. No incompatibilities have been observed between ZYNLONTA and intravenous infusion bags with product-contacting materials of polyvinylchloride (PVC), polyolefin (PO), and PAB ® (copolymer of ethylene and propylene).

Administration

Administer by intravenous infusion over 30 minutes using a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2- or 0.22-micron pore size) and catheter. Extravasation of ZYNLONTA has been associated with irritation, swelling, pain, and/or tissue damage, which may be severe [see Adverse Reactions (6.1) ] . Monitor the infusion site for possible subcutaneous infiltration during drug administration. Do not mix ZYNLONTA with or administer as an infusion with other drugs.

None. None. ( 4 )

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. Table2 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, blister, rash vesicular

AND PRECAUTIONS Effusion and Edema : 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 Serious effusion and edema 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) ] . Monitor patients for new or worsening edema or effusions. Withhold ZYNLONTA for Grade 2 or greater edema or effusion until the toxicity resolves. 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 [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. <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . ZYNLONTA should be avoided in patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (8.6 , 12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .