Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 data below reflect exposure to ADCETRIS in 931 adult patients with cHL including 662 patients who received ADCETRIS in combination with chemotherapy in a randomized controlled trial, 269 who received ADCETRIS as monotherapy (167 in a randomized controlled trial and 102 in a single arm trial), and 296 pediatric patients with high risk cHL who received ADCETRIS in combination with chemotherapy. Data summarizing ADCETRIS exposure are also provided for 347 patients with T-cell lymphoma, including 223 patients with PTCL who received ADCETRIS in combination with chemotherapy in a randomized, double-blind, controlled trial; 58 patients with sALCL who received ADCETRIS monotherapy in a single-arm trial; and 66 patients with pcALCL or CD30-expressing MF who received ADCETRIS monotherapy in a randomized, controlled trial. ADCETRIS was administered intravenously at a dose of either 1.2 mg/kg every 2 weeks in combination with AVD, 1.8 mg/kg every 3 weeks in combination with AVEPC in pediatric patients, 1.8 mg/kg every 3 weeks in combination with CHP, or 1.8 mg/kg every 3 weeks as monotherapy.

The most common adverse reactions (≥20%) with monotherapy in adult patients were peripheral neuropathy, fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, diarrhea, pyrexia, rash, and cough.

The most common laboratory abnormalities (≥20%) with monotherapy in adult patients were decreased neutrophils, increased creatinine, increased glucose, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased lymphocytes, decreased hemoglobin, and decreased platelets.

The most common adverse reactions (≥20%) with combination therapy in adult patients were peripheral neuropathy, nausea, fatigue, musculoskeletal pain, constipation, diarrhea, mucositis, vomiting, abdominal pain, pyrexia, alopecia, upper respiratory tract infection, and rash.

The most common laboratory abnormalities (≥20%) with combination therapy in adult patients were decreased neutrophils, increased creatinine, decreased hemoglobin, decreased lymphocytes, increased ALT, increased AST, increased glucose, and increased uric acid.

The most common Grade ≥3 adverse reactions (≥5%) in combination with AVEPC in pediatric patients were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.

Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON-1)

ADCETRIS in combination with AVD was evaluated for the treatment of previously untreated patients with Stage III or IV cHL in a randomized, open-label, multicenter clinical trial of 1334 patients. Patients were randomized to receive up to 6 cycles of ADCETRIS + AVD or ABVD on Days 1 and 15 of each 28‑day cycle. The recommended starting dose of ADCETRIS was 1.2 mg/kg intravenously over 30 minutes, administered approximately 1 hour after completion of AVD therapy. A total of 1321 patients received at least one dose of study treatment (662 ADCETRIS + AVD, 659 ABVD). The median number of treatment cycles in each study arm was 6 (range, 1-6); 76% of patients on the ADCETRIS + AVD arm received 12 doses of ADCETRIS [see Clinical Studies (14.1)].

After 75% of patients had started study treatment, the use of prophylactic G‑CSF was recommended with the initiation of treatment for all ADCETRIS + AVD treated patients, based on the observed rates of neutropenia and febrile neutropenia [see Dosage and Administration (2.2)]. Among 579 patients on the ADCETRIS + AVD arm who did not receive G‑CSF primary prophylaxis beginning with Cycle 1, 96% experienced neutropenia (21% with Grade 3; 67% with Grade 4), and 21% had febrile neutropenia (14% with Grade 3; 6% with Grade 4). Among 83 patients on the ADCETRIS + AVD arm who received G-CSF primary prophylaxis beginning with Cycle 1, 61% experienced neutropenia (13% with Grade 3; 27% with Grade 4), and 11% experienced febrile neutropenia (8% with Grade 3; 2% with Grade 4).

Serious adverse reactions were reported in 43% of ADCETRIS + AVD-treated patients and 27% of ABVD-treated patients. The most common serious adverse reactions in ADCETRIS + AVD-treated patients were febrile neutropenia (17%), pyrexia (7%), neutropenia and pneumonia (3% each).

Adverse reactions that led to dose delays of one or more drugs in more than 5% of ADCETRIS + AVD-treated patients were neutropenia (21%) and febrile neutropenia (8%) [see Dosage and Administration (2.2)]. Adverse reactions led to treatment discontinuation of one or more drugs in 13% of ADCETRIS + AVD-treated patients. Seven percent of patients treated with ADCETRIS + AVD discontinued due to peripheral neuropathy.

There were 9 on-study deaths among ADCETRIS + AVD-treated patients; 7 were associated with neutropenia, and none of these patients had received G-CSF prior to developing neutropenia.

Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL)

Study 7: AHOD1331

The safety of ADCETRIS was evaluated in Study 7: AHOD1331 [see Clinical Studies (14.1)]. The study included pediatric patients with previously untreated high risk cHL. Patients received ADCETRIS plus AVEPC chemotherapy at 1.8 mg/kg intravenously over 30 minutes prior to other chemotherapy in 21-day cycles (n = 296) or ABVE-PC in 21-day cycles (n = 297). Among patients who received ADCETRIS in combination with AVEPC chemotherapy, the median number of treatment cycles was 5 (range, 1-5).

Serious adverse reactions occurred in 22% of patients who received ADCETRIS plus AVEPC chemotherapy. Serious adverse reactions in >2% of patients included hypotension (3%) and febrile neutropenia (3%).

Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA)

ADCETRIS was studied in 329 patients with cHL at high risk of relapse or progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 ADCETRIS, 160 placebo) received at least one dose of study treatment. The median number of treatment cycles in each study arm was 15 (range, 1-16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles [see Clinical Studies (14.1)].

Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PJP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0-20) and 319 patients (98%) received PJP prophylaxis with a median duration of 6.5 months (range, 0-20).

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) [see Dosage and Administration (2.3)]. Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paresthesia (1%), and vomiting (1%). Serious adverse reactions were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%).

Relapsed Classical Hodgkin Lymphoma (Study 1)

ADCETRIS was studied in 102 patients with cHL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 9 cycles (range, 1-16) [see Clinical Studies (14.1)].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (16%) and peripheral sensory neuropathy (13%) [see Dosage and Administration (2.3)]. Adverse reactions led to treatment discontinuation in 20% of ADCETRIS-treated patients. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (6%) and peripheral motor neuropathy (3%). Serious adverse reactions were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas (Study 6, ECHELON-2)

ADCETRIS in combination with CHP was evaluated in patients with previously untreated, CD30-expressing PTCL in a multicenter randomized, double-blind, double dummy, actively controlled trial. Patients were randomized to receive ADCETRIS + CHP or CHOP for 6 to 8, 21-day cycles. ADCETRIS was administered on Day 1 of each cycle, with a starting dose of 1.8 mg/kg intravenously over 30 minutes, approximately 1 hour after completion of CHP [see Clinical Studies (14.2)]. The trial required hepatic transaminases ≤3 times upper limit of normal (ULN), total bilirubin ≤1.5 times ULN, and serum creatinine ≤2 times ULN and excluded patients with Grade 2 or higher peripheral neuropathy.

A total of 449 patients were treated (223 with ADCETRIS + CHP, 226 with CHOP), with 6 cycles planned in 81%. In the ADCETRIS + CHP arm, 70% of patients received 6 cycles, and 18% received 8 cycles. Primary prophylaxis with G-CSF was administered to 34% of ADCETRIS + CHP-treated patients and 27% of CHOP-treated patients.

Fatal adverse reactions occurred in 3% of patients in the A+CHP arm and in 4% of patients in the CHOP arms, most often from infection. Serious adverse reactions were reported in 38% of ADCETRIS + CHP- treated patients and 35% of CHOP-treated patients. Serious adverse reactions occurring in >2% of ADCETRIS + CHP-treated patients included febrile neutropenia (14%), pneumonia (5%), pyrexia (4%), and sepsis (3%).

The most common adverse reactions observed ≥2% more in recipients of ADCETRIS + CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Other common (≥10%) adverse reactions observed ≥2% more with ADCETRIS + CHP were febrile neutropenia, abdominal pain, decreased appetite, dyspnea, edema, cough, dizziness, hypokalemia, decreased weight, and myalgia.

In recipients of ADCETRIS + CHP, adverse reactions led to dose delays of ADCETRIS in 25% of patients, dose reduction in 9% (most often for peripheral neuropathy), and discontinuation of ADCETRIS with or without the other components in 7% (most often from peripheral neuropathy and infection).

Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2)

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 7 cycles (range, 1-16) [see Clinical Studies (14.2)].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (12%) and peripheral sensory neuropathy (7%) [see Dosage and Administration (2.3)]. Adverse reactions led to treatment discontinuation in 19% of ADCETRIS-treated patients. The adverse reaction that led to treatment discontinuation in 2 or more patients was peripheral sensory neuropathy (5%). Serious adverse reactions were reported in 41% of ADCETRIS-treated patients. The most common serious adverse reactions were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-Expressing Mycosis Fungoides (Study 4: ALCANZA)

ADCETRIS was studied in 131 patients with pcALCL or CD30-expressing MF requiring systemic therapy in a randomized, open-label, multicenter clinical trial in which the recommended starting dose and schedule was ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks or physician's choice of either methotrexate 5 to 50 mg orally weekly or bexarotene 300 mg/m2 orally daily.

Of the 131 enrolled patients, 128 (66 brentuximab vedotin, 62 physician's choice) received at least one dose of study treatment. The median number of treatment cycles in the ADCETRIS treatment arm was 12 (range, 1-16) compared to 3 (range, 1-16) and 6 (range, 1-16) in the methotrexate and bexarotene arms, respectively. Twenty-four (24) patients (36%) in the ADCETRIS-treatment arm received 16 cycles compared to 5 patients (8%) in the physician's choice arm [see Clinical Studies (14.2)].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were peripheral sensory neuropathy (15%) and neutropenia (6%) [see Dosage and Administration (2.3)]. Adverse reactions led to treatment discontinuation in 24% of ADCETRIS-treated patients. The most common adverse reaction that led to treatment discontinuation was peripheral neuropathy (12%). Serious adverse reactions were reported in 29% of ADCETRIS-treated patients. The most common serious adverse reactions were cellulitis (3%) and pyrexia (3%).

Relapsed or Refractory Large B-Cell Lymphoma (Study 8: ECHELON-3)

The safety of ADCETRIS in combination with lenalidomide and a rituximab product was evaluated in ECHELON-3, a randomized, multicenter, double-blind, placebo-controlled trial in patients with relapsed or refractory LBCL who had received at least 2 prior lines of systemic therapy and who were not eligible for HSCT or CAR T-cell therapy [see Clinical Studies (14.5)].

Patients in the treatment arm (n = 112) received ADCETRIS, 1.2 mg/kg via intravenous infusion every 3 weeks, lenalidomide, and a rituximab product. Placebo replaced ADCETRIS in the placebo plus lenalidomide and rituximab arm (n = 116).

The trial required an absolute neutrophil count ≥1,000/µL, platelet count ≥50,000/µL, creatinine clearance (CrCL) ≥45 mL/min, hepatic transaminases ≤3 times the upper limit of normal (ULN), and bilirubin <1.5 times ULN. The trial excluded patients having Eastern Cooperative Oncology Group (ECOG) performance status above 2, active central nervous system (CNS) lymphoma, and Grade 2 or higher peripheral neuropathy. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 98% of patients in the ADCETRIS plus lenalidomide and rituximab arm and 91% of patients in the lenalidomide and rituximab arm.

The median age was 71 years (range: 21 to 89 years); 44% of patients were female; 53% were White, 26% were Asian, and 4% were Hispanic or Latino. There were no Black or African American patients enrolled in ECHELON-3. Among patients who received ADCETRIS, the median number of treatment cycles was 5 (range, 1-34).

Serious adverse reactions occurred in 60% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product. Serious adverse reactions that occurred in >2% of patients included pneumonia (21%), COVID-19 (13%, includes COVID-19 pneumonia), sepsis (9%), febrile neutropenia (7%), hemorrhage (3.6%), urinary tract infection (3.6%), thrombocytopenia (2.7%) and upper respiratory tract infection (2.7%). Fatal adverse reactions occurred in 12% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product, including COVID-19 (4.5%, includes COVID-19 pneumonia), pneumonia (3.6%), and sepsis (1.8%).

Adverse reactions led to dose reduction of ADCETRIS in 6% of patients, all due to peripheral neuropathy. Adverse reactions leading to dose delay of ADCETRIS in more than 5% of patients included neutropenia (23%), COVID-19 (13%), pneumonia (8%), and thrombocytopenia (8%).

Adverse reactions led to discontinuation of ADCETRIS in 20% of patients. Adverse reactions that led to treatment discontinuation in 3 or more patients included peripheral neuropathy (4.5%) and pneumonia (2.7%).

Clinically relevant adverse reactions in <10% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product include febrile neutropenia, edema, hypotension, urinary tract infection, sepsis, respiratory tract infection, vomiting, back pain, dizziness, arthralgia, herpes virus infection, bone pain, atrial fibrillation or flutter, lower respiratory tract infection, and cardiac failure.

In studies of ADCETRIS as monotherapy (Studies 1-4), 13% of ADCETRIS-treated patients experienced infusion-related reactions. The most common adverse reactions in Studies 1-4 (≥3% in any study) associated with infusion-related reactions were chills (4%), nausea (3-4%), dyspnea (2-3%), pruritus (2-5%), pyrexia (2%), and cough (2%). Grade 3 events were reported in 5 of the 51 ADCETRIS-treated patients who experienced infusion-related reactions.

In a study of ADCETRIS in combination with AVD (Study 5, ECHELON-1), infusion-related reactions were reported in 57 patients (9%) in the ADCETRIS + AVD-treated arm. Grade 3 events were reported in 3 of the 57 patients treated with ADCETRIS + AVD who experienced infusion-related reactions. The most common adverse reaction (≥2%) associated with infusion-related reactions was nausea (2%).

In a study of ADCETRIS in combination with CHP (Study 6, ECHELON-2), infusion-related reactions were reported in 10 patients (4%) in the ADCETRIS + CHP-treated arm: 2 (1%) patients with events that were Grade 3 or higher events, and 8 (4%) patients with events that were less than Grade 3.

In a study of ADCETRIS in combination with lenalidomide and rituximab (Study 8, ECHELON-3), Grade 1 or 2 infusion-related reactions were reported in 6 patients (5%) in the ADCETRIS + lenalidomide + rituximab arm.

Pulmonary toxicity

In a trial in patients with cHL that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see Contraindications (4)].

In a study of ADCETRIS in combination with AVD (Study 5, ECHELON-1), non-infectious pulmonary toxicity events were reported in 12 patients (2%) in the ADCETRIS + AVD arm. These events included lung infiltration (6 patients) and pneumonitis (6 patients), or interstitial lung disease (1 patient).

In a study of ADCETRIS in combination with CHP (Study 6, ECHELON-2), non-infectious pulmonary toxicity events were reported in 5 patients (2%) in the ADCETRIS + CHP arm; all 5 events were pneumonitis. Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS monotherapy. In Study 3 (AETHERA), pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm.

Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions

During treatment in patients with relapsed or refractory cHL and relapsed or refractory systemic ALCL in Studies 1 and 2, two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment [see Warnings and Precautions (5.2)]. Overall, a higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies [see Clinical Pharmacology (12.6)].