Adverse Reactions in the AETHERA trial of ADCETRIS as post auto-HSCT consolidation

The safety profile in the AETHERA trial was similar to that observed in prior ADCETRIS trials1

The AETHERA trial was a multicenter, randomized, double-blind, placebo-controlled trial in which 329 patients with classical HL at high risk of relapse or progression after auto-HSCT were randomized to receive either ADCETRIS (n=165) or placebo (n=164). Of the 329 patients enrolled, 327 (167 ADCETRIS, 160 placebo) received at least one dose of study treatment.1,2

Standard international guidelines were followed for infection prophylaxis for HSV, VZV, and PCP post auto-HSCT.2

Both the ADCETRIS-treatment arm and the placebo arm received best supportive care.2

Most commonly reported (≥10% in the ADCETRIS arm) adverse reactions in the AETHERA trial2

 
Adverse Reaction ADCETRIS arm (n=167) Placebo arm (n=160)
Any Grade Grade 3-4 Any Grade Grade 3-4
Blood and lymphatic system disorders
Neutropenia* 78% 39% 34% 10%
Thrombocytopenia* 41% 6% 20% 5%
Anemia* 27% 4% 19% 2%
Nervous system disorders
Peripheral sensory neuropathy 56% 10% 16% 1%
Peripheral motor neuropathy 23% 6% 2% 1%
Headache 11% 2% 8% 1%
Infections and infestations
Upper respiratory tract infection 26% - 23% 1%
General disorders and administration site conditions
Fatigue 24% 2% 18% 3%
Pyrexia 19% 2% 16% -
Chills 10% - 5% -
Gastrointestinal disorders
Nausea 22% 3% 8% -
Diarrhea 20% 2% 10% 1%
Vomiting 16% 2% 7% -
Abdominal pain 14% 2% 3% -
Constipation 13% 2% 3% -
Respiratory, thoracic, and mediastinal disorders
Cough 21% - 16% -
Dyspnea 13% - 6% 1%
Investigations
Weight decreased 19% 1% 6% -
Musculoskeletal and connective tissue disorders
Arthralgia 18% 1% 9% -
Muscle spasms 11% - 6% -
Myalgia 11% 1% 4% -
Skin and subcutaneous tissue disorders
Pruritus 12% 1% 8% -
Metabolism and nutrition disorders
Decreased appetite 12% 1% 6% -
 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ QuickReference_5x7.pdf. Published June 14, 2010.
Derived from laboratory values and adverse reaction data.

Most commonly reported (≥10% in the ADCETRIS arm) adverse reactions in the AETHERA trial2

 
Adverse Reaction ADCETRIS arm (n=167)
Any Grade ≥Grade 3-4
Blood and lymphatic system disorders
Neutropenia* 78% 39%
Thrombocytopenia* 41% 6%
Anemia* 27% 4%
Nervous system disorders
Peripheral sensory neuropathy 56% 10%
Peripheral motor neuropathy 23% 6%
Headache 11% 2%
Infections and infestations
Upper respiratory tract infection 26% -
General disorders and administration site conditions
Fatigue 24% 2%
Pyrexia 19% 2%
Chills 10% -
Gastrointestinal disorders
Nausea 22% 3%
Diarrhea 20% 2%
Vomiting 16% 2%
Abdominal pain 14% 2%
Constipation 13% 2%
Respiratory, thoracic, and mediastinal disorders
Cough 21% -
Dyspnea 13% -
Investigations
Weight decreased 19% 1%
Musculoskeletal and connective tissue disorders
Arthralgia 18% 1%
Muscle spasms 11% -
Myalgia 11% 1%
Skin and subcutaneous tissue disorders
Pruritus 12% 1%
Metabolism and nutrition disorders
Decreased appetite 12% 1%
 
 
Adverse Reaction Placebo arm (n=160)
Any Grade ≥Grade 3-4
Blood and lymphatic system disorders
Neutropenia* 34% 10%
Thrombocytopenia* 20% 5%
Anemia* 19% 2%
Nervous system disorders
Peripheral sensory neuropathy 16% 1%
Peripheral motor neuropathy 2% 1%
Headache 8% 1%
Infections and infestations
Upper respiratory tract infection 23% 1%
General disorders and administration site conditions
Fatigue 18% 3%
Pyrexia 16% -
Chills 5% -
Gastrointestinal disorders
Nausea 8% -
Diarrhea 10% 1%
Vomiting 7% -
Abdominal pain 3% -
Constipation 3% -
Respiratory, thoracic, and mediastinal disorders
Cough 16% -
Dyspnea 6% 1%
Investigations
Weight decreased 6% -
Musculoskeletal and connective tissue disorders
Arthralgia 9% -
Muscle spasms 6% -
Myalgia 4% -
Skin and subcutaneous tissue disorders
Pruritus 8% -
Metabolism and nutrition disorders
Decreased appetite 6% -
 
*Derived from laboratory values and adverse reaction data.

Serious adverse reactions

  • The most common serious adverse reactions reported in patients receiving ADCETRIS were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%)2

Dose Delay

  • 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%)2

Discontinuation

  • 32% of patients in the ADCETRIS arm discontinued treatment due to adverse events compared with 6% of patients in the placebo arm2,3
    • 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%)2

View information on dose modification »

Please see Important Safety Information, including BOXED WARNING, and read full Prescribing Information.

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Important Safety Information

Indications

ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with:

Classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

Classical HL at high risk of relapse or progression as post auto-HSCT consolidation treatment.

Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

The sALCL 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 confirmatory trials.

Important Safety Information

Boxed Warning

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

Contraindication:

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions:

  • Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
  • Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
  • Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
  • Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
  • Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
  • Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
  • Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
  • Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
  • Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
  • Pulmonary toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
  • Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
  • Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus, have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
  • Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after final dose of ADCETRIS.

Adverse Reactions:

In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, the most common adverse reactions (≥20%), regardless of causality, were: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

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Reference
1.
Moskowitz CH, Nademanee A, Masszi T, et al; for the AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385:1853-1862.
2.
ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc.; September 2016.
3.
Data on file, Seattle Genetics, Inc.