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ECHELON-1 clinical trial primary endpoint: ADCETRIS+AVD demonstrated superior efficacy vs ABVD
ADCETRIS+AVD significantly improved modified progression-free survival vs ABVD (P = 0.035)*1
Kaplan-Meier Curve of IRF-Assessed Modified PFS (Primary Endpoint)1,2
- A modified PFS event was defined as progression, death from any cause, or receipt of additional anticancer therapy for patients not in a complete response after completion of first-line therapy1
- Median follow-up time for both treatment arms was 24.6 months1
- At 2 years (the time of the modified PFS analysis), an interim overall survival analysis did not demonstrate a significant difference1
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Recommendation: Category 1 preferred3
Brentuximab vedotin (ADCETRIS®) + AVD is now a Category 1 preferred option within the NCCN Guidelines® for first-line, adult Stage III/IV Classical Hodgkin Lymphoma with no known neuropathy.
*ECHELON-1 study design: Randomized, open-label trial in previously untreated Stage III/IV cHL. Patients received A+AVD (n = 664) or ABVD (n = 670) every 2 weeks for up to 6 cycles. The primary endpoint was modified PFS per IRF. Key secondary endpoint was overall survival.1
A+AVD = ADCETRIS + doxorubicin, vinblastine, dacarbazine; ABVD = doxorubicin, bleomycin, vinblastine, dacarbazine; CI = confidence interval; HR = hazard ratio; IRF = independent review facility; ITT = intent-to-treat; NCCN = National Comprehensive Cancer Network® (NCCN®); PFS = progression-free survival.
ECHELON-1: Large international superiority study of patients with Stage III/IV cHL1
Multicenter, Open-label, Superiority Trial (Not PET-Adaptive)1,2,5
Dosage in ECHELON-1
Study treatment was administered intravenously on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
A+AVD (ADCETRIS® [brentuximab vedotin] 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2).1
Median number of treatment cycles in each study arm was 6 (range, 1-6). 76% of patients on the A+AVD arm received 12 doses of ADCETRIS.1
The first post-treatment response assessment (CT/PET scan) was performed 3-7 weeks after the last dose of first-line therapy, corresponding to approximately 6-7 months after the first dose of study drug.5 Patients with a Deauville score of 5 following a Cycle 2 PET scan could receive additional anticancer therapy at physician's discretion.2
For more information, download the dosing and administration guide.
Study endpoints
- Primary endpoint: modified PFS per IRF; an event is defined as1:
- Progression,
- Death from any cause, or
- Receipt of additional anticancer therapy for patients not in complete remission after first-line therapy
- Key secondary endpoint: OS1
- An exploratory endpoint: PFS per INV5
- Assessed periodically, including at 6 years
- A PFS event was defined as time from randomization to earliest of disease progression or death from any cause
Primary inclusion criteria
- Adults (≥18 years) with previously untreated Stage III/IV cHL2
- ECOG ≤22
Baseline patient characteristics
- Comparable between arms1,2:
- 36%, Stage III; 64%, Stage IV
- 62% with extranodal involvement at diagnosis
- 58%, male; 84%, white
- Median age of 36 years (range 18-83); 14% were ≥60 years
- All IPS scores were included: IPS 0-1: 21%; IPS 2-3: 53%; IPS 4-7: 26%
CT/PET = computed tomography/positron emission tomography; ECOG = Eastern Cooperative Oncology Group; INV = investigator; IPS = International Prognostic Score; IRF = independent review facility; OS = overall survival; PFS = progression-free survival.
Adverse reactions in the ECHELON-1 trial
- Serious adverse reactions were reported in 43% of A+AVD patients; most common were febrile neutropenia (17%); pyrexia (7%); neutropenia and pneumonia (3% each)1
- Most common adverse reactions with A+AVD (≥20%, with ≥5% difference vs ABVD)1:
- Anemia (98%)
- Neutropenia (91%)
- Peripheral sensory neuropathy (65%)
- Constipation (42%)
- Vomiting (33%)
- Diarrhea (27%)
- Pyrexia (27%)
- Decreased weight (22%)
- Stomatitis (21%)
- Abdominal pain (21%)
The following non-prespecified, post hoc exploratory analysis is descriptive in nature and offers supportive, but not conclusive, clinical information only. This analysis was not powered to determine differences between treatment arms.
Fewer A+AVD patients received salvage chemotherapy and transplant
- In ECHELON-1, some patients required subsequent therapy including chemotherapy and transplant†2
A+AVD Reduced Need for Chemotherapy and Transplant by One-Third2
†At least 1 subsequent anticancer therapy was reported for 121 A+AVD patients and 144 ABVD patients.4
HSCT = hematopoietic stem cell transplantation.
Indications and Important Safety Information
BOXED WARNING
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
CONTRAINDICATION
Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
WARNINGS AND PRECAUTIONS
Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.
Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently 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 ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.
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. Avoid use 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. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, 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 PML diagnosis in patients 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: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, 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: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to avoid pregnancy during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
ADVERSE REACTIONS
The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.
DRUG INTERACTIONS
Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.
USE IN SPECIAL POPULATIONS
Lactation: Breastfeeding is not recommended during ADCETRIS treatment.
Females and Males of Reproductive Potential: Advise females to report pregnancy immediately and advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
Indications and Important Safety Information
BOXED WARNING
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
CONTRAINDICATION
Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
WARNINGS AND PRECAUTIONS
Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.
Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently 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 ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.
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. Avoid use 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. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, 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 PML diagnosis in patients 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: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, 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: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to avoid pregnancy during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
ADVERSE REACTIONS
The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.
DRUG INTERACTIONS
Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.
USE IN SPECIAL POPULATIONS
Lactation: Breastfeeding is not recommended during ADCETRIS treatment.
Females and Males of Reproductive Potential: Advise females to report pregnancy immediately and advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.
