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Previously untreated Stage III/IV cHL

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Adults with

Previously untreated
Stage III/IV cHL

Efficacy

Amina, a patient treated with ADCETRIS® (brentuximab vedotin)+AVD.

Amina, treated with ADCETRIS+AVD.

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AYA = adolescents and young adults.

Primary Endpoint: mPFS

ECHELON-1 primary endpoint: Modified PFS per IRF at 2 years1,2


  • HR: 0.77 (95% CI: 0.60, 0.98); P = 0.035; median follow-up: 24.6 months
  • 23% reduction in event risk*
  • Number of mPFS events reported were 117 out of 664 patients (17.6%) in the A+AVD group and 146 out of 670 patients (21.8%) in the ABVD group. The reasons leading to mPFS events were as follows1:
    • Disease progression (90 vs 102)
    • Death from any cause (18 vs 22)
    • Subsequent anticancer therapy when complete response was not achieved at completion of frontline therapy (9 vs 22)
 
* An event was defined as progression, death from any cause, or receipt of additional anticancer therapy for patients not in complete remission after first-line therapy.1

 
mPFS = modified progression-free survival.

Overall Survival

In a curative intent setting of frontline Stage III/IV cHL, A+AVD demonstrated a statistically significant overall survival benefit vs ABVD1,3,4

Overall survival estimates A+AVD vs ABVD
  • At 103 events, a benefit was considered statistically significant at P <0.03655
  • Median follow-up: 6.1 years1
  • Median overall survival was not reached in either arm1
  • At 2 years (the time of the modified PFS analysis), an interim overall survival analysis did not demonstrate a significant difference1
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In a curative intent setting, A+AVD is the first and only regimen in 35 years to demonstrate an overall survival benefit vs ABVD alone in frontline Stage III/IV cHL1,3-5

Peer perspective on overall survival

“Overall survival is really the most important endpoint for me because despite all the progress we've made over the past 30 years, cHL is still a deadly disease.” 6

Dr Adam Forman, hematologist-oncologist

Watch video
 
Dr Adam Forman is presenting this program on behalf of Pfizer and is contracted with Pfizer for this service.
 

A+AVD = ADCETRIS + doxorubicin, vinblastine, dacarbazine; ABVD = doxorubicin, bleomycin, vinblastine, dacarbazine; AVD = doxorubicin, vinblastine, dacarbazine; cHL = classical Hodgkin lymphoma; CI = confidence interval; HR = hazard ratio; IRF = independent review facility; ITT = intent-to-treat; OS = overall survival; PFS = progression-free survival.

Additional Data

PFS per INV follow-up at 6 years (ITT population)5

 

PFS per INV at 6 years was a post-hoc exploratory analysis. This non-alpha-controlled analysis cannot be used to determine differences between treatment arms and offers supportive, but not conclusive, clinical information only.

A+AVD saw a 32% reduction in risk of progression or death vs ABVD
  • PFS per INV was defined as time from randomization to the first occurrence of disease progression or death5
  • Median follow-up: 72.6 months5
  • Median PFS was not reached in either arm5
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INV = investigator.

Fewer A+AVD patients received salvage chemotherapy and transplant2

 

This 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.

In ECHELON-1, some patients required subsequent therapy, including chemotherapy or high-dose chemotherapy + transplant, by 2 years (review ‡, §, and reference 2)
†

At least 1 subsequent anticancer therapy was reported for 265 patients, 121 of 664 with A+AVD and 144 of 670 with ABVD. Recipients of these therapies in the A+AVD group vs ABVD group were as follows: radiation (in 52 patients in each group), chemotherapy (66 vs 99), high dose chemotherapy + transplant (36 vs 54), immunotherapy (10 vs 16) and chemotherapy + radiation (2 vs 3).2,7

‡

Median follow-up time for both treatment arms was 24.6 months.



  

HSCT = hematopoietic stem cell transplantation.

 

AYA Subgroup Analysis

AYA patients exhibited overall survival results consistent with the ITT population with A+AVD vs ABVD1,8

 

This post-hoc exploratory analysis of a non-prespecified subgroup is non-alpha-controlled and cannot be used to determine differences between treatment arms. This offers supportive, but not conclusive, clinical information only.

Overall survival estimates for patients aged 18-39 years at 6 years (AYA population) (review ǁ, ¶, and references 6, 7)
  • Median OS follow-up in the AYA population: 71.7 months**8

 

Overall survival rates of patients aged ≥45 years at 6 years5

A+AVD: 85.9% of patients (n=213); ABVD: 81.4% of patients (n=247); HR: 0.75 (95% CI: 0.47, 1.18)

 
 § Based on Kaplan-Meier product limit estimates [n = number of patients at risk].8
 
  Hazard ratio (A+AVD/ABVD) and 95% CI are based on unstratified Cox’s proportional hazard regression model.8
 
** Median OS follow-up is calculated from the Kaplan-Meier method switching the OS event/censored status, ie, OS event as censored and censored as OS event.8

PFS per INV results for AYA subgroup5,8

 

PFS per INV at 6 years was a post-hoc exploratory analysis. This analysis was not powered to determine differences between treatment arms and offers supportive, but not conclusive, clinical information only.

PFS per INV for patients aged 18-39 years at 6 years (AYApopulation) (review ‡‡ andreference 7)
  • Median PFS follow-up in the AYA population: 71.5 months8

Trial Design

Explore ECHELON-1 Trial Design

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Multicenter, open-label, superiority trial1,2,9

Primary inclusion criteria

  1. Adults (≥18 years) with previously untreated Stage III/IV cHL
  2. ECOG performance status ≤2
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N = 1334
Randomized 1:1


218 study sites in 21 countries

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IV on Days 1 and 15 of each 28-day cycle

A+AVD (n = 664) x 6 cycles: ADCETRIS 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2

ABVD (n = 670) x 6 cycles: doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2

Follow-up: every 3 months for 36 months, then every 6 months until study closure


Primary endpoint: modified PFS per IRF††1,2

Key secondary endpoint: OS2

Post-hoc exploratory endpoint‡‡: PFS per INV at 6 years§§5

Selected baseline patient characteristics of the ITT population1,2

  1. Age: median 36 years (range, 18-83), with 14% ≥60 years
  2. Demographics: 58% male and 84% White
  1. Stage: 36% Stage III and 64% Stage IV; 62% with extranodal involvement at diagnosis
  2. All IPS scores were included: 21% had IPS 0-1, 53% had IPS 2-3, and 26% had IPS 4-7

Patients in each treatment arm by age group¶¶1,2,8

AYA: 18-39 years

n (%)

40-59 years

n (%)

≥60 years

n (%)

A+AVD (n = 664)
396 (60%)
184 (28%)
84 (13%)
ABVD (n = 670)
375 (56%)
193 (29%)
102 (15%)
††

A modified PFS event was defined as progression, death from any cause, or receipt of additional anticancer therapy for patients not in complete remission after first-line therapy.

‡‡

Assessed periodically, though the analysis at 6 years was not prespecified.

§§

A PFS event was defined as progression or death from any cause.

¶¶

Percentages do not add up to 100% due to rounding.

 


CT/PET = computed tomography/positron emission tomography; ECOG = Eastern Cooperative Oncology Group; IPS = International Prognostic Score.

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A+AVEPC: Approved for pediatric patients 2 years and older

Explore Pediatric Efficacy

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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 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 use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 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.

Indications

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

Previously untreated Stage III/IV cHL

  1. Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine.

Previously untreated high risk cHL

  1. Pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

cHL post-auto-HSCT consolidation

  1. Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Relapsed cHL

  1. Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

Previously untreated sALCL or other CD30-expressing PTCL

  1. Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.

Relapsed sALCL

  1. Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

Relapsed pcALCL or CD30-expressing MF

  1. Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Please see full Prescribing Information, including BOXED WARNING, for 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.

arrow up red

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 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 use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 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.

Indications

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

Previously untreated Stage III/IV cHL

  1. Adult patients with previously untreated Stage III/IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine.

Previously untreated high risk cHL

  1. Pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

cHL post-auto-HSCT consolidation

  1. Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Relapsed cHL

  1. Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

Previously untreated sALCL or other CD30-expressing PTCL

  1. Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.

Relapsed sALCL

  1. Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

Relapsed pcALCL or CD30-expressing MF

  1. Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Please see full Prescribing Information, including BOXED WARNING, for ADCETRIS.

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