Seattle Genetics and Takeda Announce Additional Analyses of ADCETRIS® (Brentuximab Vedotin) ECHELON-1 and ECHELON-2 Phase 3 Clinical Trials at the 2019 ASH Annual Meeting
- Four-Year Data Continue to Show Superior Progression-Free Survival of ADCETRIS in Combination with AVD when Compared to ABVD in Frontline Advanced Hodgkin Lymphoma with 31 Percent Reduction in the Risk of Progression or Death -
- Additional Analysis from ECHELON-2 Phase 3 Clinical Trial Evaluating ADCETRIS Plus CHP Chemotherapy Also Featured at ASH Annual Meeting -
The ECHELON-1 analysis highlighted a four-year update of the phase 3 clinical trial in a poster presentation. ECHELON-1 is evaluating ADCETRIS in combination with AVD (Adriamycin [doxorubicin], vinblastine and dacarbazine) compared to ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine) in patients with Stage III or IV frontline classical Hodgkin lymphoma.
The ECHELON-2 phase 3 clinical trial data were presented in an oral session at ASH and focused on the outcomes of the subset of patients who underwent consolidative stem cell transplant. ECHELON-2 is evaluating ADCETRIS in combination with CHP (cyclophosphamide, doxorubicin, prednisone) compared to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in frontline CD30-expressing PTCL.
“For decades, the standard of care for the treatment of frontline Hodgkin lymphoma has been combination chemotherapy, called ABVD. Unfortunately, approximately 30 percent of patients with advanced stage Hodgkin lymphoma do not respond or relapse following treatment with this therapy,” said
“Updated data from the ECHELON-1 trial and further insights from ECHELON-2 build upon our continued understanding of the potential ADCETRIS offers patients with CD30-positive lymphomas,” said
Brentuximab Vedotin with Chemotherapy for Stage 3/4 Classical Hodgkin Lymphoma (cHL): 4-Year Update of the ECHELON-1 Study (Abstract #4026, poster presentation on
As previously reported, the ECHELON-1 trial achieved its primary endpoint with the combination of ADCETRIS plus AVD resulting in a statistically significant improvement in modified progression-free survival (PFS) compared to the control arm of ABVD as assessed by independent review facility (IRF; hazard ratio (HR), 0.77; p=0.035). A four-year post-hoc exploratory analysis was conducted to examine PFS outcomes per investigator assessment in the intent-to-treat population of 1,334 patients, including results by PET2 status, age, stage and prognostic risk scores. Results include:
- The four-year PFS rate for patients in the ADCETRIS plus AVD arm was 81.7 percent compared to 75.1 percent in the ABVD arm, a difference of 6.6 percent (HR, 0.69 [95% CI: 0.542, 0.881]). This represents a 31 percent reduction in the risk of progression or death. Median follow-up time was 48.4 months.
A PFS benefit at four-years for ADCETRIS plus AVD was observed for all patients independent of PET2 status, including in patients who are less than 60 years old.
- PET2-negative result was 86.2 percent in the ADCETRIS plus AVD arm compared to 81.0 percent in the ABVD arm (HR, 0.69), a difference of 5.2 percent.
- PET2-positive result was 62.1 percent in the ADCETRIS plus AVD arm compared to 47.7 percent in the ABVD arm (HR, 0.65), a difference of 14.4 percent.
Consistent improvement in PFS was observed among patients treated with ADCETRIS plus AVD compared with ABVD across the majority of pre-specified subgroups, including disease stage, age and prognostic score.
- Notably, improvements compared to ABVD were observed in patients with Stage III (HR, 0.595; [95% CI: 0.386, 0.917]) and Stage IV (HR, 0.745; [95% CI: 0.555, 1.001]) disease.
- As previously reported for the primary analysis, on the ADCETRIS plus AVD arm, peripheral neuropathy events were observed in 67 percent of patients compared to 43 percent in the ABVD arm. The four-year update shows that among patients with peripheral neuropathy, 83 percent in the ADCETRIS plus AVD arm and 84 percent in the ABVD arm reported complete resolution or improvement at last follow-up.
More than 45 countries and regions have approved ADCETRIS in combination with AVD for the treatment of patients with previously untreated Stage III or IV Hodgkin lymphoma.
An Exploratory Analysis of Brentuximab Vedotin plus CHP (A+CHP) in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant (Abstract #464, oral presentation on
As previously reported, the ECHELON-2 trial met its primary endpoint with the combination of ADCETRIS plus CHP resulting in a statistically significant improvement in PFS versus the control arm of CHOP per blinded independent central review (HR, 0.71; p=0.0110). In addition, the overall survival benefit in the ADCETRIS plus CHP arm was statistically significant compared to CHOP (HR, 0.66; p=0.0244). A post-hoc exploratory analysis evaluated the impact of consolidative stem cell transplant in the ECHELON-2 study for the patients who achieved CR treated with ADCETRIS plus CHP. In the ADCETRIS plus CHP arm, this included 38 patients in CR who received a stem cell transplant and 76 patients in CR who did not. Key findings of this analysis include:
- The PFS estimate favored the use of stem cell transplant (HR, 0.38; [95% CI: 0.18, 0.82]). After a median follow-up time of 35.9 months, the three-year PFS rate for the 38 patients who received a stem cell transplant was 76.1 percent. After a median follow-up time of 41.6 months, the three-year PFS rate for the 76 patients who did not receive a stem cell transplant was 53.3 percent.
- As previously reported, the safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
About Classical Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.
According to the
About T-Cell Lymphomas
There are more than 60 subtypes of non-Hodgkin lymphomas which are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). PTCL accounts for approximately 10 percent of non-Hodgkin lymphoma cases in the U.S. and
ADCETRIS is being evaluated broadly in more than 70 clinical trials in CD30-expressing lymphomas. These include three completed phase 3 trials: ECHELON-2 trial in frontline peripheral T-cell lymphomas, ECHELON-1 in previously untreated Hodgkin lymphoma, and ALCANZA in cutaneous T-cell lymphoma.
ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.
ADCETRIS injection for intravenous infusion has received
ADCETRIS received conditional marketing authorization from the
ADCETRIS has received marketing authorization by regulatory authorities in 73 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.
For more information, visit https://www.takeda.com
ADCETRIS (brentuximab vedotin) U.S. Important Safety Information
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.
ADCETRIS concomitant with 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. Institute dose modifications accordingly.
- 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 patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL. 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: 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 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 compared to patients with normal hepatic function. 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 and death have 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 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 antihyperglycemic 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 the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions: Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia and mucositis.
Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).
Use in Specific Populations
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.
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.
Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here .
ADCETRIS (brentuximab vedotin) Important Safety Information (
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity.
SPECIAL WARNINGS & PRECAUTIONS
Progressive multifocal leukoencephalopathy (PML):
Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed.
Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).
Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.
Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms (e.g., cough, dyspnoea) appropriately. Consider holding dosing during evaluation and until symptomatic improvement.
Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Carefully monitor patients during treatment for emergence of possible serious and opportunistic infections.
Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have been reported with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.
Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and manage according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically an effect of cumulative exposure to ADCETRIS and is reversible in most cases. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.
Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.
Febrile neutropenia: Febrile neutropenia has been reported with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of treatment. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.
When ADCETRIS is administered in combination with AVD, primary prophylaxis with G-CSF is recommended for all patients beginning with the first dose.
Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, have been reported with ADCETRIS. Promptly evaluate and treat patients if new or worsening GI symptoms occur.
Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with ADCETRIS. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Test liver function prior to treatment initiation and routinely monitor during treatment. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.
Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.
Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use with caution in other CD30+ CTCL patient types.
Sodium content in excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia. If neutropenia develops, refer to dosing recommendations for neutropenia (see SmPC section 4.2). Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS, but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.
PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus.
LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.
FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Advise men being treated with ADCETRIS not to father a child during treatment and for up to 6 months following the last dose.
Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines.
Monotherapy: The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain. Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%. Adverse events led to treatment discontinuation in 24% of patients.
Combination Therapy: In the study of ADCETRIS as combination therapy with AVD in 662 patients with previously untreated advanced Hodgkin lymphoma, the most common adverse reactions (≥ 10%) were: neutropenia, nausea, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhoea, pyrexia, alopecia, peripheral motor neuropathy, decreased weight, abdominal pain, anaemia, stomatitis, febrile neutropenia, bone pain, insomnia, decreased appetite, cough, headache, arthralgia, back pain, dyspnoea, myalgia, upper respiratory tract infection, alanine aminotransferase increased. Serious adverse reactions occurred in 36% of patients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (17%), pyrexia (6%), and neutropenia (3%). Adverse events led to treatment discontinuation in 13% of patients.
Seattle Genetics Forward-Looking Statements
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic potential of ADCETRIS for patients with previously untreated stage III or IV classical Hodgkin lymphoma and patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL). Actual results or developments may differ materially from those projected or implied in these forward-looking statements due to factors such as utilization and adoption of the approved treatment regimen by prescribing physicians, competitive conditions including the availability of alternative treatment regimens, the availability and extent of reimbursement, the risk of adverse events and adverse regulatory action. More information about the risks and uncertainties faced by
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