Takeda Reports Five-Year Overall Survival Data for ADCETRIS® (Brentuximab Vedotin) Demonstrate Durable Remissions in Relapsed/Refractory Hodgkin Lymphoma

Takeda Pharmaceutical Company Limited (TSE:4502) announced post-treatment follow up data from the pivotal phase 2 study of single-agent brentuximab vedotin for the treatment of relapsed or refractory Hodgkin lymphoma following autologous stem cell transplantation (ASCT). The data demonstrated that the estimated five-year overall survival (OS) rate among ADCETRIS-treated patients was 41 percent (95% CI: 31%, 51%); median OS was 40.5 months (95% CI: 28.7, 61.9 [range 1.8 to 72.9+]) and median progression-free survival (PFS) was 9.3 months (95% CI: 7.1 to 12.2 months). The safety profile of ADCETRIS was generally consistent with the existing prescribing information. These results were presented today at the 57^th American Society of Hematology (ASH) annual meeting in Orlando, FL.

“The five year overall survival rates reported in this pivotal trial are very promising in improving the long-term outlook for patients in this setting as outcomes have historically been very poor,” said Professor Andreas Engert, M.D., University Hospital of Cologne, Germany. “These data further reinforce the emergence of ADCETRIS as a standard of care for patients with Hodgkin lymphoma who experience relapse or disease progression following salvage therapy and ASCT.”

Also presented today at the ASH annual meeting, data from the phase 3 AETHERA trial of brentuximab vedotin consolidation therapy in Hodgkin lymphoma patients at high risk of relapse following ACST demonstrated that after three years of follow-up, patients treated with brentuximab vedotin continued to show a significant improvement in PFS per investigator assessment (61%; 95% CI:53%, 68% HR 0.52) compared to placebo (43%; 95% CI:36%, 51% HR 0.52). The safety profile of ADCETRIS was generally consistent with the existing prescribing information.

ADCETRIS (brentuximab vedotin) is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. ADCETRIS is currently approved in more than 55 countries for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL). The utility of ADCETRIS is currently being explored across a number of types of cancer, and data from six studies in the ADCETRIS clinical trial program were presented at the ASH meeting, including four as oral presentations.

“With more than 45 clinical trials across multiple lines of therapy underway and ongoing research focused on understanding the underlying pathogenesis of Hodgkin lymphoma, our commitment to advancing the care of people battling this disease is far-reaching,” said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The positive long-term results from these two pivotal studies are very important in our work to advance the care of people living with Hodgkin lymphoma whose disease has progressed.”

About the Studies

Study 1: Five-year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma [Abstract 2736, presented December 6, 2015]

Five-year follow up data from the pivotal phase 2 study evaluating the safety and efficacy of brentuximab vedotin in heavily pre-treated patients with relapsed/refractory Hodgkin lymphoma post-ASCT were presented as a poster by Robert Chen, M.D., City of Hope National Medical Center, California. In the study, the 102 enrolled patients received 1.8 mg/kg brentuximab vedotin once every three weeks as a 30 minute outpatient intravenous (IV) infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints included complete response (CR) rate, duration of response, PFS, OS, safety and tolerability. Survival and disease status were assessed every three months for two years and then every six months through year five. A study protocol amendment removed the requirement of routine CT scanning during follow up, and so disease status was assessed by the investigator. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months.

Patients received a median of nine cycles (range, 1-16) of brentuximab vedotin. The study met its primary endpoint demonstrating 72 percent ORR and a CR rate of 33 percent. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Grade 3 or higher adverse events occurred in ≥5 percent of patients and included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.

Fifteen of the 102 enrolled patients remained in follow-up and in remission at study closure. Of the 15 patients, six received consolidative allogeneic SCT and nine received no further therapy since completing treatment with brentuximab vedotin.

Study 2: Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin After Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse [Abstract 3172, presented December 6, 2015]

Updated efficacy and safety data from the phase 3 AETHERA trial were presented as a poster by John Sweetenham, M.D., Huntsman Cancer Institute, University of Utah. The AETHERA trial was designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with Hodgkin lymphoma with at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included OS, safety and tolerability. Eligible patients must have had a history of refractory Hodgkin lymphoma, have relapsed within one year from receiving frontline chemotherapy and/or had extranodule disease at the time of pre-ASCT relapse. These factors are consistently reported to be associated with poor prognosis after transplant. Patients received brentuximab vedotin or placebo every three weeks for up to approximately one year. This international multi-center trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.

A total of 329 Hodgkin lymphoma patients at risk of relapse were enrolled, including 165 on the brentuximab vedotin arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms.

As reported at the ASH annual meeting in 2014, the AETHERA trial met its primary endpoint, demonstrating significant improvement in PFS among patients who received brentuximab vedotin compared to patients who received placebo (median of 43 months versus 24 months, respectively; HR=0.57; p=0.001). Approximately three years after the last patient was randomized, consolidation therapy with ADCETRIS continued to show an improvement in PFS. At three years, PFS was 61 percent (95% CI:53–68) for patients in the brentuximab vedotin arm compared to 43 percent (95% CI 36-51) for the placebo arm.

At three years, treatment-emergent peripheral neuropathy resolved for most patients, and no additional secondary malignancies were observed in either treatment arm.

• Among the 112 patients in the brentuximab vedotin arm who experienced treatment-emergent peripheral neuropathy, 99 patients (88%) experienced some improvement (23%) or complete resolution (65%) of neuropathy symptoms at the time of analysis.
• Secondary malignancies were comparable between the two treatment arms (n=4 brentuximab vedotin, n=2 placebo).
• Discontinuation of treatment due to an adverse event (AE) occurred in 54 patients (33%) who received ADCETRIS, most commonly due to peripheral sensory and motor neuropathies (14% and 7%, respectively). Patients who discontinued brentuximab vedotin treatment as a result of an AE received a median of 9.5 cycles (range, 1 to 15). The two-year PFS rate in these patients was 69 percent (95% CI 54–79) versus 82 percent (95% CI 71–89) for patients who completed all 16 treatment cycles.

Six PFS events (2 progressions and 4 deaths) were recorded after the 24-month evaluation period in the brentuximab vedotin arm versus three in the placebo arm (2 progressions and 1 death). The hazard ratio (HR) for PFS per independent review was 0.57 (95% CI 0.41–0.82).

About ADCETRIS®

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). 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 was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma 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, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with 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 the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, one in frontline classical Hodgkin lymphoma and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS Global Important Safety Information

ADCETRIS® is indicated for the treatment of adult patients with relapsed or refractory (r/r) CD30+ Hodgkin lymphoma (HL):

1. Following autologous stem cell transplant or

2. Following at least 2 prior therapies when autologous stem cell transplantation is not a treatment option

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

ADCETRIS is contraindicated for patients who are hypersensitive to ADCETRIS. In addition, combined use of bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.

ADCETRIS can cause serious side effects, including:

• Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death has been reported in patients treated with ADCETRIS. Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML.
• Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain.
• Pulmonary Toxicity: Cases of pulmonary toxicity have been reported in patients receiving ADCETRIS. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed.
• Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, 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. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.
• Infusion-related reactions: Immediate and delayed infusion-related reactions, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion.
• Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS and should be monitored closely and managed according to best medical practice.
• Peripheral neuropathy (PN): ADCETRIS treatment may cause PN that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.
• 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. Complete blood counts should be monitored prior to administration of each dose.
• Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice.
• Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): SJS and TEN have been reported. Fatal outcomes have been reported.
• Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored.
• Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Population pharmacokinetic analysis indicated that MMAE clearance might be affected by moderate and severe renal impairment, and by low serum albumin concentrations. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.
• Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Serious adverse drug reactions were: neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

ADCETRIS was studied as monotherapy in 160 patients in two Phase 2 studies. Across both studies, adverse reactions defined as very common (≥1/10) were: infections, neutropenia, peripheral sensory neuropathy, diarrhea, nausea, vomiting, alopecia, pruritis, myalgia, fatigue, pyrexia, and infusion-related reactions. Adverse reactions defined as common (≥1/100 to <1/10) were: upper respiratory tract infection, herpes zoster, pneumonia, anemia, thrombocytopenia, hyperglycemia, peripheral motor neuropathy, dizziness, demyelinating polyneuropathy, cough, dyspnea, constipation, rash, arthralgia, back pain, and chills.

These are not all of the possible side effects with ADCETRIS. Please refer to Summary of Product Characteristics (SmPC) before prescribing.

About Takeda

Located in Osaka, Japan, Takeda (TSE:4502) is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine.

Additional information about Takeda is available through its corporate website, www.takeda.com.

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