On December 7, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported data presentations evaluating ADCETRIS (brentuximab vedotin) in frontline non-Hodgkin lymphoma at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015 (Press release, Seattle Genetics, DEC 7, 2015, View Source;p=RssLanding&cat=news&id=2120760 [SID:1234508481]). The data include an oral presentation highlighting updated results from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with chemotherapy for newly diagnosed, high risk diffuse large B-cell lymphoma (DLBCL) patients. In addition, a poster presentation highlights a three-year durability analysis from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of newly diagnosed peripheral T-cell lymphoma, also known as mature T-cell lymphoma (MTCL), patients. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma and is expressed on several types of non-Hodgkin lymphoma.
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"There is a significant need to improve frontline treatment options in aggressive non-Hodgkin lymphomas. In particular, newly diagnosed patients with high-intermediate and high-risk DLBCL and MTCL have estimated three-year progression-free survival rates of approximately 55 percent and 30 percent, respectively," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "ADCETRIS has demonstrated high complete remission and progression-free survival rates when added to frontline chemotherapy regimens for DLBCL and MTCL. Our efforts to redefine frontline therapy for these diseases are part of our goal to establish ADCETRIS as the foundation of care for all CD30-expressing lymphomas."
ADCETRIS is currently not approved for the treatment of frontline DLBCL and MTCL. For more information about the clinical trials, including enrolling centers, visit www.clinicaltrials.gov.
Brentuximab Vedotin with RCHOP as Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Results from an Ongoing Phase 2 Study (Abstract #814, oral presentation on Monday, December 7, 2015 at 5:15 p.m.)
Updated interim results were reported from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with the standard of care regimen consisting of rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) in frontline high-intermediate and high-risk DLBCL. Patients were randomized to receive standard dose RCHOP with either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS. The trial was designed to assess antitumor activity and the safety profile of ADCETRIS plus RCHOP in these patients. Exploratory endpoints included CD30 expression measured by immunohistochemistry (IHC) testing and the relationship between CD30 expression and response.
Data were reported from 51 frontline DLBCL patients with a median age of 67 years. Seventy-one percent of patients in the trial had stage IV disease, 37 percent were considered high-risk and 63 percent were considered high-intermediate risk. Key findings presented by Christopher Yasenchak, M.D., Willamette Valley Cancer Institute and Research Center/US Oncology Research, include:
Of 25 evaluable patients who had CD30-expressing disease (one percent expression or greater), 21 patients (84 percent) obtained an objective response, including 19 patients (76 percent) with a complete remission and two patients (eight percent) with a partial remission. The estimated progression-free survival rate for CD30-positive patients at both 12 and 15 months was 83 percent.
Subsets of patients known to have a poor prognosis appear to have favorable outcomes:
Eleven patients with CD30-positive activated B-cell like (ABC) DLBCL had a complete remission rate of 73 percent (eight of 11 patients). The estimated progression-free survival rate for these patients at both 12 and 15 months was 80 percent.
Six patients with Epstein-Barr virus (EBV)-positive lymphoma had a complete remission rate of 83 percent (five of six patients). The estimated progression-free survival rate for these patients at 12 months was 83 percent.
The most common treatment-emergent adverse events of any grade were fatigue and peripheral sensory neuropathy (63 percent each), diarrhea and nausea (57 percent each), and neutropenia and vomiting (37 percent each).The most common Grade 3 or 4 adverse events were febrile neutropenia (31 percent), neutropenia (33 percent) and anemia (24 percent). Based on an increased rate of Grade 3 peripheral neuropathy observed in the first 10 patients treated on the 1.8 mg/kg arm, remaining patients were treated with 1.2 mg/kg of ADCETRIS.
Based on these data, the phase 2 trial has been amended to add a randomized cohort exploring the activity and safety of ADCETRIS plus RCHP (without vincristine) versus RCHOP in frontline patients with CD30-expressing high-intermediate or high-risk DLBCL. Separately, a randomized phase 2 trial is also ongoing evaluating rituximab and bendamustine with or without ADCETRIS in relapsed or refractory DLBCL.
Frontline Treatment of CD30+ Peripheral T-cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up (Abstract #1537, poster presentation on Saturday, December 5, 2015)
Data were reported from 26 frontline MTCL patients who received the combination regimen of ADCETRIS plus cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission with combination therapy were eligible to receive continued single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients (62 percent) with anaplastic lymphoma kinase (ALK) negative disease, which is typically associated with a poor prognosis. Seven patients had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk.
Updated key findings based on a median observation time of 38.7 months from first dose of therapy include:
The estimated three-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. There have been no progression events since the previous presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2014. The estimated median progression-free survival has not yet been reached.
The estimated three-year overall survival rate was 80 percent.
The observed three-year progression-free survival and overall survival rates of 52 and 80 percent compare favorably to historical three-year progression-free survival and overall survival rates for frontline MTCL of approximately 30 and 40 percent, respectively.
The most common adverse events of any grade occurring in more than 30 percent of patients were nausea and peripheral sensory neuropathy (69 percent each), diarrhea (62 percent), fatigue (58 percent) and hair loss (54 percent). The most common Grade 3 or higher adverse events occurring in more than 10 percent of patients were febrile neutropenia (31 percent), neutropenia (23 percent), anemia (15 percent) and pulmonary embolism (12 percent).
Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 1.3 months.
A global phase 3 study called ECHELON-2 is currently enrolling patients. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate A+CHP versus CHOP as frontline therapy in patients with CD30-positive MTCL. Approximately 450 patients (approximately 225 patients per treatment arm) will be randomized to receive A+CHP or CHOP every three weeks for six to eight cycles.
About ADCETRIS
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, ECHELON-1 in frontline classical HL and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.
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 for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical 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, (2) regular approval for the treatment of classical HL 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 HL and sALCL.
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 HL 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.
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.
About Seattle Genetics
Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS (brentuximab vedotin) is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 55 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials in CD30-expressing malignancies. Seattle Genetics is also advancing a robust pipeline of clinical-stage programs, including vadastuximab talirine (SGN-CD33A; 33A), denintuzumab mafodotin (SGN-CD19A; 19A), SGN-LIV1A, SGN-CD70A, ASG-22ME, ASG-15ME and SEA-CD40. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.
ADCETRIS (brentuximab vedotin) U.S. 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: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy 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.
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.
Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.
Most Common Adverse Reactions:
ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, 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.
ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. 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.