ORLANDO, Fla.--(BUSINESS WIRE)--Seattle Genetics, Inc. (Nasdaq: SGEN) today highlighted several data presentations at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in Orlando, Florida, December 5-8, 2015, evaluating ADCETRIS (brentuximab vedotin) as both monotherapy and combination therapy in multiple Hodgkin lymphoma (HL) disease settings. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL. ADCETRIS is being evaluated globally as the foundation of therapy for HL in more than 45 ongoing clinical trials, including trials led by Seattle Genetics and its development and commercialization partner, Takeda, as well as by independent investigators.
“For the past decade, we have been committed to improving the therapeutic options for HL patients, and we have made tremendous progress with ADCETRIS, which is now FDA-approved for two HL indications and is being evaluated broadly in multiple settings and combinations across more than 45 ongoing clinical trials,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “The data presented at the ASH annual meeting continue to support our goal to establish ADCETRIS as the foundation of care for HL. Notably, final results from the pivotal HL clinical trial demonstrate that some patients remain free from recurrence after more than five years of follow-up. We continue to explore novel ADCETRIS combinations in the salvage setting and in older frontline HL patients, with data from ongoing phase 1/2 and phase 2 clinical trials demonstrating objective response rates greater than 90 percent, supporting further follow-up and evaluation of therapeutic strategies.”
ADCETRIS is currently not approved for the treatment of frontline HL or as combination therapy for HL.
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, poster presentation on Sunday, December 6, 2015)
A pivotal, single-arm trial, which supported the FDA approval in 2011 of ADCETRIS for this indication, was conducted in 102 relapsed or refractory HL patients who had previously received an autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent ADCETRIS. In addition, the trial was designed to determine duration of response, progression-free survival and overall survival. Enrolled patients had received a median of more than three prior chemotherapy regimens. After a five-year follow-up period, the final results from the pivotal trial include:
- The estimated median overall survival was 40.5 months (95% confidence interval [CI]: 28.7, 61.9 [range, 1.8 to 72.9+ mos]). The estimated five-year survival rate was 41 percent.
- Of the 102 patients treated, 15 remained in remission per investigator assessment with a median observation time of 69.5 months (range, 66.5–72.9 months) and may potentially be cured. Of these patients, nine received no further therapy and six received consolidative allogeneic stem cell transplant.
- Of the 34 patients who had a complete remission, the median overall survival and progression-free survival had not yet been reached.
- Overall, patients received a median of nine cycles of ADCETRIS treatment and patients who achieved a complete remission received a median of 13.5 cycles of therapy.
- The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia and diarrhea. Treatment emergent peripheral neuropathy was experienced by 56 patients (55 percent). Eighty-eight percent of these patients experienced improvement of their peripheral neuropathy symptoms, including 73 percent with complete resolution.
- The most common Grade 3 or higher adverse events occurring in at least five percent of patients were neutropenia (20 percent); peripheral sensory neuropathy and thrombocytopenia (eight percent each); and anemia (six percent).
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, poster presentation on Sunday, December 6, 2015)
The phase 3 AETHERA clinical trial was designed to evaluate the potential of single-agent ADCETRIS to extend progression-free survival post-ASCT in patients with classical HL who were at high risk of relapse or progression. Patients received ADCETRIS or placebo every three weeks for up to approximately one year (16 cycles). A total of 329 HL patients were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm. Based on these trial results, ADCETRIS was approved by the FDA in August 2015 for the treatment of patients with classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation. Updated three-year follow-up efficacy and safety data include:
- The three-year progression-free survival rate per investigator was 61 percent in the ADCETRIS arm compared to 43 percent in the placebo arm. Median progression-free survival per investigator was not yet reached in the ADCETRIS arm versus 15.8 months in the placebo arm. The hazard ratio was 0.52 favoring the ADCETRIS arm.
- A progression-free survival analysis evaluating subgroups, including the number of risk factors, initial response to salvage therapy and disease characteristics, showed patients with more risk factors for relapse post-ASCT appeared to have the greatest benefit from ADCETRIS consolidation therapy.
- Among patients on the ADCETRIS arm who did not experience disease progression on therapy, progression-free survival rates were higher in patients who remained on therapy longer.
- In the ADCETRIS arm, 112 patients (67 percent) reported peripheral neuropathy. To date, 88 percent of these patients had resolution or improvement in symptoms, with 66 percent having complete resolution.
- Patients remain in long-term follow-up. Final overall survival analysis is planned for 2020.
Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study (Abstract #587, oral presentation on Monday, December 7, 2015 at 11:30 a.m. ET)
Interim results were presented from an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with dacarbazine or bendamustine (Treanda) as frontline therapy for HL patients age 60 years or older. ADCETRIS combination data were reported from 22 patients treated with dacarbazine and 20 patients treated with bendamustine. The median age of patients was 69 years in the dacarbazine combination arm and 75 years in the bendamustine combination arm. At least 70 percent of patients in each arm had stage III/IV disease at the time of diagnosis and the majority were frail with multiple comorbidities. The data will be highlighted in an oral presentation by Christopher Yasenchak, M.D., Willamette Valley Cancer Institute and Research Center/US Oncology Research.
Combination data evaluating ADCETRIS and dacarbazine or bendamustine include:
- Of 21 evaluable patients in the dacarbazine combination arm, all patients (100 percent) had an objective response, including 14 patients (67 percent) with a complete remission and seven patients (33 percent) with a partial remission.
- Of 16 evaluable patients in the bendamustine combination arm, all patients (100 percent) had an objective response, including 13 patients (81 percent) with a complete remission and three patients (19 percent) with a partial remission.
- In the dacarbazine combination arm, the median observation time was 13.4 months and progression-free survival at six months was 95 percent, at nine months was 89 percent and 12 months was 66 percent. In the bendamustine combination arm the median observation time was too short to provide a reliable progression-free survival estimate.
- The most common adverse events of any grade occurring in at least 25 percent of patients in the dacarbazine combination arm were peripheral sensory neuropathy (77 percent); constipation (45 percent); fatigue and nausea (41 percent each) and joint pain and peripheral edema (32 percent each).
- The most common adverse events of any grade occurring in at least 25 percent of patients in the bendamustine combination arm were diarrhea (75 percent); nausea (60 percent); fatigue (55 percent) and decreased appetite and fever (40 percent each). Two patient deaths considered unrelated to treatment occurred within 30 days of last dose of study drug. Enrollment on the bendamustine arm was closed given the tolerability of the combination did not meet study goals for this fragile patient population. Patients in this arm continued to receive treatment with single-agent ADCETRIS.
Brentuximab Vedotin Plus Bendamustine: A Highly Active Salvage Treatment Regimen for Patients with Relapsed or Refractory Hodgkin Lymphoma (Abstract #3982, poster presentation on Monday, December 7, 2015)
Updated data were presented from an ongoing phase 1/2 single-arm, open-label clinical trial evaluating the efficacy and tolerability of ADCETRIS in combination with bendamustine in HL patients who had relapsed or were refractory to frontline therapy. The combination therapy was administered every three weeks, for up to six cycles, followed by additional treatment with single-agent ADCETRIS for up to a total of 16 cycles of therapy. After patients have received at least two cycles of combination therapy, they have the option to pause treatment to receive an ASCT and then resume treatment with single-agent ADCETRIS as consolidation. Current treatment options in this setting include salvage chemotherapy regimens that historically have resulted in variable complete remission rates of 19 to 60 percent and are associated with significant toxicities.
Data were reported from 55 patients with a median age of 36 years. The majority of patients (53 percent) had stage III/IV disease at the time of initial diagnosis, with 28 primary refractory patients (51 percent) and 27 relapsed patients (49 percent) after frontline therapy, primarily consisting of the chemotherapy regimen ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine). Updated data from this phase 1/2 trial include:
- Of the 53 evaluable patients, 49 patients (93 percent) had an objective response to combination therapy with brentuximab vedotin plus bendamustine, including 40 patients (76 percent) with a best response of complete remission and nine patients (17 percent) with a best response of partial remission. The complete remission rate was 88 percent in relapsed patients and 64 percent in primary refractory patients.
- The median overall survival for all 53 patients, including the 40 patients who received an ASCT, had not yet been reached.
- The estimated 18-month progression-free survival rate was 75 percent for the 53 evaluable patients and 83 percent for the 40 patients who proceeded to ASCT.
- For patients who achieved a complete remission during combination therapy, the percentage of progression events was similar whether patients did or did not have an ASCT (21 percent versus 17 percent, respectively).
- Patients who did not receive ADCETRIS consolidation treatment experienced a higher proportion of progression-free survival events compared to those who received consolidation therapy (29 percent versus 15 percent).
- The most common adverse events from combination treatment were infusion-related reactions (IRRs) which were seen in 58 percent of patients. The most common symptoms associated with IRRs occurring in more than 15 percent of patients were fever, chills, dyspnea, flushing and nausea. The trial protocol was amended to require premedication with corticosteroids and antihistamines, which decreased the severity of IRRs.
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.
For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at http://www.seattlegenetics.com/pdf/adcetris_USPI.pdf.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to our future clinical trials, potential future uses of ADCETRIS and our goal to establish ADCETRIS as the foundation of therapy for a broad array of CD30-expressing lymphomas including HL. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks of adverse events associated with ADCETRIS use, negative or unexpected ADCETRIS clinical trial results even after promising results in earlier company and investigator-sponsored trials, and adverse regulatory actions affecting ADCETRIS. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption “Risk Factors” included in the company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
