SAN DIEGO--(EON: Enhanced Online News)--Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, today highlighted long-term follow-up data evaluating ADCETRIS (brentuximab vedotin) in T-cell lymphoma at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016. The data included a presentation featuring five-year overall survival from the ADCETRIS pivotal phase 2 clinical trial in relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). In addition, a presentation highlighted the four-year durability analysis from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of newly diagnosed mature T-cell lymphoma (MTCL) patients. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on Hodgkin lymphoma and several types of non-Hodgkin lymphoma, including subsets of MTCL. ADCETRIS is currently not approved for the frontline treatment of MTCL.
“The long-term ADCETRIS data presented at ASH demonstrate durable remissions in these historically difficult-to-treat disease settings. We believe these clinical trials in addition to the many ongoing clinical trials support the potential to establish ADCETRIS as the foundation of care in CD30-expressing lymphomas”
“The long-term ADCETRIS data presented at ASH demonstrate durable remissions in these historically difficult-to-treat disease settings. We believe these clinical trials in addition to the many ongoing clinical trials support the potential to establish ADCETRIS as the foundation of care in CD30-expressing lymphomas,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. “End of study results were presented from the pivotal sALCL trial, demonstrating that the majority of patients treated with ADCETRIS achieved clinically significant durable remissions. After more than five years of follow-up, patients who remain in remission have the potential to be cured. In addition, four-year survival and durability data were presented from a phase 1 trial of ADCETRIS combined with chemotherapy in frontline MTCL. The survival data has not changed since last presentation at ASH 2015, with four-year progression-free survival and overall survival rates of 52 and 80 percent, respectively. These data support the ongoing phase 3 ECHELON-2 trial, which recently completed enrollment and we anticipate reporting data in the 2017 to 2018 timeframe.”
Five-Year Survival Data from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma (Abstract #4144, poster presentation on Monday, December 5, 2016)
A pivotal, single-arm clinical trial was conducted in 58 relapsed or refractory sALCL patients 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. Patients received 1.8 milligrams per kilogram (mg/kg) of ADCETRIS administered every three weeks for up to 16 cycles. As previously reported, 86 percent of patients on the trial achieved an objective response, including 59 percent with a complete remission.
Data from long-term patient follow-up in this pivotal trial after a median observation time of 71.4 months from the first dose of ADCETRIS include:
- The estimated five-year overall survival rate was 60 percent and the median overall survival was not reached.
- The median progression-free survival was 20.0 months.
- In the 38 patients who achieved a complete remission per investigator, the median duration of response was not reached. Sixteen of the 38 patients (42 percent) remained in remission at study closure, eight of whom had received consolidative transplants. The median observation time for these 16 patients was 75.4 months.
- For the 16 complete remission patients who received a consolidative transplant (either allogeneic or autologous stem cell transplant), neither median progression-free survival nor overall survival had been reached.
- For the 22 complete remission patients who had not received a consolidative transplant, the median progression-free survival was 39.4 months and median overall survival had not been reached.
- The most common adverse events of any grade occurring in 20 percent or more of patients were peripheral neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation and neutropenia. Of the 33 patients who experienced peripheral neuropathy, 30 patients (91 percent) experienced complete resolution or some improvement of symptoms at last follow-up.
- The most common Grade 3 or 4 adverse events occurring in at least five percent of patients were neutropenia (21 percent), peripheral neuropathy (17 percent), thrombocytopenia (14 percent), anemia (seven percent), fatigue and recurrent ALCL (five percent each).
Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas (Abstract #2993, poster presentation on Sunday, December 4, 2016)
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 following six cycles of ADCETRIS plus CHP were eligible to receive up to ten additional cycles of single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called 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. As previously reported, 100 percent of patients on the trial achieved an objective response, including 88 percent with a complete response and 12 percent with a partial response.
Updated key findings based on a median observation time of 53 months from first dose of therapy include:
- There have been no progression events or deaths in this trial since the previous presentation at the 2015 ASH Annual Meeting.
- The estimated four-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. Historical four-year progression-free survival rates range from 25 to 35 percent. The median progression-free survival has not yet been reached.
- The estimated four-year overall survival rate was 80 percent. Historical four-year overall survival rates range from 30 to 40 percent.
- 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 alopecia (54 percent). The most common Grade 3 or higher adverse events occurring in more than ten 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 five months.
A global phase 3 study called ECHELON-2 completed enrollment in November 2016. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate ADCETRIS plus CHP versus CHOP as frontline therapy in patients with CD30-expressing MTCL. The trial enrolled 452 patients (approximately 225 patients per treatment arm) randomized to receive ADCETRIS plus CHP or CHOP every three weeks for six to eight cycles. Data from the ECHELON-2 trial are expected in the 2017 to 2018 timeframe.
About T-Cell Lymphomas
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. Non-Hodgkin lymphomas 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. The World Health Organization identifies 22 subtypes of mature T- and NK-cell neoplasms, including systemic anaplastic large cell lymphoma (sALCL) which is an aggressive type of T-cell non-Hodgkin lymphoma that expresses CD30. Other mature T-cell lymphomas include peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma and adult T-cell lymphoma.
ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including three phase 3 studies, the ongoing ECHELON-1 trial in frontline classical Hodgkin lymphoma and the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, as well as the completed ALCANZA trial in cutaneous T-cell lymphoma for which a supplemental BLA is planned in the first half of 2017.
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 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 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. The European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.
ADCETRIS has received marketing authorization by regulatory authorities in 65 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 an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. ADCETRIS® (brentuximab vedotin), the company’s lead product, in collaboration with Takeda Pharmaceutical Company Limited, is the first in a new class of ADCs commercially available globally in 65 countries for relapsed classical Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in a phase 3 trial for acute myeloid leukemia. Headquartered in Bothell, Washington, Seattle Genetics has a robust pipeline of innovative therapies for blood-related cancers and solid tumors designed to address significant unmet medical needs and improve treatment outcomes for patients. The company has collaborations for its proprietary ADC technology with a number of companies including AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com
ADCETRIS (brentuximab vedotin) U.S. Important Safety Information
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).
Warnings and Precautions
- Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN 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. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
- 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.
- Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
- Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, 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.
In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT, 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.
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.
Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
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.
Certain of the statements made in this press release are forward looking, such as those, among others, relating to the therapeutic and commercial potential of ADCETRIS, including ADCETRIS’ potential as a treatment for MTCL, the anticipated timing of data from the ECHELON-2 trial, the anticipated benefits of Seattle Genetics’ ADCETRIS clinical development program, and the potential submission of applications (e.g., a supplemental Biologics License Application in the U.S.) seeking label expansion for ADCETRIS use in the ALCANZA and ECHELON-2 settings. 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 results from the ECHELON-2 trial even after promising results in earlier company- and investigator-sponsored trials, and adverse regulatory actions affecting ADCETRIS, all of which could result in Seattle Genetics being unable to expand ADCETRIS’ labeled indications of use to the ECHELON-2 or any other settings. Seattle Genetics may also experience delays in the conduct of and obtaining data from the ECHELON-2 and its other clinical trials, in each case for a variety of reasons, including the inherent difficulty and uncertainty of pharmaceutical product development. 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, 2016 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.