On December 3, 2016 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported data from a phase 2 clinical trial evaluating ADCETRIS (brentuximab vedotin) combination therapy in frontline diffuse large B-cell lymphoma (DLBCL) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016 (Press release, Seattle Genetics, DEC 3, 2016, View Source;p=RssLanding&cat=news&id=2227322 [SID1234516888]). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, expressed on several types of non-Hodgkin lymphoma. ADCETRIS is currently not approved for the treatment of DLBCL.
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Data from the phase 2 study in newly diagnosed intermediate-high or high-risk DLBCL included the evaluation of ADCETRIS in combination with either rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (referred to as RCHOP) in 51 patients (Part 1); or RCHP (removing the vincristine) in 11 patients (Part 2). In Part 1, the objective response rate was 83 percent, including 69 percent complete remissions. In Part 2, the objective response rate was 91 percent, including 82 percent complete remissions. The most common adverse events in Part 1 and 2 were fatigue, peripheral sensory neuropathy, diarrhea, nausea, alopecia and constipation.
"The data from this phase 2 trial demonstrate that ADCETRIS is an active agent in the treatment of frontline DLBCL," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "However, based on prioritization of our pipeline, we are discontinuing this trial and have decided not to pursue a registrational pathway for ADCETRIS in frontline DLBCL. We continue to evaluate ADCETRIS in the treatment of relapsed or refractory DLBCL through an ongoing randomized phase 2 trial, as well as more broadly for other CD30-expressing lymphomas, including the ECHELON-1 and ECHELON-2 phase 3 trials in frontline classical Hodgkin lymphoma and frontline mature T-cell lymphoma, respectively."
Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with RCHP as Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (Abstract #104, oral presentation at 9:45 a.m. PT)
Data were reported from Parts 1 and 2 of the phase 2 clinical trial for intermediate-high or high-risk frontline DLBCL. In Part 1, 51 patients were treated once every three weeks with up to six cycles of either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS plus RCHOP. In Part 2, 11 patients were treated once every three weeks with up to six cycles of 1.8 mg/kg of ADCETRIS plus RCHP. The median age of patients in Part 1 was 67 years and in Part 2 was 59 years. More than 90 percent of patients had stage III or IV disease.
Key findings presented in an oral presentation include:
For the 49 response-evaluable patients in Part 1, 25 patients had CD30-expressing disease and 24 patients had CD30-undetectable disease. Of the 25 with CD30-expressing disease, 21 patients (84 percent) had an objective response, with 19 patients (76 percent) achieving a complete remission. Of the 24 patients who had CD30-undetectable disease, 20 patients (83 percent) had an objective response, with 15 patients (63 percent) achieving a complete remission. Median progression-free survival (PFS) and overall survival have not yet been reached. For CD30-expressing patients, the estimated PFS rate at two years was 79 percent and the estimated two-year overall survival rate was 92 percent. For CD30-undetectable patients, the estimated two-year PFS rate at was 52 percent and the estimated two-year overall survival rate was 67 percent.
For the 11 patients in Part 2, ten patients (91 percent) had an objective response, with nine patients (82 percent) achieving a complete remission. One patient (nine percent) had a partial remission and one patient (nine percent) had progressive disease. All responding patients had confirmed CD30-expression by central review; the patient with progressive disease was determined to be CD30-undetectable.
The most common treatment-emergent adverse events of any grade in Part 1 and 2 were fatigue (65 and 64 percent, respectively), peripheral sensory neuropathy (63 and 55 percent, respectively), diarrhea (57 and 27 percent, respectively), nausea (56 and 73 percent, respectively), alopecia (27 and 73 percent, respectively) and constipation (33 and 55 percent, respectively). The most common Grade 3 or 4 adverse events were neutropenia, febrile neutropenia, dyspnea and anemia. When combined with RCHP, 1.8 mg/kg of ADCETRIS appears more tolerable than in combination with RCHOP, with no Grade 3 neuropathy, no motor neuropathy and lower incidence of febrile neutropenia.
About ADCETRIS (Brentuximab Vedotin)
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
BOXED WARNING
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.
Contraindication
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.
Adverse Reactions
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.
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.
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.
For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.