On December 11, 2017 Seattle Genetics, Inc. (NASDAQ:SGEN) and Bristol-Myers Squibb Company (NYSE:BMY) reported highlighted updated interim results from an ongoing phase 1/2 clinical trial evaluating the combination of ADCETRIS (brentuximab vedotin) and Opdivo (nivolumab) in relapsed or refractory classical Hodgkin lymphoma (HL) at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Atlanta, Georgia, December 9-12, 2017 (Press release, Seattle Genetics, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322109 [SID1234522562]). The data were also simultaneously published online in the journal Blood. The data reported from 62 patients, including 60 evaluable for response, were featured in an oral presentation and selected to be included in the 2018 Highlights of ASH (Free ASH Whitepaper) post-meeting program. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor growth and survival. Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to harness the body’s own immune system to help restore anti-tumor immune response. ADCETRIS and Opdivo are not approved in combination for the treatment of relapsed or refractory HL or for other indications.
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"The phase 1/2 study combining the antibody-drug conjugate ADCETRIS with the PD-1 immune checkpoint inhibitor Opdivo is a promising investigational approach as it combines a CD30-targeted therapy with a therapy designed to activate the immune system. The antitumor activity of the drugs may be enhanced when administered in combination," said Alex Herrera, M.D., lead trial investigator and assistant professor at the City of Hope Medical Center, Duarte, California. "The interim results evaluating the combination regimen in relapsed or refractory HL patients continue to look compelling, demonstrating both promising activity in addition to a manageable overall safety profile. These data support further exploration of this novel, chemotherapy-free investigational regimen in HL patients."
"We are evaluating ADCETRIS broadly as the foundation of care for CD30-expressing lymphomas, including combination strategies that have the potential to improve efficacy. At this year’s ASH (Free ASH Whitepaper) Annual Meeting, we are presenting significant clinical updates that support this goal, including results from the phase 3 ECHELON-1 clinical trial evaluating ADCETRIS in combination with chemotherapy in frontline HL as well as interim results from this phase 1/2 study evaluating ADCETRIS in combination with Opdivo in relapsed HL," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Interim results from the trial evaluating ADCETRIS in combination with Opdivo as pre-transplant salvage therapy for classical HL patients continue to look promising, demonstrating an 83 percent objective response rate, with a 62 percent complete response rate and an acceptable safety profile. We look forward to further evaluation of this innovative combination regimen in other disease settings, including the ongoing pivotal phase 3 CHECKMATE 812 study in patients with relapsed HL, in partnership with Bristol-Myers Squibb."
"Our ongoing collaboration to evaluate Opdivo in combination with Seattle Genetics’ ADCETRIS reinforces Bristol-Myers Squibb’s commitment to addressing cancer from all angles for patients with high unmet needs," said Fouad Namouni, M.D., head of Oncology Development, Bristol-Myers Squibb. "We look forward to further evaluation of the ADCETRIS and Opdivo combination in Hodgkin lymphoma and other hematologic malignancies in several ongoing trials."
Interim Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma (Abstract #649, oral presentation at 10:30 a.m. ET)
Data were reported from 62 patients with relapsed or refractory HL who received the combination regimen of ADCETRIS plus Opdivo after failure of frontline therapy. Patients were treated once every three weeks, with up to four cycles of combination therapy in the outpatient setting. After completion of the fourth cycle of treatment, patients were eligible to undergo an autologous stem cell transplant (ASCT). The median age of patients was 36 years. The majority of patients (95 percent) were refractory or had relapsed after receiving the standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine) or some variation of the standard of care (ABVE-PC, R-ABVD).
Key findings presented include:
Of 60 response-evaluable patients, 50 patients (83 percent) had an objective response, including 37 patients (62 percent) with a complete response and 13 patients (22 percent) with a partial response. Five patients (eight percent) had stable disease and five patients (eight percent) had progressive disease. Median follow-up time was eight months and median duration of response was not yet reached. The estimated six-month progression-free survival rate was 89 percent.
Of the 62 patients enrolled, 58 patients completed all four cycles of study treatment and four patients discontinued prior to the end of treatment. At the time of data analysis, 54 patients received an ASCT. Preliminary analysis shows no impact of combination treatment with ADCETRIS and Opdivo on stem cell mobilization or engraftment.
The most common adverse events (AEs) of any grade occurring prior to ASCT or subsequent salvage therapy in at least 20 percent of patients were nausea, fatigue, infusion-related reaction (IRR), pruritus, diarrhea, headache, cough, vomiting, dyspnea, nasal congestion, pyrexia and rash. Grade 3 or 4 adverse events occurred in 19 patients (31 percent), with 17 patients (28 percent) having Grade 3 AEs (fatigue, IRR, pruritus and diarrhea) and two patients (three percent) having Grade 4 AEs (thrombocytopenia and increased lipase).
Infusion-related reactions (IRRs) were observed in 44 percent of patients, of which the majority (41 percent) were Grade 1 or 2. No patients discontinued treatment due to an IRR.
Potential immune-related adverse events, excluding IRRs, occurred in 50 patients (82 percent), and five patients required treatment with systemic steroids, including patients with Grade 3 diarrhea and Grade 2 colitis, Grade 3 aspartate aminotransferase elevation, Grade 4 colitis and pneumonitis (after receiving additional salvage therapy), Grade 2 pneumonitis, and Grade 4 pneumonitis (after BEAM, as part of the conditioning regimen). No patients discontinued treatment due to an immune-related adverse event.
ADCETRIS and Opdivo are being evaluated as combination therapy in multiple ongoing clinical trials. In addition to the study presented at ASH (Free ASH Whitepaper), a trial titled "A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas" is ongoing and enrolling patients with relapsed or refractory disease, including diffuse large B-cell lymphoma (DLBCL), and other rare subtypes of B-cell lymphoma, including mediastinal B-cell lymphoma and mediastinal gray zone lymphoma. The companies have also extended the clinical evaluation of ADCETRIS and Opdivo into a clinical trial evaluating the combination as frontline treatment for older HL patients. Lastly, the companies initiated a pivotal phase 3 clinical trial called CHECKMATE 812 trial evaluating ADCETRIS alone versus ADCETRIS in combination with Opdivo in relapsed/refractory HL patients.
About Classical Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: HL, also known as Hodgkin disease, and non-Hodgkin lymphoma. HL is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system. The disease is most often diagnosed in early adulthood (ages 20-40) and late adulthood (older than 55 years of age). Classical Hodgkin lymphoma is the most common type of HL, accounting for 95% of cases. Classical HL is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells.
According to the American Cancer Society, approximately 8,260 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and more than 1,000 will die from the disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.
About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30 and is being evaluated broadly in more than 70 clinical trials, including three phase 3 studies: the completed ECHELON-1 trial in frontline classical Hodgkin lymphoma that supported the recent FDA Breakthrough Therapy Designation and submission of the supplemental Biologics License Application (BLA) for use in this setting, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, and the ongoing CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.
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 injection for intravenous infusion has received FDA approval for four indications: (1) regular approval for adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, (2) 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, (3) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (4) 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 in 2013, and non-conditional approval for post-ASCT consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.
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 marketing authorization 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 69 countries for relapsed or refractory Hodgkin lymphoma and sALCL. 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 Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.
Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo + Yervoy combination was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.