The first reported data from an ongoing phase I/II clinical trial evaluating brentuximab vedotin (Adcetris®; Seattle Genetics)  in combination with nivolumab (Opdivo; Bristol-Myers Squibb Company) in relapsed or refractory classical Hodgkin lymphoma (HL) were presented at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016.

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.

58th American Society of hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 3 - 6, 2016.
Photo 1.0: 58th American Society of hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 3 – 6, 2016.

According to the American Cancer Society, approximately 8,500 cases of HL will be diagnosed in the United States during 2016 and more than 1,100 will die from the disease. According to the Lymphoma Coalition, over 62,000 people worldwide are diagnosed with HL each year and approximately 25,000 people die each year from this cancer. In the European Union, about 12,200 new cases and 2,600 deaths occurred in 2012 as a result of HL.

Trial data presented at ASH
The first data reported include 42 patients, including 29 evaluable for response, were featured in an oral presentation and selected to be included in the 2017 Highlights of ASH post-meeting program.

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  • Brentuximab vedotin, an antibody-drug conjugate or 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, a defining marker of classical Hodgkin lymphoma that plays a role in tumor growth and survival.
  • Nivolumab is a programmed death-1 or PD-1 immune checkpoint inhibitor 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, nivolumab has become an important treatment option across multiple cancers. The drug 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 clinical trial phases, including Phase III, in a variety of tumor types. To date, the nivolumab clinical development program has enrolled more than 25,000 patients. Trial with nivolumab have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from this drug across the continuum of PD-L1 expression.

In the presented trial, patients were treated once every three weeks with up to four cycles of combination therapy. 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 37 years. The majority of patients (88%) were refractory or had progressed after receiving the standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine).

All 42 enrolled patients (100%) received one or more dose of the study therapies.  Twelve patients (29%) remain on treatment while 28 patients (67%) have completed treatment and two patients (5%) discontinued prior to the end of treatment. At the time of data analysis, nine patients (21%) initiated an ASCT and two patients (5%) received an alternative salvage therapy prior to ASCT. Preliminary analysis shows no impact of brentuximab vedotin and nivolumab combination on stem cell mobilization or engraftment.

Promising approach
“The phase I/II study combining the antibody-drug conjugate brentuximab vedotin with the PD-1 immune checkpoint inhibitor nivolumab is a promising investigational approach as it combines a targeted therapy with a therapy designed to activate the immune system and the combination may have synergistic activity,” said Alex Herrera, M.D., lead trial investigator and assistant professor at the City of Hope Medical Center, Duarte, California.

“The preliminary results are compelling and support further exploration of this novel regimen, free of traditional chemotherapy,” Herrera further added.

“We are evaluating brentuximab vedotin broadly as the foundation of care for CD30-expressing lymphomas, including combination strategies that have the potential to improve efficacy,” said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Key findings
“Preliminary data from the trial evaluating brentuximab vedotin in combination with nivolumab as pre-transplant salvage therapy for classical HL patients demonstrate a 90% objective response rate, with a 62% complete response rate and an acceptable safety profile. We look forward to further evaluation of this innovative combination regimen in other disease settings, including frontline older HL patients and CD30-expressing non-Hodgkin lymphoma, in partnership with Bristol-Myers Squibb,” Drachman added.

Fouad Namouni, M.D., Head of Development, Oncology, Bristol-Myers Squibb, commented, “With these new data presented at ASH, Bristol-Myers Squibb continues its efforts to strengthen its broad Immuno-Oncology and hematology development programs for nivolumab. Through our continued partnership with Seattle Genetics, we hope to build on the significant progress we’ve made with nivolumab as monotherapy and deliver new combination treatment options with the potential to improve the lives of patients impacted by blood cancers with high unmet needs.”

Treatment and adverse events
The median number of doses administered for both brentuximab vedotin and nivolumab was four. Of the 42 patients, no patients had a dose reduction during treatment due to an adverse event for either therapy. Dose delays occurred for three patients (7%) with brentuximab vedotin treatment and four patients (10%) with nivolumab treatment. Reasons for dose delays were urticaria, thrombosis, elevated lipase, chills and hypoxia.

The most common adverse events of any grade occurring prior to ASCT in more than 20% of patients were fatigue, nausea, infusion related reaction, pruritus and rash. One patient had a treatment-related serious adverse event after Cycle 1 of brentuximab vedotin, with Grade 3 dehydration, Grade 1 asthenia and nausea, Grade 2 hypercalcemia and malaise.

Infusion-related reactions (IRR) were observed in 38% of patients and most symptoms included flushing and nausea (14 percent each); chest discomfort, dyspnea, urticaria (12% each); cough and pruritis (10% each). A protocol amendment was made requiring premedication with low-dose corticosteroids and antihistamine. No patients discontinued treatment due to an IRR.

Potential immune-related adverse events included IRR (36% [one IRR not reported as associated with infusion]; Grade 1 or 2), rash (29%; Grade 1 or 2), diarrhea (26%; Grade 1 or 2), transaminase elevation (10%; Grade 1 and 3/4) and hypothyroidism (5%; Grade 2). There were no occurrences of pneumonitis or colitis.

More ongoing trials
Brentuximab vedotin is evaluated broadly in more than 70 ongoing clinical trials, including three phase III 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. Furthermore, the combination of  brentuximab vedotin and nivolumab is investigated in multiple ongoing phase I/II clinical trials.

In addition to the study presented at ASH, a trial titled A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas (NCT02581631) is ongoing and focused on patients with relapsed or refractory disease, including diffuse large B-cell lymphoma (DLBCL), and other rare subtypes of B-cell, including mediastinal B-cell lymphoma and mediastinal gray zone lymphoma. In addition, the companies recently extended the clinical evaluation of brentuximab vedotin and nivolumab into a clinical trial evaluating the combination as frontline treatment for older HL patients.

Brentuximab vedotin and nivolumab are not approved in combination for the treatment of relapsed or refractory HL or for other indications.

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