Updated and long-term follow-up analyses from two clinical trials evaluating brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda) and nivolumab (Opdivo®; Bristol‑Myers Squibb) in frontline Hodgkin lymphoma patients aged 60 years and older and in relapsed or refractory classical Hodgkin lymphoma were presented at the 61st annual meeting of the American Society of Hematology (ASH) taking place December 7-10, 2019 in Orlando, Florida.
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. Classical Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.
According to the American Cancer Society, approximately 8,110 cases of Hodgkin lymphoma will be diagnosed in the United States during 2019 and 1,000 will die from the disease. Approximately half of all newly diagnosed Hodgkin lymphoma patients have Stage III/IV 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.
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma. The drug includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). 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.
Antibody-drug Conjugates are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With five approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
“We continue to evaluate brentuximab vedotin in combination with novel therapies, such as checkpoint inhibitors, with the goal of identifying new options for CD30-expressing lymphomas where there is high unmet need,” said Roger Dansey, MD, Chief Medical Officer at Seattle Genetics.
“The data presentations at the annual meeting reinforces our strong commitment to the brentuximab vedotin clinical development program, potentially moving into new patient populations and novel combination treatment strategies,” Dansey added.
Data were presented from an updated analysis from the phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab as frontline therapy for Hodgkin lymphoma patients aged 60 years and older. Data were reported from 21 patients, and the median age was 72 years. The majority of patients (76%) had stage III/IV disease at the time of diagnosis.
These results were highlighted in an oral presentation by Christopher A. Yasenchak, MD, Willamette Valley Cancer Institute and Research Center/US Oncology Research, Oregon. 
The trial included 19 response-evaluable patients, 18 patients (95%) had an objective response, including 13 patients (68%) with a complete response and five patients (26%) with a partial response.
All response-evaluable patients experienced tumor reduction (complete response + partial response + stable disease) following treatment with brentuximab vedotin in combination with nivolumab. Median duration of response was not yet reached and the maximum duration of response was 22 months and ongoing (95% CI: 7.06, -).
The most common treatment-related adverse events of any grade occurring in at least 20% of patients were fatigue, diarrhea, pyrexia, infusion related reaction, peripheral motor neuropathy, peripheral sensory neuropathy and increase in lipase.
One treatment-related serious adverse event was pyrexia. Fifty-seven percent of patients (12/21) had at least one treatment-related adverse event greater than or equal to Grade 3, most commonly increase in lipase (24%, 5/21), peripheral motor neuropathy and peripheral sensory neuropathy (each 14%, 3/21), and fatigue and hyponatremia (each 10%, 2/21).
These data suggest that brentuximab vedotin + nivolumab is an active treatment with an encouraging CR rate (72%) and appears well tolerated. The results also suggest that with further follow-up and validation, treatment with brentuximab vedotin + Nivo may improve patient outcomes.
Relapsed or Refractory Hodgkin Lymphoma
A second presentation reported data from 93 patients with relapsed or refractory classical Hodgkin lymphoma after failure of frontline therapy who received the combination regimen of brentuximab vedotin plus nivolumab.
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 34 years.
These results were highlighted in an oral presentation by Alison J. Moskowitz, MD, Memorial Sloan Kettering Cancer Center, New York, NY. 
The study results of this trial showed that of the 91 treated patients, 85% (77/91) had an objective response, including 67% (61/91) with a complete response, 16 patients with a partial response and six patients had stable disease.
From the ninety-one treated patients, sixty-seven patients received an ASCT per trial protocol with no additional salvage therapy. For all treated patients, the two-year progression-free survival (PFS) was 79% (95% CI: 68%, 87%). For the 67 patients who received an ASCT per trial protocol, the two-year PFS was 92% (95% CI: 80%, 97%). Median follow-up for all treated patients was 24.2 months (range 1.8-41.7) and the median PFS was not reached. Estimated overall survival at two years was 94% (95% CI: 85%, 97%) and median overall survival was not yet reached.
Peripheral immune signatures were consistent with an activated T-cell response. Prior to ASCT, the most common adverse events of any grade occurring in more than 20% of patients were nausea, infusion related reaction, fatigue, diarrhea, pruritus, headache, vomiting and pyrexia. Other adverse events included peripheral neuropathy in 16 patients (18%) and neutropenia in six patients (7%). Two patients (2%) discontinued treatment due to adverse events, Grade 3 peripheral neuropathy and increased gamma-glutamyltransferase. Serious adverse events occurred in 14 patients (15%), including pneumonia, pneumonitis and pyrexia (two patients each); and Grade 3 Guillain-Barre syndrome (one patient).
 Yasenchak CA, Bordoni R, Yazbeck V, Patel-Donnelly D, Anderson T, Larson T, Newhook T, Mei M, et al. Phase II Study of Frontline Brentuximab Vedotin Plus Nivolumab in Patients with Hodgkin Lymphoma Aged ≥60 Years. 61st annual meeting of the American Society of Hematology (ASH). Program: Oral and Poster Abstracts. Type: Oral. Abstract 237. Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Immunotherapy Approaches in Hodgkin Lymphoma Hematology Disease Topics & Pathways: Diseases, Biological, antibodies, Therapies, Non-Hodgkin Lymphoma, T-Cell Lymphoma, Lymphoid Malignancies.[Abstract]
 Moskowitz AJ, Advani R, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, LaCasce AS, Christian BA, et al. Brentuximab Vedotin and Nivolumab for Relapsed or Refractory Classic Hodgkin Lymphoma: Long-Term Follow-up Results from the Single-Arm Phase I/II Study. 61st annual meeting of the American Society of Hematology (ASH).Program: Oral and Poster Abstracts
Type: Oral Abstract 238. Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Immunotherapy Approaches in Hodgkin Lymphoma. Hematology Disease Topics & Pathways:Diseases, Biological, Therapies, Hodgkin Lymphoma, checkpoint inhibitors, immunotherapy, Lymphoid Malignancies. [Abstract]