An updated interim analysis from the ongoing phase I/II clinical trial evaluating  brentuximab vedotin (Adcetris®; Seattle Gentics) and nivolumab (Opdivo®; Bristol-Myers Squibb) in relapsed or refractory (R/R) classical Hodgkin lymphoma presented at the 14th International Conference on Malignant Lymphoma (ICML), held in Lugano, Switzerland, June 14 – 17, 2017, show an 85% Objective Response Rate (ORR) and 63% Complete Response Rate (CRR) with an acceptable safety profile in pre-transplant relapsed or refractory classical Hodgkin lymphoma patients. [1]

During the 14th-ICML, data were reported from 62 patients, including 59 evaluable for response, were be featured in an oral presentation on June 15, 2017.

Most common blood cancer
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: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma 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 Hodgkin lymphoma, accounting for 95% of all cases. Classical Hodgkin lymphoma is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells.

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According to the American Cancer Society, more than 8,000 cases of Hodgkin lymphoma will be diagnosed in the United States during 2017 and approximately 1,000 will die from the disease. Furthermore, 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. In the European Union, about 12,200 new cases and 2,600 deaths occurred in 2012 as a result of Hodgkin lymphoma.

Combination brentuximab vedotin + nivolumab
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical Hodgkin lymphoma. Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to help restore anti-tumor immune response, and based on recently published data, classical Hodgkin lymphoma (cHL) is ideally suited to therapy with checkpoint inhibitors. One reason being that in Reed-Sternberg cells, the near uniform upregulation of programmed death-ligands 1 and 2 (PD-L1 and PD-L2) result from copy number alterations in chromosome 9p24.1.

The combination of the two agents are not approved in combination for the treatment of relapsed or refractory classical Hodgkin lymphoma or for other indications.

“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 additive activity,” explained Alex Herrera, M.D., lead trial investigator and assistant professor at the City of Hope, Duarte, California.

“The interim results support further exploration of this novel regimen, free of traditional chemotherapy,” Herrera added.

“We are evaluating [brentuximab vedotin] in novel combinations in order to identify potential treatment regimens for patients with CD30-expressing lymphomas,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics.

“We are pleased to share updated interim results from this ongoing phase I/II clinical trial evaluating [brentuximab vedotin] in combination with nivolumab in relapsed or refractory Hodgkin lymphoma patients. Since our first patient treated with the combination regimen, the data continue to demonstrate encouraging activity with an acceptable safety profile. These updated data support findings first presented at the annual meeting of the American Society of Hematology (ASH) held in December 2016. We have nearly doubled the number of patients in our trial evaluating the brentuximab vedotin/nivolumab combination strategy and recently announced a collaboration with BMS to initiate a pivotal phase 3 clinical trial in relapsed HL patients in mid-2017.” [2]

“Bristol-Myers Squibb continues to strengthen our broad Immuno-Oncology and hematology development programs for nivolumab,” noted Fouad Namouni, M.D., head of Oncology Development, Bristol-Myers Squibb.

“Our continued partnership with Seattle Genetics, combines our deep I-O experience and shared commitment to innovative combination treatment options that have the potential to improve the lives of patients impacted by blood cancers. Welook forward to further evaluation of [brentuximab vedotin] in combination with nivolumab for the treatment of relapsed Hodgkin lymphoma,” Namouni added.

Trial Design
Data were reported from 62 patients with RR classical HL after failure offrontline therapy who received the combination regimen of brentuximab vedotin plus nivolumab. 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 36 years. Forty-five percent of patients had primary refractory disease and 55% progressed after responding to frontline therapy, among whom 90% received standard of care frontline treatment ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine).

Key findings
Of 59 response-evaluable patients, 50 patients (85%) had an objective response, including 37 patients (63%) with a complete response and 13 patients (22%) with a partial response. Five patients (8%) had stable disease and four patients (7%) had progressive disease.

Of the 62 patients enrolled, 61 patients (98%) received one or more dose of the study therapies. No patients remain on treatment, 58 patients (94%) have completed treatment and four patients (6%) discontinued prior to the end of treatment.

At the time of data analysis in the ongoing trial, 37 patients (60%) initiated an ASCT and 12 patients (19%) received an alternative salvage therapy subsequent to combination therapy. No unusual post-ASCT adverse events were reported. Preliminary analysis shows no impact of brentuximab vedotin and nivolumab combination on stem cell mobilization or engraftment.

Prior to ASCT, the most common adverse events of any grade occurring in more than 25% of patients were nausea (56%); fatigue (43%); infusion-related reactions (IRRs, 36%); pruritus (31%); headache (28%); and diarrhea, rash and vomiting (all at 26%). Treatment-related serious adverse events occurred in five patients (8%), including pneumonitis and pyrexia (two patients each) and colitis, malaise, nausea, pneumonia, respiratory failure and sepsis (1% patient each).

Infusion related reactions (IRRs) were observed in 41% of patients. All IRRs were Grade 3 or less, with the rate of Grade 3 IRRs less than 5%.

Ongoing trials
Brentuximab vedotin and nivolumab are being evaluated as combination therapy in multiple ongoing clinical trials. In addition to the study presented during the 14th-ICML, a pivotal phase III clinical trial evaluating brentuximab vedotin in combination with nivolumab compared to brentuximab vedotin alone in relapsed/refractory HL patients is planned to begin enrollment in mid-2017.

In addition, a trial titled “A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab Vedotin to Treat Non-Hodgkin Lymphomas” 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. The companies recently extended the clinical evaluation of brentuximab vedotin and nivolumab into a clinical trial evaluating the combination as frontline treatment for older Hodgkin lymphoma patients.

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