Interim Results from Ongoing Studies of Brentuximab Vedotin + Nivolumab in Frontline or Relapsed Hodgkin Lymphoma Presented at ISHL 2018

Multiple presentations evaluating brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda*) across a broad range of Hodgkin lymphoma (HL) settings were presented at the 11th International Symposium on Hodgkin Lymphoma (ISHL) taking place in Cologne, Germany, October 27-29, 2018.  This year’s presentations will highlighted Phase III and other clinical data from brentuximab vedotin and continue to build upon our research in CD30-positive lymphoma.

More than 1,100 delegates from over 70 countries participated in an intensive scientific discourse organized by the German Hodgkin Study Group (GHSG).

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 8,500 cases of Hodgkin lymphoma will be diagnosed in the United States during 2018 and more than 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.

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After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma…

Trial evaluation
The data presented at the 11th International Symposium on Hodgkin Lymphoma included both encore and additional analyses from the Phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline Stage III or IV classical HL adult patients, which formed the basis of U.S. Food and Drug Administration (FDA) approval in this indication in March 2018.

Interim results will be presented from two ongoing clinical trials evaluating brentuximab vedotin in combination with nivolumab (Opdivo®; Bristol-Myers Squibb Company), including in newly diagnosed older HL patients.

Finally, five-year follow-up from the phase III AETHERA clinical trial were presented.

Antibody-drug Conjugate
Bentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL that plays a role in tumor pathogenesis.  The agent uses a protease-cleavable linker system that is designed to be stable in the bloodstream but to release monomethyl auristatin E (MMAE), a microtubule disrupting agent, upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin is being evaluated globally as the foundation of therapy for HL in more than 50 ongoing clinical trials. Brentuximab vedotin and nivolumab are not approved in combination for the treatment of HL.

Progress
“After more than a decade of dedicated clinical research with brentuximab vedotin, we have made significant progress in improving the treatment outcomes for patients with Hodgkin lymphoma,” said Nancy Whiting, Pharm.D., Senior Vice President, Clinical Development and Global Medical Affairs at Seattle Genetics.

“At ISHL, we [presented] additional analyses from the ECHELON-1 trial, which demonstrated that Brentuximab vedotin plus AVD improves upon a frontline standard of care regimen, ABVD, in advanced patients and resulted in the first change in advanced stage HL in over 40 years. In addition, three oral presentations will highlight brentuximab vedotin plus nivolumab combination data in frontline and relapsed/refractory HL and five-year data from the phase III AETHERA trial. We are pleased to share these results from our broad brentuximab vedotin clinical development program with the Hodgkin lymphoma community.”

“The presented data a continue to reinforce our dedication to advancing treatment for those affected by Hodgkin lymphoma,” said Jesús Gómez-Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.

“[Overall,] the progress we have made in the development of brentuximab vedotin serves as a true testament to the leadership role we have established in the treatment of CD30-positive malignancies, which confirm the long-term benefits of brentuximab vedotin across treatment lines and support its role as an important targeted therapy for Hodgkin lymphoma,” he added.

Analyses
Data from four analyses of the phase III ECHELON-1 clinical trial were be presented at ISHL. Among the presentations are an oral and poster presentation included an analysis from the ECHELON-1 study (Abstract #0038) showing PFS data per investigator that is consistent with the previously reported modified PFS data per Independent Review Facility (IRF).

The ECHELON-1 abstracts included the following:

• Frontline brentuximab vedotin plus chemotherapy exhibits superior modified progression-free survival vs chemotherapy alone in patients with stage III or IV Hodgkin lymphoma: Phase III ECHELON-1 study (Abstract #0038, oral presentation and poster on Monday, October 29 at 07:30-07:50 CEST)
• Population pharmacokinetic modeling and exposure-response assessment of brentuximab vedotin efficacy and safety in patients with advanced classical Hodgkin lymphoma from the Phase III ECHELON-1 study (Abstract #0137, poster presentation)
• Serum sCD30 and TARC do not correlate with PET-based response assessment in patients with stage III or IV classical Hodgkin lymphoma (cHL): phase III ECHELON-1 study of brentuximab vedotin plus chemotherapy vs. chemotherapy alone (Abstract #0159, poster presentation)
• Brentuximab vedotin plus chemotherapy in high risk advanced-stage classical Hodgkin lymphoma (cHL) patients: Results of pre-specified sub-group analyses from the ECHELON-1 study (Abstract #0136, poster presentation)

Combination
Additional data presentations at 11th International Symposium on Hodgkin Lymphoma also included the results from a follow-up results from the Phase I/II study with brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin Lymphoma  (Abstract #0005, oral presentation on Monday, October 29 at 14:40-14:50 CEST)

Thi presentation included data from 62 patients with relapsed or refractory HL who received the combination regimen of brentuximab vedotin plus nivolumab after failure of frontline therapy. In this study 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 37 years. The majority of patients (95%) 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 were presented in an oral presentation by Alex Herrera, M.D., Assistant Professor at the City of Hope Medical Center, Duarte, California.

Herrera showed that of 61 response-evaluable patients, 49 patients (80%) had an objective response, including 37 patients (61%) with a complete response and 12 patients (20 percent) with a partial response.
Of the 61 response-evaluable patients, the estimated 21-month overall survival (OS) and PFS were 95 % and 82%, respectively.

The median follow-up time was 21.8 months and both median OS and PFS were not yet reached. Of 42 patients who underwent ASCT directly after treatment with brentuximab vedotin plus nivolumab, estimated PFS at 21-months was 97 percent and median PFS was not yet reached.

PFS was evaluated by response to treatment. The estimated PFS at 21-months for patients with a complete response was 97%, for patients with a partial response was 83% and patients with stable disease was 50 percent.

As previously reported, the most common adverse events (AEs) of any grade occurring prior to ASCT or subsequent salvage therapy in at least 20% of patients were nausea, infusion-related reaction (IRR), fatigue, pruritus, diarrhea, headache, vomiting, cough, pyrexia, dyspnea and nasal congestion.

Combination in patients older than 60 years
Another presentation discussed the results from a phase II study of frontline brentuximab vedotin plus nivolumab in patients with Hodgkin Lymphoma aged ≥60 years (Abstract #0153, oral presentation on Monday, October 29 at 15:05-15:15 CEST).

Jonathan Friedberg, M.D., Director of the University of Rochester Medical Center, NY and presented the interim results from an ongoing Phase II clinical trial evaluating brentuximab vedotin in combination with nivolumab as frontline therapy for HL patients age 60 years or older. The reported results included data from 14 patients. The median age of patients was 71.5 years. The majority of patients (79%) had stage III/IV disease at the time of diagnosis.

Friedberg showed that of 11 response-evaluable patients with a median follow-up time of eight months, nine patients (82%) had an objective response, including six patients (55%) with a complete response and three patients (27%) with a partial response. In addition, two patients (18%) had stable disease which equates to all 11 patients (100%) experiencing disease control (complete response + partial response + stable disease) as a result of treatment with brentuximab vedotin in combination with nivolumab.

The most common Adverse Events of any grade occurring in at least 25% of patients were fatigue, diarrhea, constipation, nausea, arthralgia, chills, decreased appetite, pyrexia, IRR, aspartate aminotransferase increased and peripheral sensory neuropathy.

Grade 3 or higher adverse events occurred in seven patients (50%), and the most common were peripheral neuropathy and lipase increased (three patients each); nausea and alanine aminotransferase increased (two patients each).

Five patients (36%) had IRRs, with the majority of symptoms at Grade 1 and there were no Grade 3 or higher symptoms. Four patients (29%) were treated with corticosteroid and no patients discontinued treatment due to an IRR.

Consolidation after Autologous Stem-Cell Transplantation
Five-Year Progression-Free Survival Outcomes from a Pivotal Phase III Study of Consolidative Brentuximab Vedotin after Autologous Stem-Cell Transplantation (ASCT) in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression (AETHERA) (Abstract #0110, oral presentation on Monday, October 29 at 17:10-17:20 CEST)

The five-year follow-up efficacy and safety data from the Phase III AETHERA clinical trial designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with classical HL who were at high risk of relapse or progression were presented by Craig Moskowitz, M.D., Physician in Chief, Sylvester Comprehensive Cancer Center, University of Miami.

Brentuximab vedotin was approved by the FDA in August 2015 for the treatment of adult patients with classical HL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

Moskowitz showed that the five-year PFS rate per investigator was 59% in the brentuximab vedotin arm compared to 41% in the placebo arm. Median PFS per investigator was not yet reached in the brentuximab vedotin arm versus 15.8 months in the placebo arm. The hazard ratio was 0.521 indicating a 48% reduction in the risk of progression or death with treatment of brentuximab vedotin compared to placebo.

Fewer patients in the brentuximab vedotin arm of the study received subsequent anti-cancer therapies versus the placebo arm (32% versus 54%, respectively). In addition, fewer patients in the brentuximab vedotin arm received allogeneic stem-cell transplants versus the placebo arm (17 patients versus 31 patients).

A PFS analysis evaluating subgroups included patients in the brentuximab vedotin arm with either two or more or three or more risk factors, showed patients with a greater number of risk factors for relapse post-ASCT appeared to have the greatest benefit from brentuximab vedotin consolidation therapy. In both subgroups evaluating either two or more or three or more risk factors, median PFS was not reached in the brentuximab vedotin arm and was 9.7 months and 6.3 months, respectively, in the placebo arm.
In the brentuximab vedotin arm, 112 patients (67%) reported peripheral neuropathy.

To date, 90% of these patients had resolution or improvement in symptoms, with 73% having complete resolution.

* 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.