Hodgkin lymphoma: Phase 3 AETHERA clinical trial data reported

Takeda UK Ltd has reported data demonstrating that Hodgkin lymphoma (HL) patients at risk of relapse following an autologous stem cell transplant (ASCT) who received ADCETRIS (brentuximab vedotin) as consolidation therapy immediately after ASCT had significant improvement in progression-free survival (PFS) compared to patients who received placebo (median of 43 months versus 24 months, respectively; hazard ratio=0.57; p-value=0.001).¹ The data from the AETHERA trial was presented in an oral session at 4.30pm PT on 8th December at the 56th American Society of Hematology (ASH) Annual Meeting. Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical HL.¹ It has been approved in more than 45 countries for the treatment of relapsed or refractory HL and relapsed or refractory systemic anaplastic large cell lymphoma (sALCL) and is currently not approved in the AETHERA treatment setting.

"The AETHERA trial is the first Phase 3, comparative clinical trial for brentuximab vedotin and the positive results from this study establish the ability of brentuximab vedotin to prolong progression free survival in patients with high risk Hodgkin lymphoma who are undergoing an autologous stem cell transplant" said Karl Peggs, Reader in Stem Cell Transplantation and Immunotherapy, University College London. "The data suggest that patients with high risk Hodgkin lymphoma who are undergoing an autologous stem cell transplant may derive clinical benefit from consolidation treatment with brentuximab vedotin".

"The AETHERA data provide compelling evidence regarding the potential utility of brentuximab vedotin as consolidation therapy post-transplant in these Hodgkin lymphoma patients, and we look forward to submitting these data to health authorities around the world," said Michael Vasconcelles, M.D., Global Head, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company Limited. "Going forward, we are conducting a robust clinical development program to more fully understand the potential of CD30 targeting with brentuximab vedotin in frontline disease through our ongoing Phase 3 ECHELON-1 and ECHELON-2 trials in HL and mature T-cell lymphomas."

The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin Lymphoma (Abstract #673, oral presentation on 8th December, 2014)

The Phase 3 AETHERA trial was designed to evaluate the potential of single agent brentuximab vedotin to extend PFS post-ASCT in patients with HL who have at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included overall survival (OS), safety and tolerability. Eligible patients must have had a history of refractory HL, have relapsed within one year from receiving frontline chemotherapy and/or have had disease outside of the lymph nodes at the time of pre-ASCT relapse. These factors are consistently reported to be associated with poor prognosis after transplant. Patients received brentuximab vedotin or placebo every three weeks for up to approximately one year. This international multi-centre trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.¹

A total of 329 HL patients at risk of relapse were enrolled, including 165 on the brentuximab vedotin arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms, with an average of 12 cycles on the brentuximab vedotin arm and 11 cycles on the placebo arm. Key findings, which were highlighted by Dr. Moskowitz, include¹:

• The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility (IRF), with a hazard ratio of 0.57 and a p-value of 0.001. Median PFS per IRF was 43 months for patients who received brentuximab vedotin versus 24 months for patients who received placebo. The two-year PFS rate per IRF was 63 percent in the brentuximab vedotin arm compared to 51 percent in the placebo arm.
• Per investigator, the hazard ratio was 0.50. The two-year PFS rate per investigator was 65 percent in the brentuximab vedotin arm compared to 45 percent in the placebo arm. The median PFS per investigator has not yet been reached for patients who received brentuximab vedotin versus 16 months for patients who received placebo. Very few progression events have been observed beyond two years.
• The PFS benefit was consistent across all pre-specified subgroups, including primary refractory patients, patients who relapsed within twelve months of frontline therapy and patients who relapsed after twelve months with extranodal disease.
• Patients in both arms of the study who experienced disease progression received a variety of subsequent therapies. In the brentuximab vedotin arm, only eight of 51 patients (16 percent) receiving subsequent therapy were treated with brentuximab vedotin following relapse. In the placebo arm, 72 of 85 patients (85 percent) receiving subsequent therapy were treated with single agent brentuximab vedotin. Twenty-four patients in the placebo arm and 13 patients in the brentuximab vedotin arm received stem cell transplant as subsequent therapy, the majority of which were allogeneic transplants.
• OS data are immature, and no statistically significant difference in OS has been observed between the treatment arms (hazard ratio 1.15; p-value=0.62). A further analysis of overall survival is planned in 2016.
• The most common adverse events in the brentuximab vedotin arm were peripheral sensory neuropathy (56 percent), neutropenia (35 percent), upper respiratory tract infection (26 percent), fatigue (24 percent) and peripheral motor neuropathy (23 percent). The most common adverse events in the placebo arm were upper respiratory tract infection (23 percent), fatigue (18 percent) peripheral sensory neuropathy (16 percent), cough (16 percent) and neutropenia (12 percent). Eighty-five percent of patients with peripheral neuropathy on the brentuximab vedotin arm had resolution or improvement in symptoms with a median time to improvement of 23.4 weeks.
• Grade 3 or higher adverse events in the brentuximab vedotin arm included neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, nausea, fatigue and diarrhoea. Grade 3 or higher adverse events in the placebo arm included neutropenia, fatigue, peripheral motor neuropathy, diarrhoea and peripheral sensory neuropathy. No Grade 4 peripheral neuropathy events occurred.
• One death occurred within 30 days of brentuximab vedotin treatment from treatment-related acute respiratory distress syndrome (ARDS) associated with pneumonitis. One death occurred on the brentuximab vedotin arm at Day 40 from ARDS following an episode of treatment-related acute pancreatitis, which had resolved at the time of death.

About Adcetris (brentuximab vedotin)

Brentuximab vedotin is an innovative antibody-drug conjugate composed of a CD30-directed monoclonal antibody (recombinant chimeric immunoglobulin G1 [IgG1], produced by recombinant DNA technology in Chinese Hamster ovary cells) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Once inside the cell, the MMAE is released from the antibody and the cancer cell is destroyed. The innovative mechanism of action and precise cancer cell targeting means that patients generally cope better with the side effects. ²

Brentuximab vedotin was granted a conditional licence in 2012 by the European Medicines Agency (EMA). A conditional licence is granted to a medicinal product that fulfils an unmet medical need when the benefit to public health of immediate availability outweighs the risk, despite the fact that additional data are still required.

Further information on brentuximab vedotin can be found in the Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL) which can be obtained at www.medicines.org.uk.

About Adcetris® (brentuximab vedotin) trials

The pivotal phase II HL and sALCL trials were designed to assess the efficacy and safety of single-agent brentuximab vedotin in relapsed or refractory patients. Both trials have been published in the peer reviewed medical journal, Journal of Clinical Oncology, but patients are continuing to be followed up.^3,4

HL trial^3,5

Overall, 102 patients were enrolled in the HL trial and the median age of patients was 31 years. Patients had received a median of 3.5 (range 1-13) prior chemotherapy regimens and all patients had relapsed following a prior ASCT.

In the pivotal phase II trial for brentuximab vedotin, 75 percent of patients with relapsed or refractory HL, post ASCT, achieved the primary end point of objective response rate (ORR), with 33 percent achieving a complete remission (CR).

sALCL trial^4,6

Overall, 58 patients were enrolled in the sALCL trial and the median age of patients was 52 years. Patients had received a median of two (range 1-6) prior chemotherapy regimens and 26 percent had failed prior ASCT.

In the pivotal phase II trial for brentuximab vedotin, 86 percent of patients with relapsed or refractory sALCL achieved the primary end point of objective response rate (ORR), with 59 percent achieving a complete remission (CR).