Brentuximab Vedotin in Front-Line Therapy of Hodgkin Lymphoma (HL) and CD30-Expressing Peripheral T-Cell Lymphoma (PTCL) in Adults Age 60 and Above
Authors: Yasenchak Christopher A. , Bordoni Rodolfo , Yazbeck Victor , Patel-Donnelly Dipti , Larson Timothy , Newhook Trevor , Ho Linda , Mei Matthew 
Published: November 2019

Background

Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients >60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need.

Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment.

Study Design

Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction <45% or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease study equation.

Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review.

Disclosures

Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips & Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.