Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up
Authors: Horwitz Steven M , Shustov Andrei R. , Forero-Torres Andres , Bartlett Nancy L , Advani Ranjana , Pro Barbara , Chen Robert , Davies Andrew J , Illidge Tim , Huebner Dirk , Kennedy Dana A. , Fanale Michelle A. 
Published: October 2019

Abstract
Background: Peripheral T-cell lymphomas (PTCL) encompass a subset of aggressive non-Hodgkin lymphomas. Many PTCL tumor cells express the surface marker CD30, including systemic anaplastic large cell lymphoma (ALCL) where CD30 is uniformly expressed. Multi-agent chemotherapy regimens provide inadequate long-term outcomes: complete remission (CR) rates range from 39-53% and 5-year overall survival (OS) rates are 12-49%, depending on subtype. Three-year progression-free survival (PFS) and OS rates are approximately 30% and <40% (excluding anaplastic lymphoma kinase [ALK] -positive), respectively (Vose 2008; Reimer 2009; D'Amore 2012). A phase 1 trial evaluated brentuximab vedotin (ADCETRIS®; BV), a CD30-directed antibody-drug conjugate, in sequence with CHOP or in combination with CHP (CHOP without vincristine) in treatment-naive pts with PTCL, including systemic ALCL (Fanale 2014; ClinicalTrials.gov NCT01309789). We are presenting updated durability data and peripheral neuropathy resolution from the combination-therapy arm of this trial.
Methods: The analysis set consisted of patients who received the combination treatment (tx) regimen (BV+CHP; 6 cycles, q3wk, IV). Patients who achieved at least a partial remission (PR) following BV + CHP could subsequently receive up to 10 additional cycles of single-agent BV (1.8 mg/kg q3wk). ALK+ systemic ALCL pts must have had an International Prognostic Index (IPI) score ≥2. Antitumor response assessments were per investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy endpoints included PFS and OS, which were estimated using Kaplan-Meier methodology.
Results: Twenty-six pts received BV + CHP combination treatment. Diagnoses included systemic ALCL (n=19; 3ALK+, 16 ALK-), peripheral T-cell lymphoma-NOS (n=2), angioimmunoblastic T-cell lymphoma (n=2), adult T-cell leukemia/lymphoma (n=2), and enteropathy-associated T-cell lymphoma (n=1). The objective response rate to tx was 100% and CR rate was 88%. Treatment-emergent adverse events (TEAEs) with a severity of at least Grade 3 (≥10% incidence) were febrile neutropenia, neutropenia, anemia and pulmonary embolism with 73% reporting any grade peripheral neuropathy.
At the time of this analysis, 20 pts remained on study for long term follow-up (LTFU). The median observation time from first dose was 38.7 months (range, 4.6 to 44.3). The 3-year OS rate was 80% (95% CI: 59, 91 months) and the median PFS was not reached (95% CI: 12.3, -). Twenty one pts received a median of 10 doses (range, 1 to 10) of BV post BV-CHP. Nine/19 (47%) ALCL and 5/7 (71%) non-ALCL pts have not experienced disease progression or death. A Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) was performed for peripheral neuropathy (PN). Eighteen of 19 (95%) patients who received combination therapy experienced either complete resolution (n=7, 37%) or improvement by at least 1 grade level (n=11, 58%) in neuropathy symptoms. There were a total of 44 PN events of which 23 (52%) resolved and 14 (32%) improved. Five pts (19%) who experienced disease progression after completing treatment received subsequent treatment with BV in LTFU, and 3 patients received stem cell transplants (1 autologous, 2 allogenic). There were no patients who received a consolidative stem cell transplant in first remission.
Conclusions: Durable remissions were observed with BV in combination with CHP in newly diagnosed pts with PTCL. After over 3 years of follow-up, clinical outcomes compare favorably with historical data in PTCL pts. An ongoing randomized trial with 450 pts is comparing BV+CHP with CHOP for the frontline treatment of CD30+ PTCL (ClinicalTrials.gov NCT01777152). Final resultsfrom this trial are expected in 2017 to 2018.
Progression-Free Survival: Brentuximab Vedotin in Combination with CHP
Figure 1. Figure 1.

Disclosures
Off Label Use: Brentuximab vedotin (BV) is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study evaluates the use of brentuximab vedotin as a frontline treatment in patients with systemic ALCL or CD30-positive mature T-cell and NK-cell neoplasms in combination with multiagent chemotherapy.. Shustov:Seattle Genetics: Research Funding. Forero-Torres:Seattle Genetics: Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Advani:Genetech: Consultancy; Seattle Genetics, Inc.: Research Funding. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Davies:Takeda: Honoraria; Seattle Genetics: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics,Inc: Employment, Equity Ownership, Honoraria, Speakers Bureau. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.