Brentuximab Vedotin Administered Before, During, and After Multi-Agent Chemotherapy In Patients (pts) With Newly-Diagnosed CD30+ Mature T- and NK-Cell Lymphomas
Authors: Fanale Michelle A. , Horwitz Steven M. , Forero-Torres Andres , Bartlett Nancy L. , Advani Ranjana H. , Pro Barbara , Chen Robert , Davies Andrew , Illidge Tim , Huebner Dirk , Kennedy Dana A. , Shustov Andrei R. 
Published: October 2019

Abstract

Background
Mature T/NK-cell lymphomas comprise a subset of aggressive non-Hodgkin lymphomas. Some of these subtypes are known to express CD30, including systemic anaplastic large cell lymphoma (sALCL) where CD30 expression is pathognomonic. Few advances have occurred in the frontline treatment of sALCL and other T-cell lymphomas over the past 30 years, with treatment typically consisting of anthracycline-containing regimens such as CHOP. Overall outcomes with frontline therapy are poor, with a complete remission (CR) rate of 39–53% (Reimer 2009; D’Amore 2012) and a 5-year overall survival rate of 12–49%, depending on subtype (Vose 2008). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Efficacy was demonstrated in a pivotal phase 2 study of relapsed sALCL pts, where an objective response rate (ORR) of 86% and a CR rate of 57% were observed (Pro 2012).

Methods
A total of 39 pts were enrolled in this phase 1, open-label study designed to assess the safety and efficacy of brentuximab vedotin administered sequentially with standard-dose CHOP or in combination with CHP (CHOP without vincristine) (A+CHP) for the frontline treatment of sALCL and other CD30+ mature T/NK-cell lymphomas (ClinicalTrials.gov NCT01309789). ALK+ sALCL pts were required to have an IPI score ≥2. Pts in Arm 1 received sequential treatment (q3wk): 2 cycles of 1.8 mg/kg brentuximab vedotin followed by 6 cycles of CHOP. Arm 2 was designed to determine the recommended dose of brentuximab vedotin in A+CHP to be evaluated in Arm 3 (6 cycles q3wk). Responders were eligible to receive single-agent brentuximab vedotin (1.8 mg/kg q3wk) for 8–10 additional cycles (16 total cycles) in all 3 arms.

Results
On Arm 1, 13 pts received sequential treatment with brentuximab vedotin and CHOP. Pts had a median age of 62 years (range, 23–81). All pts were diagnosed with sALCL (10 ALK–). Following initial treatment with single-agent brentuximab vedotin, 13 pts (100%) achieved an objective response (CR rate 38%). At the end of subsequent treatment with CHOP, 11 of 13 pts (85%) achieved an objective response (CR rate 62%). Treatment-emergent adverse events (TEAEs) (≥40%) included peripheral sensory neuropathy, nausea, fatigue, vomiting, dyspnea, constipation, and peripheral edema. TEAEs with a severity ≥ Grade 3 (≥10%) included febrile neutropenia, anemia, neutropenia, peripheral sensory neuropathy, constipation, and fatigue. Following sequential treatment, 12 of 13 pts remained on-treatment and received single-agent brentuximab vedotin. After a median observation time of 23 months, the 1-year PFS rate was 77% (95% CI 44, 92).
The remaining 26 pts received combination treatment with A+CHP on Arms 2 and 3. The median age of pts was 56 years (range, 21–82). sALCL was diagnosed in 19 pts (16 ALK–). Other diagnoses included 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 maximum tolerated dose of brentuximab vedotin in A+CHP was not exceeded at 1.8 mg/kg IV, based on 1 DLT (Grade 3 rash). 23 of 26 pts completed 6 cycles of A+CHP; 21 of these pts went on to receive subsequent single-agent brentuximab vedotin treatment. The median number of brentuximab vedotin cycles, including combination treatment and subsequent monotherapy, was 13 (range, 3–16). TEAEs (≥40%) included peripheral sensory neuropathy, nausea, fatigue, diarrhea, alopecia, and dyspnea. TEAEs with a severity ≥ Grade 3 (≥10%) included febrile neutropenia, anemia, and neutropenia.
All 26 pts were assessed for a clinical response at the end of treatment with A+CHP. The ORR was 100%, with a CR rate of 88%. All 7 non-ALCL pts achieved a CR. After a median observation time of 16 months, the 1-year PFS rate was 71% (95% CI 49, 85).

Conclusions
At a dose of 1.8 mg/kg, brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, exhibited manageable toxicity in the treatment of newly-diagnosed CD30+ mature T/NK-cell lymphomas. A+CHP exhibited substantial antitumor activity, with an ORR of 100% (CR rate 88%) and a 1-year PFS rate of 71%. A phase 3 study comparing A+CHP to CHOP in the frontline treatment of mature T-cell lymphomas is underway (ClinicalTrials.gov NCT01777152).

Disclosures:
Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other. Off Label Use: Brentuximab vedotin is indicated 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. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other. Advani:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Davies:Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Honoraria. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Honoraria. Huebner:Takeda Cambridge US: Employment; Takeda: Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.