Four-Year Survival and Durability Results of Brentuximab Vedotin in Combination with CHP in the Frontline Treatment of Patients with CD30-Expressing Peripheral T-Cell Lymphomas
Authors: Fanale Michelle A , Horwitz Steven M , Forero-Torres Andres , Bartlett Nancy L , Advani Ranjana H , Pro Barbara , Chen Robert W , Davies Andrew J , Illidge Tim , Uttarwar Mayur , Huebner Dirk , Ren Hong , Shustov Andrei R 
Published: October 2019

Abstract
Background
Peripheral T-cell lymphomas (PTCLs) encompass ~10-15% of aggressive non-Hodgkin lymphomas. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or variations thereof, are the most commonly used treatment regimens with complete remission (CR) rates ranging from 39-55% (Reimer 2009, d'Amore 2012). With the exception of low international prognostic index (IPI)-anaplastic lymphoma kinase (ALK)-positive ALCL, with 4-year progression-free survival (PFS) and overall survival (OS) ranging from 25-35% and 30-40%, respectively (Ellin 2014). We previously reported the results of this phase 1 trial that evaluated brentuximab vedotin (BV) administered in sequence with CHOP, or in combination with CHP (CHOP without vincristine) in treatment-naive patients (pts) with CD30-expressing PTCL (NCT01309789). The combination therapy (BV+CHP) showed safety and activity at standard doses, with an objective response rate (ORR) of 100% and complete response (CR) rate of 88% (Fanale 2014). The most common adverse events (AEs) experienced by pts were nausea and peripheral sensory neuropathy (69% each). Four-year durability data and updated results on peripheral neuropathy (PN) resolution from the BV+CHP combination treatment arm are presented herein.
Methods
Adults with CD30-expressing PTCL, including systemic ALCL (anaplastic large cell lymphoma, ALK-negative, or ALK-positive with IPI score ≥2) were eligible for this study. CD30 expression for non-ALCL pts was defined as ≥1% CD30 expression in malignant cells. Pts on the combination treatment arm received 1.8 mg/kg BV and standard-dose CHP q3wk for up to 6 cycles. Pts who achieved at least a partial response (PR) following treatment could receive continued BV 1.8 mg/kg q3wk as single-agent for up to 10 additional cycles. Antitumor response was assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
Results
Twenty-six previously untreated pts received BV+CHP. Disease diagnoses included systemic ALCL (n=19; including ALK-negative, n=16 and ALK-positive, n=3), PTCL-NOS (n=2), angioimmunoblastic T-cell lymphoma (AITL, n=2), adult T-cell leukemia/lymphoma (ATLL, n=2), and enteropathy-associated T-cell lymphoma (EATL, n=1). Twenty-one of the 26 pts who achieved remission with combination treatment continued on to receive single-agent BV. Overall, the 26 pts received a median of 13 cycles (range, 3 to 16) of BV.
After a median observation period of 52 months (range 4.6 to 58.3) from first dose, 18 pts remain on study. The estimated 4-year PFS and OS rates are 52% (95% CI: 31, 69) and 80% (95% CI: 59, 91), respectively. The median PFS has not been reached (95% CI: 12.3, -). To date, 15 of 19 ALCL (3/3 ALK-positive, 12/16 ALK-negative), and 6 of 7 non-ALCL pts were alive at last follow-up. Five pts (19%) received subsequent treatment with single-agent BV in long-term follow-up and 3 pts received stem cell transplants (1 autologous, 2 allogeneic) for relapsed disease. There were no pts who underwent a consolidative stem cell transplant.
Of the 26 pts treated with combination therapy, 19 (73%) experienced PN. Of these pts, 95% (18 of 19) experienced complete resolution (8 pts), or some resolution or improvement (defined as a decrease by at least 1 grade from worst grade, 10 pts). Of the pts who experienced improvement, 1 pt each improved from Grade 3 to a lowest Grade 2 and from Grade 3 to a lowest Grade 1, and 5 pts improved from Grade 2 to a lowest Grade 1. The median time to resolution of PN symptoms was 5.7 months. Eleven pts had ongoing neuropathy at last follow-up, of which, 9 pts had Grade 1 severity and 2 pts had Grade 2.
Conclusions
These 4-year durability results demonstrate that among pts with PTCL, initial therapy with BV in combination with CHP can induce long-term remissions with a tolerable safety profile. A phase 3 randomized trial comparing BV+CHP with CHOP for the frontline treatment of CD30-expressing PTCL is ongoing (NCT01777152).
Progression-free Survival
Figure Figure.

Disclosures
Horwitz: Celgene: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Research Funding; Infinity: Research Funding; Huya: Consultancy; FortySeven: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Bartlett:Gilead: Consultancy. Pro:Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Davies:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Bayer: Research Funding; Karyopharma: Honoraria, Research Funding; Pfizer: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Uttarwar:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Ren:Seattle Genetics: Employment, Equity Ownership.