Retrospective Analysis of the Safety and Efficacy of Brentuximab Vedotin in Patients Aged 60 Years or Older with Relapsed or Refractory CD30+ Hematologic Malignancies
Authors: Fanale Michelle A. , Bartlett Nancy L. , Forero-Torres Andres , Younes Anas , Chen Robert W. , Friedberg Jonathan W. , Matous Jeffrey V. , Shustov Andrei R. , Smith Scott E. , Zain Jasmine , O'Meara Megan M. , Gopal Ajay K. 
Published: October 2019

Abstract
Abstract 3687

Background
Patients ≥60 years of age comprise a significant portion of the population with hematologic malignancies. In addition, advanced age is a known negative prognostic indicator in many cancers including CD30+ malignancies such as Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL). Novel treatments with significant antitumor activity and increased tolerability are needed in this patient population that is often underrepresented in clinical trials.
Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) comprised of the microtubule-disrupting agent monomethyl auristatin E (MMAE) conjugated to an antibody that binds human CD30. This ADC has been studied in 2 phase 2 single-arm studies of patients aged ≥12 years with relapsed or refractory CD30+ lymphomas (median age 36.5, 13% ≥60). Brentuximab vedotin (1.8 mg/kg) administered once per 3-week cycle demonstrated objective response rates (ORRs) of 75% and 86% and complete remission (CR) rates of 34% and 57%, in HL and sALCL patients respectively. These objective responses were durable with a median duration of 6.7 and 13.0 months, respectively. The 3 most common adverse events (AEs) in HL and sALCL patients were peripheral sensory neuropathy (42% HL, 41% sALCL), nausea (35% HL, 40% sALCL), and fatigue (34% HL, 38% sALCL). Grade ≥3 neutropenia was observed in 20% of HL patients and 21% of sALCL patients.

Methods
This study presents a retrospective analysis of a subset of 40 patients aged 60 years or older with relapsed or refractory CD30+ lymphomas who received brentuximab vedotin in 1 or more of 7 clinical studies. Patients enrolled in the hepatic/renal impairment arm of a brentuximab vedotin pharmacokinetics study were excluded. The dosing schedule was either weekly (range 0.6–1.0 mg/kg) or every 3 weeks (range 1.2–2.7 mg/kg) with most patients receiving 1.8 mg/kg IV every 3 weeks. Antitumor activity was assessed by best response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). AEs were continually monitored in all studies from the start of dosing to 30 days after the last dose.

Results
The median age of patients was 66 years (range 60–82). There were 22 sALCL patients and 15 HL patients (median age 66.5 and 68.0 years, respectively) in the analysis set. Three patients (8%) were diagnosed with other CD30+ lymphomas and had a median age of 62.0 years. The majority of patients were male (65%). Patients had received a median of 2.0 prior cancer-related systemic therapies (range 1–6) and 34 of 40 had received a prior stem cell transplant. Baseline B symptoms were reported in 8 patients (20%). Patients received a median of 7.5 cycles (range 1–22) of single-agent brentuximab vedotin treatment with a median dose intensity of 0.56 mg/kg/week (range 0.3–0.9). All sALCL patients and 53% of HL patients achieved an objective response (CR rate, 50% and 40%, respectively). Across diagnoses, the ORR was 78% with 43% of patients achieving a CR. The median duration of response was 13.0 months for sALCL patients and was not reached in HL patients at the time of analysis. Resolution of B symptoms was observed in half of the patients (4 of 8) who presented with baseline B symptoms.
Treatment-emergent AEs of any grade (incidence ≥30%) included fatigue (58%), peripheral sensory neuropathy (58%), and nausea (38%). Treatment-emergent AEs ≥ Grade 3 in severity (incidence ≥20%) included neutropenia (25%) and anemia (20%). Serious adverse events (SAEs) were reported in 53% of patients with the most common (≥10%) being mental status changes (10%). AEs leading to treatment discontinuation occurred in 30% of patients. Death occurred within 30 days of the last dose in 1 patient with the cause of death considered unrelated to brentuximab vedotin or disease. Overall, 30% of patients received growth-factor support.

Conclusions
Brentuximab vedotin showed substantial antitumor activity and evidence of B-symptom resolution in these patients ≥60 years of age. Antitumor activity and the durability of clinical responses were consistent with those observed in the phase 2 studies of patients aged ≥12 years. AEs of fatigue and sensory neuropathy were more frequent in the older population, while other AEs such as nausea and neutropenia occurred with a similar incidence as in the phase 2 studies. Future studies will explore the safety and efficacy of brentuximab vedotin in earlier lines of therapy for this underserved population.

Disclosures:
Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Friedberg:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Zain:Seattle Genetics, Inc.: Honoraria, Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding.