Lymphoma - Therapy with Biologic Agents, excluding Pre-Clinical Models: Novel approaches for T Cell and Mantle Cell Lymphoma
Complete Remissions with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma
Andrei R. Shustov, MD*,1,
Ranjana Advani, MD2,
Pauline Brice, MD*,3,
Nancy L. Bartlett, MD4,
Joseph D. Rosenblatt, MD5,
Tim Illidge, MD*,6,
Jeffrey Matous, MD7,
Radhakrishnan Ramchandren, MD8,
Michelle A. Fanale, MD9,
Joseph M. Connors, MD10,
Yin Yang, MS*,11,
Eric L. Sievers, MD11,
Dana A. Kennedy, PharmD*,11 and
Barbara Pro, MD*,12
1 Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, WA, USA, 2 Stanford University Medical Center, Stanford, CA, USA, 3 Hôpital Saint-Louis, Paris, France, 4 Washington University School of Medicine, St. Louis, MO, USA, 5 Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA, 6 Christie Hospital NHS, Manchester, United Kingdom, 7 Rocky Mountain Cancer Center, Denver, CO, USA, 8 Karmanos Cancer Institute, Detroit, MI, USA, 9 MD Anderson Cancer Center, Houston, TX, USA, 10 British Columbia Cancer Agency, Vancouver, BC, Canada, 11 Seattle Genetics, Inc., Bothell, WA, USA, 12 Fox Chase Cancer Center, Philadelphia, PA, USA
Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-expressingmalignancy comprising approximately 2–3% of all casesof non-Hodgkin lymphoma. The antibody-drug conjugate (ADC) brentuximabvedotin (SGN-35) delivers the highly potent antimicrotubuleagent monomethyl auristatin E (MMAE) to CD30-positive malignantcells by binding specifically to CD30 on the cell surface andreleasing MMAE inside the cell via lysosomal degradation. Bindingof MMAE to tubulin disrupts the microtubule network within thecell, induces cell cycle arrest, and results in apoptotic deathof the CD30-expressing tumor cell. In phase 1 studies, brentuximabvedotin demonstrated good tolerability and notable antitumoractivity in patients with relapsed or refractory sALCL: 6 of7 treated patients achieved complete remissions (CR).
Methods: A phase 2, single-arm, multicenter study was conducted to evaluatethe efficacy and safety of brentuximab vedotin in patients withrelapsed or refractory sALCL. Brentuximab vedotin 1.8 mg/kgwas administered every 3 weeks as a 30-minute outpatient IVinfusion for up to 16 cycles of treatment. Determination ofantitumor efficacy was based on objective response assessmentsaccording to the Revised Response Criteria for Malignant Lymphoma(Cheson 2007).
Results: A total of 58 patients were treated in this study; interim dataare presented for the first 30 treated patients. 53% of patientswere female and median age was 55 years (range 14–71).The majority of patients had ALK-1 negative tumor (70%, or n=21)and 4 patients (13%) had bone marrow involvement at baseline.The median number of prior chemotherapy regimens was 2 (range1–6) and 8 patients (27%) had failed previous autologoushematopoietic stem cell transplant (SCT). 19 patients (63%)had primary refractory disease, and 16 patients (53%) had notresponded to the most recent prior therapy. The objective responserate (ORR) by investigator assessment was 87%; 57% of patientsachieved a CR (n=17) and 30% of patients achieved a partialremission (PR; n=9). The remaining patients had stable disease(n=3) or were not evaluable for response (n=1). Similar proportionsof ALK-1 negative and ALK-1 positive patients achieved CR andPR. Reduction in tumor burden was observed in 97% of patients.The median time to objective response was 6 weeks (range 5–12)and the duration of objective responses currently range from4–36 weeks, with responses ongoing in 18 patients. B symptomsresolved in 9 of 10 patients (90%) who had these symptoms atbaseline. After achieving a CR with brentuximab vedotin, 10patients (33%) went on to receive an autologous or allogeneicSCT. The most common (>20%) adverse events (AEs) of any gradewere nausea (47%), diarrhea (40%), peripheral sensory neuropathy(40%), pyrexia (33%), dyspnea (30%), fatigue (27%), insomnia(23%), and neutropenia (23%). Grade 3/4 AEs considered relatedto brentuximab vedotin observed in >1 patient were neutropenia(17%), peripheral sensory neuropathy (13%), diarrhea (7%), andanemia (7%); no treatment-related Grade 5 events were observed.7 patients (23%) discontinued treatment due to an AE.
Conclusion: In this interim analysis of 30 patients with relapsed or refractorysALCL, the investigator-assessed ORR was 87% and the CR ratewas 57%. Brentuximab vedotin treatment was associated with manageableAEs; the most common in the study were nausea, diarrhea, andperipheral sensory neuropathy. The rate of complete remissionsobserved thus far in this study with single-agent treatmentsuggests that brentuximab vedotin has potential for the treatmentof sALCL. Results of the independent assessment of responsefor all patients, duration of response, progression-free survival,and updated safety data will be presented at the meeting.
Disclosures:Shustov:Seattle Genetics, Inc.: Research Funding, SteeringCommittee member. Off Label Use: The clinical trial uses aninvestigational drug, brentuximab vedotin (SGN-35). Advani:Seattle Genetics, Inc.: Research Funding. Brice:Seattle Genetics,Inc.: Research Funding. Bartlett:Seattle Genetics, Inc.: ResearchFunding. Rosenblatt:Seattle Genetics, Inc.: Research Funding.Illidge:Seattle Genetics, Inc.: Research Funding; Roche: Consultancy;Biogen Idec: Consultancy; Amgen: Consultancy. Matous:SeattleGenetics, Inc.: Research Funding; Celgene: Honoraria, SpeakersBureau; Millennium: Speakers Bureau; Cephalon: Speakers Bureau.Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics,Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment.Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership.Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership.Pro:Seattle Genetics, Inc.: Membership on an entity's Boardof Directors or advisory committees, Research Funding.
* Asterisk with author names denotes non-ASH members.