Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive malignancy that accounts for 2–5% of all non-Hodgkin lymphoma (NHL) cases. Approximately 40–65% of patients with sALCL develop recurrent disease after frontline treatment and few effective treatment options exist for this population. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); long-term follow-up data from this ongoing trial are presented.

Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).

58 patients were enrolled at 22 clinical sites in the US, Canada, and Europe. The median age was 52 years (range 14–76) and 57% were male. 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the ORR was 86% (50 of 58 patients) and the CR rate was 59% (34 of 58 patients). At the time of this analysis (datacut April 2012), all patients had discontinued treatment and the median observation time from first dose was 22.8 months (range, 0.8–32.2). The median duration of objective response for all patients was 13.2 months (range, 0.1–27.7+) and the median duration of response for patients who obtained a CR has not yet been met (range, 0.7–27.7+). Of the patients who achieved a CR, over half (18 of 34; 53%) were in continued remission at the time of this analysis. The median progression-free survival (PFS) for all patients was 14.6 months and the median overall survival has not yet been reached. After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The median PFS has not yet been met for the group of patients who achieved a CR and received a subsequent SCT (range, 8.1–29+), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 months (range, 2.6–26+). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity regardless of baseline disease characteristics, tumor burden, or prior treatment history. Median PFS did not appear to be influenced by ALK status; in the subgroup of ALK-positive patients (n=16) PFS was 14.6 months versus 14.3 months for ALK-negative patients (n=42). The median overall survival has not yet been met for either ALK-positive or ALK-negative patients. The most common (reported in ≥20% of patients) adverse events (AEs) observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined by a Standardised MedDRA Query; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in peripheral neuropathy has occurred in 79% of patients with neuropathy events (26 of 33 patients) and the median time to resolution or improvement was 13.4 weeks (range, 0.3–48.7).

34 of 58 patients (59%) with relapsed or refractory sALCL obtained a durable CR with brentuximab vedotin and treatment was associated with manageable toxicity. PFS did not appear to be influenced by ALK status. These long-term follow-up results underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is planned to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas.

Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. 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. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, 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.