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Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. James's Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 50% of patients (pts) with sALCL develop recurrent disease after frontline treatment (Savage, 2008). Outcomes have historically been poor for pts with relapsed T-cell lymphomas, including sALCL, with a median overall survival (OS) and progression-free survival (PFS) of 5.5 months (mos) and 3.1 mos, respectively (Mak, 2013). A phase 2 study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Four-year follow-up data from this ongoing trial are presented. Methods: Pts received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. Response was assessed according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, response is now being assessed per the investigator. Survival and disease status are being assessed every 3 mos for 2 years, every 6 mos during years 3 to 5, and annually thereafter. CT scans are required if progression is suspected clinically. Results: The enrolled population of 58 pts was heavily pretreated with poor prognosis. As previously reported, 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). Pts had received a median of 2 prior systemic chemotherapy regimens (range, 1 to 6). Per investigator, the objective response rate (ORR) with brentuximab vedotin was 83% (48 pts) and the CR rate was 62% (36 pts), which were similar to the previously reported ORR (86%) and CR (59%) rates per IRF. At the time of this analysis (data cut June 2014), all pts had discontinued treatment and the median observation time from first dose was 46.3 mos (range, 0.8 to 57.7). Sixty-two percent (36 of 58) of pts were alive at last follow-up and the estimated 4-year survival rate by Kaplan-Meier analysis was 64% (95% CI: 51%, 76%). Median OS by best clinical response was CR (n=36): median not reached; partial remission (n=12): 11.6 mos; stable disease (n=4): 6.9 mos; and progressive disease (n=2): 4.2 mos. Median PFS was 20.0 mos (95% CI: 9.4, – [range, 0.8 to 54.9+]) for all pts and was not reached in pts with CR. Median PFS for pts with ALK-positive (25.5 mos) and ALK-negative (20.0 mos) disease were similar. Median PFS for pts with PET-negative disease at Cycle 4 (n=28) was not reached, whereas median PFS for pts with PET-positive disease at Cycle 4 (n=20) was 6.7 mos. After discontinuing treatment, 18 pts received a hematopoietic SCT (9 allogeneic, 9 autologous). The median PFS for the pts who achieved a CR and did not receive a post-treatment SCT (n=21) was 37.7 mos (95% CI: 14.1, - [range, 2.8 to 51.1+]) and the median PFS was not reached for the pts who achieved a CR and received a subsequent SCT (n=15) (95% CI: 9.5, - [range, 8.0 to 54.4+]). Of the 36 pts who achieved CR per the investigator, 17 (47%) remain in follow-up free of progression: 10 pts received a consolidative SCT following treatment with brentuximab vedotin and 7 pts received no further therapy after completing brentuximab vedotin treatment. As previously reported, adverse events (AEs) in ≥20% of pts were peripheral sensory neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, and neutropenia. AEs ≥ Grade 3 that occurred in ≥5% of pts were neutropenia, thrombocytopenia, peripheral sensory neuropathy, anemia, recurrent ALCL, and fatigue. Conclusions: After a median observation time of approximately 4 years from first dose of brentuximab vedotin, the 4-year survival rate was 64%. Forty-seven percent of patients with CR remain in follow-up with no evidence of progression, suggesting that brentuximab vedotin treatment may be curative for some patients. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Figure 1 Figure 1. Disclosures Pro: Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Other, Research Funding. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Other, Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Ramchandern:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding. Wang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Research Funding.

Background Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive aggressive subtype of mature T-cell lymphoma. Approximately 40–65% of patients (pts) with sALCL develop recurrent disease after frontline treatment. Outcomes are poor for pts with relapsed T cell lymphomas, including sALCL, with a median overall survival (OS) of 7.0 mos (Mak et al, 2013). Few effective therapies are available to address this unmet need. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising a CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. A phase 2 study evaluated the efficacy and safety of brentuximab vedotin in 58 pts with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047). Long-term follow-up data from this ongoing trial are presented. Methods Pts 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). Results In this heavily pre-treated pt population with poor prognosis, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 mos of frontline therapy), 26% had failed a prior autologous stem cell transplant (SCT), and 72% had ALK-negative disease. As previously reported, the ORR with brentuximab vedotin was 86% (50 of 58 pts) and the CR rate was 59% (34 of 58 pts). At the time of this analysis (datacut June 2013), all pts had discontinued treatment and the median observation time from first dose was 33.4 mos (range, 0.8-45.6). The median duration of objective response for all pts was 13.2 mos (95% CI: 5.7, 26.3) and the median duration of response for pts who obtained a CR was 26.3 mos (95% CI: 13.2, -). Of the 34 pts who achieved a CR, 16 (47%) remained in remission at the time of this analysis. Thirty-seven of 58 pts (64%) were alive at the time of last follow up. The median progression-free survival (PFS) for all pts was 14.6 mos and the median OS has not yet been reached. The estimated 3-year survival rate was 63% (95% CI: 51%, 76%). Median OS for pts who obtained a CR has not yet been reached while median OS for pts who did not obtain a CR was 7.7 mos (95% CI: 4.5, 13.7). Median OS for pts with PET-negative disease at Cycle 4 has not yet been reached while median OS for pts with PET-positive disease at Cycle 4 was 14.6 mos. After discontinuing treatment in the study, 17 pts (29%) received a hematopoietic SCT (9 allogeneic, 8 autologous). The median PFS has not yet been met for the group of pts who achieved a CR and received a subsequent SCT (95% CI: 14.6, -), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 mos (95% CI: 8.4, 33.7). As previously reported, adverse events (AEs) in ≥20% of pts 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. Conclusions After a median observation time of 33.4 mos from first dose of brentuximab vedotin, 64% of pts with relapsed or refractory sALCL were alive at the time of last follow up and the median OS has not yet been reached. Pts who achieved a CR with brentuximab vedotin experienced longer OS than pts who did not achieve a CR and early PET-negative status appeared to be important for long-term survival. These long-term follow-up results further underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas, including sALCL (ClinicalTrials.gov #NCT01777152). Disclosures: Pro: Seattle Genetics, Inc.: Advisory/Scientific board membership and travel expenses Other, Consultancy, Research Funding. Advani:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Advisory/Scientific Board Membership and Travel Expenses Other, Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda: Equity Ownership; Takeda Cambridge US: Employment. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding, Speakers Bureau.