Huebner, Dirk

TPS8612 Background: Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, has conditional approval in Europe for relapsed/refractory (RR) CD30-positive HL following autologous stem cell transplant (ASCT) or following ≥2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ABVD, a common front-line regimen for advanced HL, achieves complete response (CR) rates of 70–80%. However, 10–20% of patients (pts) are refractory to front-line treatment and up to 35% relapse after front-line multi-modality therapy. In pts with relapsed HL post-ASCT, single-agent brentuximab vedotin yields an objective response rate of 75% (CR, 33%; Chen ASH 2012). In a phase 1 study in treatment-naïve HL pts, A+AVD was associated with manageable toxicity and a CR rate of 96%; brentuximab vedotin + ABVD was contraindicated due to pulmonary toxicity (Ansell ASH 2012). We hypothesized that substituting bleomycin with brentuximab vedotin would eliminate bleomycin-associated pulmonary toxicity and improve progression-free survival (PFS) compared to a standard ABVD regimen. Methods: This ongoing, open-label, randomized, multicenter study (NCT01712490) will compare A+AVD vs ABVD in 1040 pts with stage III/IV classical HL. Primary endpoint: modified (m) PFS (death, progression, and receipt of chemotherapy or radiotherapy by pts not in CR after completing A+AVD or ABVD will count as progression event). Key secondary endpoint: overall survival. Key inclusion criteria: histologically-confirmed previously untreated stage III/IV classical HL. Pts will be stratified by region and International Prognostic Score, and will be randomized 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD administered intravenously on Days 1 and 15 of 28-day cycles, for up to 6 cycles. Disease status and survival will be evaluated regularly until study closure. Safety assessments: incidence and severity of adverse events, changes to physical and laboratory tests. Clinical trial information: NCT01712490.

Abstract Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period. Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min 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). 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, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months. Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin. Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). Figure 1. Overall Survival Figure 1. Overall Survival Disclosures Chen: Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

Abstract Background Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory HL is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT). However, approximately 50% of pts experience relapse of HL after auto-SCT and this population represents a pronounced unmet need. In a 756-pt retrospective analysis, the median overall survival (OS) in HL pts who relapsed after auto-SCT was 2.4 years, as measured from the time of auto-SCT, with shorter time to relapse after auto-SCT being the most predictive factor for shortened survival (Arai 2013). Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. A pivotal phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in 102 pts with relapsed or refractory HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Data representing approximately 3 years of follow up from this ongoing trial are described, including characterization of patients who experienced long-term remissions. 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). Long-term follow-up assessments to determine survival and disease status occurred every 3 months (mos) for 2 years, every 6 mos during years 3 to 5, and annually thereafter. Results In this high-risk population with poor prognosis, the median time to relapse after auto-SCT was 6.7 mos (range, 0–131 mos). Pts received a median of 9 cycles of brentuximab vedotin and the ORR was 75% (76 of 102 pts), with complete remissions (CRs) in 33% of pts (n=34). As previously reported, the most common (≥15%) brentuximab vedotin-related adverse events of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At the time of this analysis (May 2013), the median observation time from first dose was 32.7 mos (range, 1.8 to 48.3 mos). Of the 102 pts enrolled, 51 (50%) were alive at the time of last follow up. The median OS was 40.5 mos (95% CI: 28.7, – [range, 1.8 to 48.3+ mos]) and the estimated 36-mo survival rate was 54% (95% CI: 44%, 64%). Median OS by best clinical response was CR (n=34): median not yet reached; partial remission (PR, n=42): 31.6 mos; stable disease (SD, n=22): 20.6 mos; and progressive disease (PD, n=3): 10.2 mos. Of the 51 pts who were alive at the time of this analysis, 14 remain in remission and have not started a new anti-cancer therapy other than 5 pts who received consolidative allo-SCT following brentuximab vedotin. Demographics/baseline characteristics of these 14 pts show that the majority are female (10/14; 71%) and white (12/14; 86%), with a median age of 26.5 years (range, 15–54). Eleven of the 14 pts had CRs and 3 had PRs following brentuximab vedotin; all 3 of the pts with PRs received subsequent allo-SCT. The observation time for the 14 pts who remain in remission ranges from 31.5 mos to 44.4 mos and their progression-free survival ranges from 27.2+ mos to 44.4+ mos. Additional characterization of the pts who achieved long-term remissions following brentuximab vedotin will be presented at the meeting. Conclusions After a median observation time of approximately 3 years from first dose of brentuximab vedotin, 50% of pts with relapsed or refractory HL were alive at the time of last follow up. The median OS was 40.5 mos. Fourteen patients remain in follow up with no evidence of lymphoma progression, providing early suggestion that a fraction of these patients may be cured. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for frontline treatment of HL (ClinicalTrials.gov #NCT01712490). Disclosures: Gopal: Biogen, Idec: Research Funding; Merck: Research Funding; BioMarin: Research Funding; Gilead: Research Funding; Emergent/Abbott: Research Funding; Pfizer: Research Funding; Cephalon/Teva: Research Funding; Janssen: Research Funding; Millennium: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; Piramal: Research Funding; Spectrum: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Trave expenses Other. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding; University of Miami: Employment. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Huebner:Takeda Cambridge US: Employment; Takeda: Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Incyte: Honoraria; Millennium: Honoraria; Pharmacyclics: Honoraria; Curis: Honoraria; Genentech: Research Funding; Gilead: Research Funding; Johnson and Johnson: Research Funding; Infinity: Research Funding.

Key Points A total of 38% of patients who achieved CR (13 of 34) on brentuximab vedotin have remained in remission for >5 years and may be cured. Nine of the 13 patients (9% of all enrolled patients) have remained in long-term remission without a consolidative allogeneic transplant.