* Authors on the Steering Committee contributed equally to the oversight of the study, including study design and maintaining the quality of study conduct. CONTRIBUTORS Owen O'Connor, Barbara Pro, Tim Illidge and Lorenz Trumper formed the ECHELON-2 steering committee and contributed equally to the oversight of the study, including study design and maintaining the quality of study conduct.

The ECHELON-2 Trial: 5-year results of a randomized, phase 3 study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma * , Annals of Oncology (2022), doi: https://doi.org/10.1016/j.annonc.2021.12.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Introduction Despite improved response and survival for patients (pts) with follicular lymphoma (FL) receiving rituximab (R) plus chemotherapy, new options are needed. FL is typically characterized by the presence of chromosomal translocation t(14;18), which results in overexpression of the anti-apoptotic protein BCL-2. BCL-2 may also contribute to resistance to chemoimmunotherapy such as bendamustine+R (BR), a regimen commonly used in FL. Venetoclax (VEN), a selective, potent oral BCL-2 inhibitor, is in development for the treatment of B-cell malignancies. Preclinical and early clinical data suggest VEN+R or VEN+BR may improve response over R or chemotherapy alone and is feasible. This open-label study will assess efficacy and toxicity of VEN+R as well as VEN+BR vs BR alone, in pts with relapsed/refractory (R/R) FL (NCT02187861). Methods R/R pts (age ≥18 yrs, confirmed Gr 1-3a FL, ECOG PS 0-2, adequate hematologic function) were assigned (at investigators' discretion) to chemotherapy-free (chemo-free) or randomized to chemotherapy-containing (chemo) arms. Those in the chemo-free Arm (Arm A) received VEN 800mg daily for 1 yr + R (cycles [C] 1, 4, 6, 8, 10 and 12). After a safety run-in (9 pts at 600mg VEN daily + 6 cycles BR), those in the chemo Arm were randomized 1:1 to Arm B (VEN 800mg + 6 cycles BR) or C (BR only). The primary endpoint was complete response (CR) rate by PET-CT. Secondary endpoints include CR rate by CT and overall response rate. Response assessment was per Lugano non-Hodgkin lymphoma assessment (Cheson et al. 2014) 6-8 wks after D1 of C6 (or the cycle non-VEN agents were permanently discontinued: whichever came first). Results One hundred sixty-four pts were enrolled as of May 13, 2016 (Table 1); 53 chemo-free (Arm A) and 111 chemo (9 run-in; 51 Arm B; 51 Arm C). 61% were refractory to prior treatment: 79% Arm A; 56% safety run-in; 43% Arm B; 62% Arm C. One hundred fifty-three of 160 safety evaluable pts (94%) experienced any AE (Table 2). Common AEs (all grades): diarrhea (37%), neutropenia (29%), nausea (25%), fatigue (25%), and IRR (25%). Common AEs for Arm B vs Arm C: nausea (61% vs 38%), neutropenia (51% vs 26%), diarrhea (41% vs 12%), thrombocytopenia (39% vs 20%) and fatigue (37% vs 24%). Neutropenia and thrombocytopenia were the most common Gr 3-4 AEs among all groups. 40 pts had serious AE (SAEs): 14 (27%) Arm A; 4 (44%) run-in; 15 (31%) Arm B; 7 (14%) Arm C. SAEs in >1 pt in any arm: febrile neutropenia (2 run-in; 5 Arm B; 1 Arm C), pneumonia (2 Arm A; 1 Arm B), and LDH increase (2 Arm A). Laboratory tumor lysis syndrome (TLS) events occurred in 2 pts (1 Arm A; 1 Arm B): both manageable and resolved with no clinical complications. Five deaths occurred on study: 3 Arm A (colitis, pulmonary hemorrhage, PD), 1 Arm B (pneumonia), 1 Arm C (PD). Pts with AEs leading to dose interruptions or modification: 28 (54%) Arm A; 7 (78%) run-in; 37 (76%) Arm B; 12 (24%) Arm C. Pts with early drug discontinuations of VEN: 29 (56%) Arm A; 5 (56%) run-in; 11 (22%) Arm B. Early R discontinuations: 28 (54%) Arm A; 3 (33%) run-in; 7 (14%) Arm B; 5 (10%) Arm C. Early B discontinuations: 3 (33%) run-in; 7 (14%) Arm B; 4 (8%) Arm C. Efficacy by PET+CT for safety evaluable patients who reached an assessment event is shown in Table 3. Arm A had 17 (33%) responders with 14% CR. Arm A was predominantly refractory to last treatment (79%): among non-refractory pts (21%), ORR was 64% with 27% CR. There was 68% ORR in Arm B with 50% CR compared with 64% ORR with 41% CR in Arm C. 55 (51%) of chemo pts have yet to reach a response-relevant event. Correlation with expression of BCL-2 family members is pending. Conclusion Early results from the first study evaluating VEN+R and VEN+BR in pts with FL show that daily VEN 800mg has an acceptable benefit/risk ratio. As expected with the known VEN safety profile, both VEN+R and VEN+BR are associated with hematologic and GI toxicity, which appears manageable. Laboratory TLS was rare (<2%) and manageable with no clinical sequelae. Objective response with VEN+R is 33% even in a highly refractory pt population and 64% among non-refractory pts, providing a potential chemotherapy-free option for both groups. While early data shows VEN+BR is associated with more toxicity and some early treatment discontinuations compared with BR alone, data suggest it may be a tradeoff for increased CR and decreased PD. Future data will help determine whether continued VEN treatment beyond initial chemotherapy deepens response. Disclosures Zinzani: Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy. Rusconi:Janssen: Consultancy, Other: Congress attendance; Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance. Fleury:Novartis: Consultancy, Speakers Bureau; Lundbeck: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Pro:Celegene: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Hsu:Genetech, Inc.: Employment. Punnoose:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Hiddermann:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML &lt;60 years. A sub-group analysis of 46 patients with FLT3-ITD, indicated a trend for improved overall survival (OS) in the sorafenib (SOR) arm compared to placebo (PBO). Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR &lt; or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML