Abstract: 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

Abstract: Introduction The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized trial (AMLM16) combining the FLT3 inhibitor sorafenib (SOR) or placebo (PBO) with intensive induction and consolidation chemotherapy, followed by 12 months of maintenance therapy in patients with FLT3-ITD mutant AML. The clinical results of the AMLM16 study are detailed in a companion abstract co-submitted to ASH 2020. We hypothesized that the optimal time to administer sorafenib would be d4-10 of induction in order to limit overlap with anthracyclines on d1-3 and to avoid high FLT3 ligand (FLT3L) levels beyond d10, which could abrogate FLT3 on-target activity and diminish the therapeutic index. Key objectives of the correlative studies were to correlate in vivo SOR activity on suppression of FLT3 phosphorylation (P-FLT3) using the plasma inhibitory assay (PIA) with relapse risk and to assess for the presence of FLT3-ITD measurable residual disease (MRD) after therapy. Methods Patients aged 18-65 years with newly diagnosed AML (excluding APML) were enrolled to a National Blood Cancer Registry; those with a FLT3-ITD mutant: wild-type allelic ratio (AR) ≥ 0.05 were eligible for enrolment to the AMLM16 study. Patients were randomized 2:1 to SOR or PBO 400mg orally bd on d4-10 of induction and each consolidation cycle in combination with intensive chemotherapy and for 12 months as maintenance monotherapy. Serum FLT3-L levels were measured by ELISA, SOR and its metabolites by mass spectrometry. SOR mediated inhibition of FLT3 was measured in serum samples using the PIA as previously described (Levis, Blood 2006) in which P-FLT3 inhibition to ≤15% baseline is defined as response. Quantitation of FLT3-ITD levels by NGS was performed at study screening and after each induction and consolidation chemotherapy cycle. Quantitation was by amplicon-based sequencing which detected ITDs & gt;6 bp with a sensitivity of 0.001%: levels below and above this were termed measurable residual disease (MRD) negative and positive respectively. Prepared libraries were sequenced (Illumina) using 150 bp paired-end reads with a minimum coverage of 400,000 reads. Bioinformatics analysis was performed using getITD (Blätte, Leukemia, 2019). Results 98 evaluable patients were randomized to induction with either SOR (n=65) or PBO (n=33) with a FLT3-ITD AR ranging from 0.05 to 8.4. FLT3-ITD AR was ≥ 0.5 or ≥ 0.7 in 48% and 29%, respectively. During induction, FLT3-L levels increased by an average of 150-fold from d4 to d10 and a further 1.6-fold to d15, with a return to baseline by d28. Serial plasma samples to assess PIA were available for 63 patients (Fig A). Response to ≤15% on d10 (relative to d4) was observed in 88% of SOR patients, compared with 4.5% receiving PBO. The relapse risk was 32% and 62% among PIA responders and non-responders, respectively (Fig A). Among patients with PIA response to ≤15% by d10 (the last day of SOR/PBO), only 8.3% had evidence of a sustained PIA response by d15. Reduction of FLT3-ITD to undetectable levels (VAF & lt;0.001%) after induction, consolidation 1 and 2 was achieved in 43%, 63% and 77% of patients in the SOR arm and 32%, 59% and 75% in the PBO arm, respectively (Fig B, C). Patients with FLT3-ITD MRD detected or not detected after induction had a relapse risk of 54% vs 32%, respectively. Additional MRD results will be presented, along with serum SOR and metabolite levels. We compared the relationship between inhibition of P-FLT3 on d10 and bone marrow FLT3-ITD MRD after induction with relapse risk (Fig D, E). In the SOR arm, if P-FLT3 was not reduced to ≤15%, all patients had persistent FLT3-ITD MRD after induction and the relapse risk was 80% (Fig D). In contrast, if P-FLT3 inhibition was ≤15% and FLT3-ITD MRD not detected, the relapse risk was only 20%. In the PBO arm after induction, persistent and undetectable FLT3-ITD MRD (VAF & lt;0.001%) were associated with relapse risks of 81% vs 50%, respectively (Fig E). Conclusions These studies demonstrate that in vivo SOR inhibited P-FLT3 to ≤15% during induction in the majority of cases and was associated with reduced relapse risk. Persistent FLT3-ITD MRD post-induction was associated with a high relapse risk in both treatment arms. For patients receiving SOR, failure to reduce P-FLT3 response to ≤15% was associated with a high risk of persistent FLT3-ITD MRD and clinical relapse. Disclosures Anstee: Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. 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:AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties. Wei:Astra Zeneca: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Roche: Honoraria; Macrogenics: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Abstract: 8051 Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naïve (TN) and relapsed/refractory (R/R) patients with WM. Methods: Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Results: Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged 〉 65 years; 21% aged 〉 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusions: Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients was tolerable. Clinical trial information: NCT02343120 . [Table: see text]

Abstract: Purpose: Treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge, largely due to the genetic heterogeneity of these malignancies. Our study goal was to design a rational treatment strategy that simultaneously targets multiple disease drivers to provide safe, efficacious, and durable responses in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Experimental procedures and data summary: Venetoclax is a selective BCL-2 inhibitor that induces apoptosis and is efficacious in chronic lymphocytic leukemia; however, single-agent efficacy in other lymphoid neoplasms is limited. Using pharmacologic and genetic studies, we identified the pro-survival BCL-2 protein family member MCL-1 as a venetoclax resistance factor in NHL cell lines. We found that the monomethyl auristatin E (MMAE) payload of the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system, thus providing a strong rationale for combination with venetoclax. Mechanistically, polatuzumab vedotin combined with venetoclax promoted apoptotic NHL cell death. In NHL animal models, venetoclax, polatuzumab vedotin, and the anti-CD20 antibody obinutuzumab, that activates targeted antibody- and complement-dependent cell cytotoxicity, produced durable tumor regressions. In a phase 1b clinical trial, 33 patients with relapsed or refractory follicular lymphoma were evaluable for response over 6 dose levels with 19 complete responses and 6 partial responses (overall response rate 76%). All patients (8 of 8) treated with the recommended phase 2 regimen (venetoclax 800mg + polatuzumab vedotin 1.8mg/kg + obinutuzumab 1000mg) achieved complete responses at end of induction. The median duration of follow-up for all dose levels was 17.7 months. This triplet combination was well-tolerated by most patients and had an expected and acceptable safety profile. Conclusions: Our studies implicate MCL-1 as a key venetoclax resistance factor in NHL that can be overcome by polatuzumab vedotin, which promotes MCL-1 degradation. Pre-clinical NHL animal models and early clinical data confirmed that the combination of venetoclax, polatuzumab vedotin, and obinutuzumab is safe and promotes durable responses. Because MMAE and other anti-tubulin agents are likely not the only therapeutics that antagonize MCL-1, our study provides scientific rationale to pursue the broader strategy of identifying other therapeutics that similarly neutralize MCL-1 function. Such agents could be used in combination with venetoclax in other malignancies where MCL-1 is a venetoclax resistance factor. Our mechanism-based treatment regimen that directly targets oncogenic drivers in NHL patients may serve as a framework for treating other malignancies with complex etiologies. Citation Format: Dhara N. Amin, Rajat Bannerji, Raghuveer Singh Mali, Jason Oeh, Eva Lin, Anuradha Zindal, MaryAnn Go, Shang-Fan Yu, Maxwell Krem, Chris Arthur, Uwe Hahn, Anna M. Johnston, Vinit G. Karur, Nadia Khan, Paula Marlton, Tycel Phillips, Giuseppe Gritti, John F. Seymour, Monica Tani, Sam Yuen Yuen, Scott Martin, Matthew T. Chang, Christopher M. Rose, Victoria C. Pham, Elizabeth A. Lasater, Andrew G. Polson, YiMeng Chang, Jamie Hirata, Lisa Musick, Deepak Sampath, Christopher R. Flowers, Ingrid E. Wertz. Targeting BCL-2 and MCL-1 overcomes treatment resistance in relapsed and refractory non-Hodgkin lymphoma: Pre-clinical rationale and results from an open-label phase 1b study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT133.

Abstract: Inhibitors of Bruton’s tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Abstract: 7530 Background: About 40-50% of older patients (pts) with AML attain complete remission (CR) with induction chemotherapy (IC) but relapse is common.Effective, well-tolerated maintenance treatment (Tx) is needed for older pts in remission who are not eligible for hematopoietic stem cell transplant (HSCT). CC-486 is an oral hypomethylating agent that allows for extended dosing schedules ( 〉 7 days [d]/cycle) to sustain therapeutic activity. In the phase III placebo (PBO)-controlled QUAZAR AML-001 trial (NCT01757535), CC-486 maintenance therapy in pts with AML in first remission following IC produced significant improvements in overall and relapse-free survival. Here we report safety and tolerability findings among pt subgroups defined by age at study entry. Methods: Eligible pts were ≥ 55 yrs of age, with de novo or secondary AML, intermediate or poor risk cytogenetics, and ECOG PS ≤ 3; had achieved first CR or CRi after IC ± consolidation; and were not candidates for HSCT. Within 4 mo of CR/CRi, pts were randomized 1:1 to CC-486 300 mg or PBO QD on d 1–14 of repeated 28d Tx cycles. Safety was assessed across 3 age subgroups (≥ 55 to 〈 65, ≥ 65 to 〈 75, and ≥ 75 yrs) in pts who received ≥ 1 dose of study drug. Adverse events (AEs) were coded using MedDRA v. 22.0 and graded by NCI-CTCAE v. 4.0. Results: 469 pts ( 〉 99% of all enrolled pts) were evaluable for safety (CC-486 n = 236; PBO n = 233). Median age was 68 yrs (range 55-86). Age distribution was similar between the two Tx arms (Table). Between Tx arms, AE rates within each age stratum were similar to rates in the overall study population. The most common AEs (any grade) with CC-486 were GI events, which were more frequent than in the PBO arm across age groups. Within the CC-486 arm, AE rates were generally consistent across age groups, except for constipation, which was 〉 20% more frequent in pts aged ≥ 75 yrs, and thrombocytopenia, which was ≥ 20% less frequent in this group (Table). Overall, 13% and 4% of pts in the CC-486 and PBO groups discontinued Tx due to AEs. Conclusions: In QUAZAR AML-001, CC-486 was generally well tolerated in all age groups, including elderly pts aged ≥ 75 yrs. Clinical trial information: NCT01757535 . [Table: see text]

Abstract: Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

Abstract: 8007 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to receive ZANU (160 mg twice daily) or IBR (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received ZANU, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs 〉 3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory (R/R) WM. Primary analysis was planned to occur at ~ 12 months after last patient enrolled. Results: In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, except in the ZANU arm there were more elderly patients (aged 〉 75 years, 33.3% vs 22.2%) and more anemia (hemoglobin ≤110 g/L, 65.7% vs 53.5%). At a median follow-up of 19.4 months, the rate of CR+VGPR was 28.4% vs 19.2% with ZANU vs IBR, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events (AEs) leading to discontinuation or death were lower with ZANU. The rate of neutropenia was higher with ZANU (Table); however, grade ≥ 3 infection rates were similar (17.8% vs 19.4%). Conclusions: ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although not statistically significant, ZANU was associated with a higher CR+VGPR response rate, and demonstrated clinically meaningful advantages in safety and tolerability compared to IBR. Clinical trial information: NCT03053440 . [Table: see text]

Abstract: Objective This study examined the practices and attitudes of Australian biobanks regarding access to samples and data, as well as local and global networking with other biobanks. Methods This was a mixed-methods study, including an online survey of Australian biobank administrators and qualitative interviews with survey participants. The survey examined the criteria applied when considering requests to share or network. The interviews explored attitudes and practices regarding sharing and networking. Results Most (90.9%; 30/33) biobanks offered access to their samples and data to others, principally for research (90.6%; 29/32). The most common criteria used to evaluate access requests included ethical oversight (84.8%; 28/33), scientific merit (84.8%; 28/33) and intended use (81.8%; 27/33). Just over two-thirds (69.7%; 23/33) of biobanks participated in Australian networks, and 39.1% (9/23) participated in global networks. Networking took the form of both sharing standardised operating procedures and policies (60.9%) and sharing samples and data (43.5%). Thirteen of the 16 interviewees participated in networks. Motivations for sharing included scientific necessity, sharing expertise and standardising operations and governance. Significant barriers to networking remain, including insufficient resources, inconsistent regulations and procedures, and cultural and political issues to do with the conduct of research. Conclusions Many Australian biobanks are already active participants in various types of global biobanking. If biobanks are to expand and make the most of their involvement in global networks, then important barriers need to be overcome. What is known about the topic? Biobanks that store human tissue and associated data are increasingly forming local, national and global networks. These networks create opportunities for enhancing the utility and sustainability of biobanks, but also raise considerable technical, legal and ethical challenges. What does this paper add? This paper reports findings from a mixed-methods study of Australian biobanks and reveals contemporary practices and perspectives concerning sample and data sharing, as well as local and global networking. It found most Australian biobanks currently take part in these activities. What are the implications for practitioners? Many Australian biobanks are networking in various ways across regional and national borders. A better understanding of current practices and views on significant and emerging issues is relevant to the diverse range of biobank stakeholders involved in any agenda to expand biobank networking, including patients, consumers, clinicians, scientists, policy makers and regulators.

Abstract: Introduction: Polatuzumab vedotin (Pola) combined with rituximab (R) demonstrated activity and tolerability in a Phase (Ph) II trial of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Morschhauser et al. Lancet 2019). The pro-survival MCL-1 protein has been identified as a mechanism of resistance to venetoclax (Ven), a potent inhibitor of BCL-2, in non-Hodgkin lymphoma cell lines. Preclinical studies have demonstrated that concurrent treatment with Pola promotes MCL-1 degradation and enhances anti-tumor efficacy in vivo, thus providing a strong rationale for the combination with Ven (Amin et al. AACR 2020). We sought to determine whether the combination of Pola-Ven-R might further enhance anti-tumor response. Here, we present the primary efficacy and safety analysis from a Ph Ib/II study of Pola-Ven-R in pts with R/R DLBCL (GO29833; NCT02611323). Methods: GO29833 is an open-label, multicenter study of pts with R/R DLBCL who had received ≥1 prior anti-CD20 chemo-immunotherapy regimen. The recommended Ph II dose (RP2D) combination for Pola-Ven-R was initially defined in a 3+3 dose escalation phase and was then expanded into Ph II. Pts in the expansion cohort received induction therapy with six 21-day cycles of: intravenous (IV) Pola 1.8mg/kg (Cycle [C] 1-6: Day [D]1), Ven 800mg by mouth daily and R 375mg/m2 IV (C1-6: D1). Responders received consolidation therapy for 8 months (Ven 800mg daily and R 375mg/m2 on D1 every 2 months). The primary safety objectives were to determine the RP2D for Pola and Ven when given in combination with R and to evaluate the safety and tolerability of the Pola-Ven-R combination. The primary efficacy endpoint was complete response (CR) at end of induction (EOI), as determined by the Independent Review Committee (IRC) based on positron emission tomography-computed tomography (PET-CT) scans using modified Lugano 2014 response criteria. Secondary objectives included CR-rate at EOI and best overall response (BOR) determined by the investigator (INV). Exploratory objectives included INV-assessed progression-free survival (PFS) and overall survival (OS). Results: At the primary analysis (January 30, 2020), 57 pts from the Ph Ib/II populations were enrolled and received at least one study drug; the median duration of follow-up was 7.0 (range 0.2-30.4) months. Baseline characteristics of the safety-evaluable pts are shown in Table 1: median age, 65 years; male, 49%; Ann Arbor Stage III-IV, 84%; International Prognostic Index (IPI) ≥3, 54%; median prior lines of therapy, 3; refractory to last line, 83%; primary refractory, 65%. Dose limiting toxicity was not observed in Ph I and the maximum dose level was chosen as RP2D. All except two pts experienced at least one adverse event (AE), 21 (37%) had a serious AE, and 45 (79%) had a Grade 3-4 AE. The most common Grade 3-4 AEs were neutropenia (30 pts, 53%), infections (9 pts, 16%), and anemia (6 pts, 11%). AEs leading to dose reduction or interruption of any drug occurred in 10 (18%) and 35 (61%) pts, respectively; the majority of dose modifications were changes to Ven dosing. Seven (12%) pts had an AE that led to the discontinuation of any study drug (Pola [n=5]; Ven [n=7] ; R [n=6]). One grade 5 AE was reported (pneumonia); however, it was not considered related to study treatment as the pt had received new anti-lymphoma therapy following disease progression. In the primary efficacy-evaluable population (n=48), the IRC-assessed modified Lugano CR rate at EOI was 29% (Table 2). The INV-assessed CR rate at EOI and BOR were 31% and 65%, respectively, with a median duration of response of 5.8 months (95% confidence interval [CI] : 3.4-6.7). The median PFS and OS were 4.4 months (95% CI: 3.0-7.1) and 11.0 months (95% CI: 6.7-not evaluable), respectively. Conclusions: Our study of the novel triplet combination, Pola-Ven-R, demonstrates a safety profile consistent with the known profiles of the individual drugs. This first report of the full efficacy population showed promising activity in a heavily pre-treated and refractory population of pts with R/R DLBCL. Further evaluation of Pola-Ven-R and the impact of consolidation therapy is warranted to address the significant unmet medical need in this patient population. Disclosures Gritti: Autolus: Consultancy; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Amgen: Honoraria; Kite: Consultancy; Italfarmaco: Consultancy; Jannsen: Other: Travel Support; IQVIA: Consultancy. Marlton:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Phillips:Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy. Arthur:Royal North Shore Hospital: Current Employment. Bannerji:Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Corradini:Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; BMS: Other; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Johnston:MSD: 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. Seymour:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy; Mei Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Nurix: Honoraria. Hirata:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Musick:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Roche/Genentech, Inc.: Current Employment. Saha:Genentech, Inc.: Consultancy; Genentech, Inc.: Current Employment. Croft:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Flowers:OptumRx: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Bayer: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; Spectrum: Consultancy; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding; Kite: Research Funding. OffLabel Disclosure: Polatuzumab vedotin (Polivy) is approved in combination with bendamustine and rituximab or use in third-line or later treatment of relapsed/refractory (R/R) DLBCL in the USA and in second-line or later treatment in the EU. Venetoclax (Venclexta) is approved for the treatment of adult patients with CLL or SLL, and in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed AML in adults & gt;75 years, or who have comorbidities that preclude use of intensive induction chemotherapy. Rituximab (Rituxan) is approved for use in relapsed/refractory low-grade NHL and in previously untreated DLBCL with CHOP, but is not approved for use in R/R DLBCL.