Abstract: Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, IkB and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl & gt;60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl & gt;60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl & lt;60 mL/min) compared to those with normal (CrCl ≥60 mL/min) renal function. No dose adjustments are required in patients with renal dysfunction and DLBCL who are treated with selinexor. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients & lt;65 versus those ≥65 years old. Results: Of the 134 patients enrolled in the study, 52 (39%) were & lt;65 and 82 (61%) were ≥65 years old. In the & lt;65 group, 14% patients had baseline creatine clearance (CrCl) of 30- & lt;60 mL/min compared with 33% in ≥65 group. Patients with transformed DLBCL accounted for 17% and 27% of patients in the & lt;65 and ≥65 groups, respectively. Subtype analysis revealed 43% GCB and 55% non-GCB DLBCL in ≥65 year olds, and 54% GCB and 40% non-GCB in the & lt;65 group. The & lt;65 group had baseline ECOG performance status of 2 in 8% compared with 13% in the ≥65 group. Patients & lt; 65 received numerically higher median doses of selinexor (1360 and 770 mg [p=0.079] ) and a longer duration of treatment (13.5 vs. 8.0 weeks [p=0.049]). There was no statistical difference in ORR in patients & lt;65 vs. ≥65 years old: 36.5% vs. 24.4% (p=0.189). The complete response (CR) rates were 17.3% and 11% (p=0.431), respectively. Median DORs were similar at 9.7 months in the & lt;65 compared to 9.2 months in the ≥65 year olds. While the median progression-free survival (PFS) (3.6 and 2.3 months) was similar between groups, the OS was higher in the & lt;65 year olds: 13.7 vs. 7.8 months (p=0.037). The incidence of treatment-related AEs was comparable between both groups: The most common grade ≥3 AEs in & lt;65 versus ≥65 year olds were thrombocytopenia (42.3% vs. 39.0%), nausea (3.8% vs. 7.3%), and fatigue (5.8% vs. 13.4%). Treatment-related serious AEs occurred in 11.5% of patients & lt;65 (n=6) and 26.8% ≥65 (n=22), with general disorders and administration site conditions (n=12) and fatigue (n=6) as the largest contributors in the ≥65 group. Treatment discontinuations due to AEs occurred at a lower incidence in the & lt;65 group compared with & gt;65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those & lt;65 when treated with selinexor, with comparable ORR, CR, PFS, DOR, and safety profile. As expected, younger patients ( & lt;65 years old) had a longer overall survival than those ≥65 years old, most likely due to comorbid medical conditions in the patients ≥65 years. These results indicate that selinexor can induce durable responses in younger and older patients with heavily pretreated DLBCL with similar tolerability. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract: BACKGROUND: Targeted B-cell receptor signaling pathway inhibitors have changed the treatment landscape of chronic lymphocytic leukemia (CLL); however, treatment decisions remain challenging due to emergence of therapeutic resistance and uncertainties regarding optimal sequencing of therapies. Clinical trials have focused on single treatment options and reported limited outcome data. With increasing options for CLL treatment, research on how to best sequence CLL treatments is needed to optimize patient outcomes. METHODS: The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, international, collaborative observational study of patients (pts) with CLL treated at either community or academic sites. For this analysis, pts were randomly selected and eligible for inclusion if they started 1st-line CLL therapy from January 1st, 2012 through present. Demographics, clinical characteristics, treatment patterns, and progression-free survival (PFS) were evaluated. The reason(s) for discontinuing 1st-line and initiating 2nd-line therapy were collected; multiple reasons could be selected. For this analysis, pts were grouped according to whether they received novel agent-based therapy (eg, ibrutinib, idelalisib, venetoclax) or chemotherapy/chemoimmunotherapy (CT/CIT) as 1st-line treatment. RESULTS: Of 351 pts studied, 179 received CT/CIT and 172 received novel agents as 1st-line therapy. Patient data, stratified by 1st-line therapy (CT/CIT vs. novel agents), are shown in Table 1. Most pts were treated in community settings (81%). The median ages were 62 and 66 years for pts receiving CT/CIT and novel agents, respectively. Demographics were generally similar between CT/CIT and novel agent groups with one exception: 17p deletion/TP53 mutations were present in 20% who received novel agents, compared to only 4% who received CT/CIT (p 〈 0.0001). The most common 1st-line CT/CIT treatments were bendamustine + rituximab (56%; 101/179), fludarabine + cyclophosphamide + rituximab (20%), chlorambucil + obinutuzumab (8%), and fludarabine + rituximab (5%). The most common novel-agent based therapies were ibrutinib (80%; 138/172), ibrutinib + rituximab (7%), and venetoclax-based treatments (7%). Median follow up was longer for pts who received CT/CIT compared to novel agents in the 1st-line (15.6 vs. 9.9 months). For pts with intact 17p and nonmutated TP53 (n=286), the 12-month PFS was 90% and 87% for pts who received CT/CIT and novel agents as 1st-line, respectively (unadjusted hazard ratio: 1.11 [95% CI 0.6-2.0]; p = 0.73). Among pts treated with 1st-line CT/CIT, 27% (n=49) received 2nd-line therapy after a median of 14.2 months; the majority initiated 2nd-line due to relapse/progression (84%; 41/49). Of pts treated with novel agents in the 1st-line, 31% (n=53) discontinued and 18% (n=31) initiated 2nd-line therapy; common reasons for discontinuing novel agents were disease progression/refractory to treatment (34%; 18/53), completed scheduled duration of treatment (30%; 16/53), and adverse events/intolerance (19%; 10/53). The most common reason for initiating 2nd-line therapy after 1st-line novel agent was relapse (48%; 15/31); median time to next treatment was 8.0 months. Regardless of 1st-line therapy, 〉 80% of pts received a novel agent-based therapy as 2nd-line treatment. CONCLUSIONS: In this study, pts with CLL treated since 2012 with CT/CIT or novel agent-based therapies (87% ibrutinib-based) in 1st-line had similar demographics; notably, more pts with 17p deletion/TP53 mutation were treated with novel agents. Although treatment failure was the primary reason for initiating 2nd-line therapy, many pts discontinued novel agents for other reasons, including adverse events and, unexpectedly, completion of therapy. With limited follow-up, in patients largely from community setting, PFS was similar between pts treated with CT/CIT and novel agents; more analyses are necessary to determine whether outcomes are impacted due to discontinuation of treat-to-progression novel agents for reasons other than progression. Overall, novel agents were the 2nd-line therapy of choice, irrespective of 1st-line therapy. These data constitute a first-look at CORE, a long-term study designed to determine how novel therapies and treatment sequencing impacts adverse events and outcomes in the treatment of CLL. Disclosures Mato: TG Therapeutics: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Prime Oncology: Speakers Bureau; AstraZeneca: Consultancy; Acerta: Research Funding; Regeneron: Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Janssen: Consultancy, Honoraria. Sarraf Yazdy:Bayer: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shadman:Abbvie: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding; AstraZeneca: Consultancy; Gilead: Research Funding; Mustang: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy, Research Funding; Acerta: Research Funding; Verastem: Consultancy. Kennard:AbbVie, Gilead, Verastem: Consultancy. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees. Ujjani:AbbVie: Consultancy, Speakers Bureau. Brander:Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Nabhan:Cardinal Health: Employment, Equity Ownership. Barr:AbbVie, Gilead: Consultancy. Brown:Abbvie: Consultancy; Verastem: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Celgene: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Roche/Genentech: Consultancy. Fox:Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Sunesis: Consultancy. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Eyre:AbbVie, Gilead, Janssen: Honoraria, Other: Travel support. Lamanna:AbbVie, Genentech, Gilead, Verastem, Bei-Gene, TG Therapeutics, Acerta: Research Funding; AbbVie, Celgene, Roche-Genentech, Janssen, Pharmacyclics, Gilead, Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Cellectis: Research Funding; Servier: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Verastem: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Abbvie: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bannerji:AbbVie, Inc.: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Samp:AbbVie: Employment, Equity Ownership. Nielsen:AbbVie, Inc: Employment, Equity Ownership. Pauff:AbbVie: Employment, Equity Ownership. Kipps:Celgene: Consultancy; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Genentech Inc: Consultancy, Research Funding. Schuster:Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding. Follows:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding.

Abstract: BACKGROUND Novel agents have changed the treatment landscape in chronic lymphocytic leukemia (CLL), however little has been reported about real-world treatment sequence patterns and associated outcomes post-introduction of novel agents. Studies have demonstrated that venetoclax is effective for patients (pts) who have discontinued ibrutinib, however treatments and outcomes post-venetoclax discontinuation remain unclear. The objective of this study was to examine real-world treatment sequence patterns post-introduction of novel agents and specifically understand treatment sequencing following venetoclax. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) is a retrospective, multicenter, collaborative observational study of pts with CLL/small lymphocytic leukemia (SLL). For this analysis, adult pts were eligible for inclusion if they started therapy for CLL/SLL in the relapsed/refractory setting after February 12, 2014 (FDA approval date of first novel agent for CLL/SLL). Interim data are presented; data collection for this analysis is ongoing and is expected to be completed by October 31, 2019. Treatment sequences were characterized specifically focusing on treatment sequencing following venetoclax and other novel agents (i.e., BCRi: e.g., ibrutinib, idelalisib or acalabrutinib). Clinical response, as assessed by physician, was also reported from medical charts (iwCLL criteria were provided as a reference only). RESULTS Of the 267 pts available at the time of interim data analysis, 231 pts (87%) received a novel agent in at least one line of therapy (first-line: 35 pts [15%]; second-line: 133 pts [58%] ; third-line or later: 63 pts [27%]). Among novel agents, ibrutinib was the most commonly used first novel agent for 198 pts (86%) followed by venetoclax for 18 pts (8%) and idelalisib for 12 pts (5%). Of those 267 pts, 143 pts (54%) received chemotherapy/chemoimmunotherapy (CT/CIT) followed by a novel agent; 63 pts (24%) received a novel agent followed by a novel agent; 17 (7%) received a novel agent followed by CT/CIT; and 47 (18%) received a CT/CIT followed by CT/CIT. At the time of this interim data cut there were 220 pts (82%) who received BCRi-based regimens (first-line: 33 pts [15%]; second-line: 123 pts [56%] ; third-line or later: 64 pts [29%]) and 62 pts (23%) who received venetoclax-based regimens (first-line: 2 pts [3%] ; second-line: 22 pts [36%]; third-line or later: 38 pts [61%] ). Of the 220 pts who received BCRi-based regimens, 50 (23%) achieved complete remission (CR) and 83 (38%) achieved partial remission (PR) (responses based on physician assessment). Of the 220 pts, 88 (40%) went on to receive a subsequent line of therapy. The most common subsequent treatments administered were venetoclax containing regimens (n= 34, 39%). Of the 88 pts who received a subsequent line of therapy after BCRi-based regimens, 22 pts (25%) achieved CR and 24 pts (27%) achieved PR. Of the 62 pts who received venetoclax-based regimens, 20 pts (32%) achieved CR and 14 pts (23%) achieved PR. Of the 62 pts, 15 pts (24%) went on to receive a subsequent line of therapy. The most common subsequent treatment administered were BCRi containing regimens (n= 10, 67%) primarily ibrutinib-based. Of the 15 pts receiving a subsequent line of therapy after venetoclax-based regimens, 3 pts (20%) achieved CR and 4 pts (27%) achieved PR. While preliminary results are encouraging, further data collection efforts are ongoing and will be included for presentation to confirm the results and outcomes associated with different sequencing options. CONCLUSIONS The treatment paradigm is evolving with the introduction of novel agents. Results from this study will provide a baseline description of treatment sequence patterns enabling clinicians to benchmark the impact of the introduction of novel agents and associated outcomes. Early evidence from these results also suggests that novel agents are most commonly introduced during second line treatment and that other novel agents, including ibrutinib, following venetoclax treatment are being utilized in the real-world settings. Table. Disclosures Mato: Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy. Sail:AbbVie: Employment, Other: may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shadman:Bigene: Research Funding; TG Therapeutics: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Gilead: Research Funding; Merck: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Celgene: Research Funding; Sunesis: Research Funding. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ujjani:PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Atara: Consultancy; Astrazeneca: Consultancy; Gilead: Consultancy. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy. Brown:Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Schuh:Pharmacyclics: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Verastem: Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Eyre:Janssen: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support. Wierda:Pharmacyclics LLC: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Miragen: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; AbbVie: Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Gilead: Other: travel support; Celgene: Consultancy; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy; Pharmacyclics: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy, travel support; Merck: Other: travel support, Patents & Royalties: IP rights. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Schuster:Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau. Cheson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Gilead: Research Funding; Epizyme: Research Funding. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:Genentech: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; MEI: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Lamanna:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Introduction: R/R DLBCL patients who have received ≥2 lines of therapy, including those progressed post stem cell transplantation (SCT) or who are not candidates for SCT, have limited treatment options. Selinexor, a selective oral XPO1 inhibitor leads to nuclear accumulation and activation of tumor suppressor proteins and reductions in c-Myc and Bcl-2 oncogenes. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in relapsed/refractory myeloma in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. We conducted the SADAL study to evaluate the efficacy and safety of single agent selinexor in patients with R/R DLBCL. In this patient population, selinexor demonstrated deep and durable responses with an overall response rate (ORR) of 28.3% including a 11.0% complete response (CR) rate. The median duration of response (DOR) was 9.2 months. In patients with CR, the DOR was 13.4 months. Here we evaluate the effect of prior therapy on the efficacy and safety of selinexor. Methods: SADAL is a multicenter, open-label study in R/R DLBCL patients with 2-5 prior lines of therapy, who may have progressed post SCT or are not candidates for SCT. Patients were stratified by subtype (germinal center B-cell or non-GCB) and treated with 60 mg selinexor BIW per 28-day cycle. The primary endpoint was ORR. Secondary endpoints included duration of response (DOR) and safety. We performed post-hoc analyses to compare outcomes based on the number (2 vs. 〉 2) and type (SCT vs. no SCT) of prior lines of therapy received. Results: Of 127 patients, 83 (65%) received 2 prior lines of therapy and 43 (34%) received 〉 2 prior lines of therapy. Thirty-six patients (28%) received prior SCT and 91 (72%) had no prior SCT. In general, patient demographic and baseline characteristics were well balanced in both subgroups. ORR was 30.1% vs. 25.6% (P=0.74) in patients with 2 vs 〉 2 prior lines of therapy respectively. The CR rate was 10.8% in patients with 2 prior lines of therapy compared with 11.6% in patients with 〉 2 prior lines of therapy (P=1.00). The median DOR was 9.2 months in patients with 2 prior lines of therapy compared with 8.4 months in those with 〉 2 prior lines of therapy (P=0.64). Median progression free survival was 3.7 months and 1.9 months (P=0.37) and median overall survival was 11.0 months and 9.8 months (P=0.69) in patients with 2 and 〉 2 prior lines of therapy respectively. In patients with prior SCT, the ORR was 44.4% compared with 22.0 % (P=0.02) in patients with no prior SCT. The CR rate was 16.7% in patients with prior SCT compared with 8.8% in patients with no prior SCT (P=0.34). The DOR was 8.4 months in patients with prior SCT and 9.2 months with no prior SCT (P=0.80). Median progression free survival was 5.9 months and 2.3 months (P=0.07) and median overall survival was 9.1 and 9.8 months (P=0.36) in patients with prior SCT and no prior SCT respectively. The most common related adverse events (AEs) [grade ≥3] included thrombocytopenia (2 prior lines: 36%, 〉 2 prior lines: 42%; prior SCT: 58%, no prior SCT: 31%), neutropenia (2 prior lines: 19%, 〉 2 lines: 23%; prior SCT: 25%, no prior SCT: 20%), and anemia (2 prior lines: 15%, 〉 2 prior lines: 14%, prior SCT: 17%, no prior SCT: 14%). Treatment-related serious AEs were reported in 23%, 14%, 25%, and 19% of patients with 2 prior lines, 〉 2 prior lines, prior SCT, and no prior SCT respectively. Conclusions: Single agent oral selinexor with its novel mechanism of action demonstrated deep and durable responses with no new safety signals regardless of prior therapy. Patients with 2 prior lines of therapy had a higher response rate (30.1% vs. 25.6%) compared with those with 〉 2 prior lines of therapy. The greatest benefit, with an ORR of 44.4% was observed in patients with prior SCT. Collectively, these data support the clinical benefit of single agent selinexor and importantly in earlier lines of therapy. Further evaluation of selinexor in combination with other agents to improve outcomes in R/R DLBCL is ongoing. Disclosures Cavallo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goy:Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Casasnovas:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Choquet:Keocyt: Honoraria. Gurion:Roche: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria. Sancho:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genentech: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau; Astellas: Speakers Bureau; Actinium: Research Funding; Incyte: Research Funding; Karyopharm Therapeutics: Research Funding; Morphosys: Research Funding; Nordic Nanovector: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau; Rafael: Research Funding; F2G Ltd.: Research Funding; AbbVie: Speakers Bureau; Amgen: Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Vassilakopoulos:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. McCarthy:Karyopharm Therapeutics: Employment, Equity Ownership. Ma:Karyopharm: Employment, Equity Ownership. Corona:Karyopharm Therapeutics: Employment, Equity Ownership. Saint-Martin:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Van Den Neste:Gilead: Other: travel support. Canales:Sandoz: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau.

Abstract: BACKGROUND The recent approval of novel agents (NAs) has changed the treatment landscape in chronic lymphocytic leukemia (CLL), however, there remains uncertainty regarding treatment discontinuation patterns in real-world (RW) settings. This study assessed patterns of and reasons for discontinuation for patients (pts) treated with chemotherapy/chemoimmunotherapy (CT/CIT) and NAs in first (1L) and second (2L) lines of therapy in CLL. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, observational study. Adult CLL patients (pts) were included if they were diagnosed with CLL, initiated 1L or 2L therapy for CLL on/after 01/01/2012 (excluding lines of therapy received as part of clinical trials). Discontinuation patterns were assessed among CT/CIT and NAs, more specifically in four treatment cohorts: fludarabine+cyclophosphamide+rituximab (FCR), bendamustine+rituximab (BR), B-cell receptor inhibitors (BCRi)-based (e.g., acalabrutinib, ibrutinib, or idelalisib) and venetoclax-based regimens. Treatment discontinuation was operationally defined as ending therapy for reason(s) other than completion of planned duration of therapy. RESULTS Of 671 pts receiving 1L therapy, 81 (12%) received FCR (median age=58, 70% males); 153 (23%) BR (median age=63, 61% males), 255 (38%) BCRi-based (median age=65, 65% males); and 13 (2%) venetoclax-based (median age=59, 54% males). The remaining 169 pts received other regimens (e.g., other CT/CIT). The most common BCRi-based therapy in 1L was ibrutinib-containing regimens (97%). Median duration of follow-up was 24, 27, 11 and 8 months for FCR, BR, BCRi-based and venetoclax-based regimens, respectively. Treatment discontinuation occurred in 18 (22%), 41 (27%), 51 (20%) and 4/13 pts receiving FCR, BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuation in FCR (11/18 pts; 61%), BR (15/41 pts; 37%) and BCRi-based (24/51 pts; 47%) cohorts was adverse events (AEs), with 〉 70% being severe AEs in each cohort. Common AEs leading to discontinuations were hematological abnormalities (e.g., neutropenia, thrombocytopenia) in the FCR (6/18 pts; 33%) and BR (6/41 pts; 15%) cohorts. In the BCRi-based cohort the most common AEs leading to discontinuations were cardiac (4/51 pts; 8%), skin and subcutaneous tissue disorders (e.g., rash; 6/51 pts; 12%), hemorrhage/bleeding (3/51; 6%), and musculoskeletal and connective tissue disorders (3/51; pts; 6%). For the relatively small number of pts treated with venetoclax-based regimens and discontinued, disease progression was the common reason for discontinuations (3/4 pts); no pts discontinued venetoclax-based regimens due to adverse events. In the relapsed/refractory setting specifically in 2L, 15 (7%), 113 (56%) and 16 (8%) pts received BR, BCRi-based and venetoclax-based regimen respectively, of which the most common BCRi-based therapy regimen was ibrutinib-based (95%). Treatment discontinuation occurred in 5/15 pts (33%), 27/113 pts (24%) and 4/16 pts (25%) receiving BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuations were severe AEs for BR (3/5 pts) and BCRi-based (13/27 pts) cohorts and disease progression for venetoclax-based regimens (2/4). CONCLUSIONS Despite the relatively short follow-up, in both 1L and 2L, similar discontinuation patterns emerge. CT/CIT is often discontinued prior to completion of planned cycles of therapy, suggesting that these regimens are difficult to tolerate. Additionally, treat to progression BCRi-based regimens are also discontinued for severe AEs, discordant to results from clinical trials. With a small cohort and limited information collected, results on venetoclax discontinuation warrants additional studies. Well tolerated chemotherapy-free combinations with finite treatment duration in treatment naïve and relapsed/refractory settings may limit continuous exposure to treatment and prevent discontinuations due to AEs. Table Disclosures Shadman: Atara: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Mustang Biopharma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; ADC Therapeutics: Consultancy. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:AstraZeneca: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Ujjani:Atara: Consultancy; Gilead: Consultancy; Astrazeneca: Consultancy; Genentech: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding. Emechebe:AbbVie: Employment, Other: and may hold stock or stock options. Kamalakar:AbbVie: Employment, Other: and may hold stock or stock options. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Brown:Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy. Schuh:AbbVie: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Verastem: Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Eyre:Janssen: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Wierda:Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding. Skarbnik:Jazz Pharmaceuticals: Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Celgene: Consultancy; Celgene: Consultancy; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Gilead: Other: travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy, travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Gilead: Other: travel support. Pauff:AbbVie: Employment, Other: and may hold stock or stock options. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Follows:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cheson:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:BeiGene: Research Funding; ArQule: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:DTRM Biopharma: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Tolero: Research Funding; Acerta: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Guerin:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member, Research Funding.

Abstract: Introduction: Patients (pts) with relapsed/refractory (R/R) DLBCL after two or more lines of therapy and who are not candidates for stem cell transplantation have limited effective treatment options and a poor prognosis. Selinexor, an oral XPO1 inhibitor, causes nuclear accumulation and activation of tumor suppressor proteins including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes. In a phase 1 clinical study (NCT01607892), pts with R/R DLBCL treated with selinexor had an overall response rate (ORR) of 32%, with 4 complete responses (CRs, 6%). Based on these findings, a phase 2b open-label study (SADAL) of selinexor in pts with R/R DLBCL not candidates for transplantation was initiated. Methods: Pts with R/R DLBCL were stratified by subtype (GCB or non-GCB). Pts achieving a best response of PR/CR on prior therapy required a 8 week washout before enrolling on trial. The primary objectives included efficacy (ORR and associated DOR) and safety.Pts were initially randomized to 60 or 100 mg of selinexor twice weekly (8 doses) per 28-day cycle. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014). Results: Preliminary results from the planned interim analysis showed similar ORRs on the 60 and 100 mg doses, but reduced DOR and tolerability at the higher dose; the 100 mg arm was therefore discontinued. 110 pts were enrolled on the 60 mg arm (66 M/ 44 F, median age 67 yrs) with a median of 3 (range 2-5) prior treatment regimens. The most frequently reported treatment related adverse events (AEs) included(all grades, grades 3, 4): nausea (51%, 6%, 0%), fatigue (50%, 10%, 0%), thrombocytopenia (47%, 22%, 15%), anorexia (35%, 2%, 0%), neutropenia (27%, 20%, 0%), and anemia (27%, 12%, 1%). These AEs were managed with dose modifications and/or standard supportive care. At the planned interim analysis (N=32, 60 mg) the ICRR determined ORR was 34.4% (5 CRs and 6 partial responses (PRs)). The median duration of response (DOR) was 8.4 months. ORR was 33.3% in GCB and 35.3% in non-GCB subtypes. The median overall survival (OS) was 9.0 months. Median OS (Figure 1) in pts ≥PR was not reached and was significantly longer vs median OS for pts ≤ stable disease (SD) of 4.1 months (p= 〈 0.001). Conclusion: Single agent oral selinexor is active in pts with R/R DLBCL across both GCB and non-GCB subtypes. Responses were deep with CRs noted on therapy and durable, with some responses 〉 24 months, consistent with significant clinical benefit. Importantly, response to therapy (≥PR) was associated with significant improvement in OS of 9.0 months vs 4.1 months for those with ≤SD. Enrollment completion is expected by September 2018. Full study results (N=130) will be presented, including longer follow up (DOR and OS) of pts from the original interim analysis. Pts enrolled in SADAL represent an unmet medical need population, and selinexor may help address this need. Disclosures Casasnovas: Roche: Consultancy, Research Funding; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Gilead: Consultancy, Research Funding. Goy:Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics/J & J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hackensack University Medical Center: Employment; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Seattle Genetics: Research Funding; COTA: Membership on an entity's Board of Directors or advisory committees. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows:Gilead, Janssen, Roche, Abbvie, Takeda, BMS: Membership on an entity's Board of Directors or advisory committees. Jaeger:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Kuruvilla:Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Princess Margaret Cancer Foundation: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria; Leukemia and Lymphoma Society Canada: Research Funding. Caimi:Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Matczak:Karyopharm Therpeutics: Employment. Ma:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.