Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b Sadal Study
Authors: Maerevoet Marie , Vermaat Joost , Canales Miguel A. , Casasnovas René-Olivier , Van Den Neste Eric , Goy Andre , Hill Brian T. , Thieblemont Catherine , De La Cruz Maria De Fatima , Cavallo Federica , Follows George , Choquet Sylvain , Gurion Ronit , Bouabdallah Reda , Jaeger Ulrich , Nagy Agnes , Kuruvilla John , Warzocha Krzysztof , Kalakonda Nagesh , Caimi Paolo , Bakhshi Sameer , Ku Matthew , Hamad Nada , Veelken Hendrik , Matczak Ewa , Ma Xiwen , Saint-Martin Jean-Richard , Shah Jatin J. , Kauffman Michael G. , Shacham Sharon , Zijlstra Josée M 
Published: October 2019

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.