Contributions
Abstract: S469
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:45 - 17:00
Location: Hall C
Background
Patients (pts) with persistent DLBCL after two or more lines of therapy have limited effective treatment options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies, including DLBCL, and has pleiotropic effects on tumorigenesis including functional downregulation of tumor suppressor proteins (TSPs) and increased export and translation of mRNAs for oncoproteins c-Myc and key survival proteins such as Bcl-2. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of TSPs including p53, p21, and IkBa, the latter of which serves to suppress NF-kB driven transcription, along with reductions in c-Myc and Bcl-2 family proteins. In a Phase I clinical study, pts with relapsed/refractory (R/R) DLBCL treated with SEL presented an overall response rate (ORR) of 32% including 4 CRs. Interestingly, 2 of these pts remain in CR for >1 yr.
Aims
In this clinical study we assess the efficacy of single agent SEL in pts with R/R DLBCL after ≥2 prior regimens.
Methods
Pts with R/R DLBCL were randomized to 60 or 100 mg of SEL twice weekly (8 doses) per 28-day cycle. Pts were also stratified by DLBCL subtype (GCB or non-GCB). The primary objectives are to determine the ORR and evaluate the safety of 60 vs 100 mg doses. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014).
Results
72 pts were enrolled: 37 pts on 60 mg (24 M/ 13 F, median age 71 yrs) and 35 pts on 100 mg (23 M/ 12 F, median age 68 yrs). Both groups had a median of 3 prior treatment regimens. The most common related adverse effects (AEs) across both dosing groups (Grade 1/2) were: fatigue (47%), nausea (46%), anorexia (42%), and vomiting (33%). Common Grade 3/4 AEs were: thrombocytopenia (39%), fatigue (18%), neutropenia (18%), and anemia (13%). These were managed with dose interruption/reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (26% v 11%) and thrombocytopenia (46% v 32%) were higher in 100 mg arm as compared to the 60 mg arm. Among the 63 evaluable pts (9 pts pending response), the ICRR determined ORR was 28.5% (Table 1). Nine responders, including 6 pts in CR, remain on treatment. Responders on the 60 mg arm have a median time on treatment of 8.9 months as compared with 3.8 months on the 100 mg arm.
Category | N | ORR (%) | CR (%) | PR (%) | SD (%) | DCR (%) |
All Doses | 63 | 18 (28.5%) | 7 (11.1%) | 11 (17.4%) | 9 (14.2%) | 27 (42.8%) |
60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.3%) | 12 (37.5%) |
100 mg | 31 | 9 (29%) | 3 (9.6%) | 6 (19.3%) | 6 (19.3%) | 15 (48.3%) |
GCB-Subtype | 32 | 8 (25%) | 3 (9.3%) | 5 (15.6%) | 6 (18.7%) | 14 (43.7%) |
Non-GCB Subtype | 31 | 10 (32.2%) | 4 (12.9%) | 6 (19.3%) | 3 (9.6%) | 13 (41.9%) |
Conclusion
SEL monotherapy shows activity in pts with R/R DLBCL including in pts with GCB subtype. 60 mg SEL twice weekly was more tolerable than 100 mg twice weekly, with fewer interruptions due to toxicity. Objective responses to SEL were durable at 60 mg BIW, suggesting these responses were associated with clinical benefit.
Session topic: 20. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Phase II, Oral, DLBCL
Abstract: S469
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:45 - 17:00
Location: Hall C
Background
Patients (pts) with persistent DLBCL after two or more lines of therapy have limited effective treatment options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies, including DLBCL, and has pleiotropic effects on tumorigenesis including functional downregulation of tumor suppressor proteins (TSPs) and increased export and translation of mRNAs for oncoproteins c-Myc and key survival proteins such as Bcl-2. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of TSPs including p53, p21, and IkBa, the latter of which serves to suppress NF-kB driven transcription, along with reductions in c-Myc and Bcl-2 family proteins. In a Phase I clinical study, pts with relapsed/refractory (R/R) DLBCL treated with SEL presented an overall response rate (ORR) of 32% including 4 CRs. Interestingly, 2 of these pts remain in CR for >1 yr.
Aims
In this clinical study we assess the efficacy of single agent SEL in pts with R/R DLBCL after ≥2 prior regimens.
Methods
Pts with R/R DLBCL were randomized to 60 or 100 mg of SEL twice weekly (8 doses) per 28-day cycle. Pts were also stratified by DLBCL subtype (GCB or non-GCB). The primary objectives are to determine the ORR and evaluate the safety of 60 vs 100 mg doses. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014).
Results
72 pts were enrolled: 37 pts on 60 mg (24 M/ 13 F, median age 71 yrs) and 35 pts on 100 mg (23 M/ 12 F, median age 68 yrs). Both groups had a median of 3 prior treatment regimens. The most common related adverse effects (AEs) across both dosing groups (Grade 1/2) were: fatigue (47%), nausea (46%), anorexia (42%), and vomiting (33%). Common Grade 3/4 AEs were: thrombocytopenia (39%), fatigue (18%), neutropenia (18%), and anemia (13%). These were managed with dose interruption/reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (26% v 11%) and thrombocytopenia (46% v 32%) were higher in 100 mg arm as compared to the 60 mg arm. Among the 63 evaluable pts (9 pts pending response), the ICRR determined ORR was 28.5% (Table 1). Nine responders, including 6 pts in CR, remain on treatment. Responders on the 60 mg arm have a median time on treatment of 8.9 months as compared with 3.8 months on the 100 mg arm.
Category | N | ORR (%) | CR (%) | PR (%) | SD (%) | DCR (%) |
All Doses | 63 | 18 (28.5%) | 7 (11.1%) | 11 (17.4%) | 9 (14.2%) | 27 (42.8%) |
60 mg | 32 | 9 (28.1%) | 4 (12.5%) | 5 (15.6%) | 3 (9.3%) | 12 (37.5%) |
100 mg | 31 | 9 (29%) | 3 (9.6%) | 6 (19.3%) | 6 (19.3%) | 15 (48.3%) |
GCB-Subtype | 32 | 8 (25%) | 3 (9.3%) | 5 (15.6%) | 6 (18.7%) | 14 (43.7%) |
Non-GCB Subtype | 31 | 10 (32.2%) | 4 (12.9%) | 6 (19.3%) | 3 (9.6%) | 13 (41.9%) |
Conclusion
SEL monotherapy shows activity in pts with R/R DLBCL including in pts with GCB subtype. 60 mg SEL twice weekly was more tolerable than 100 mg twice weekly, with fewer interruptions due to toxicity. Objective responses to SEL were durable at 60 mg BIW, suggesting these responses were associated with clinical benefit.
Session topic: 20. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): Phase II, Oral, DLBCL