PATIENTS WITH HEAVILY PRETREATED DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) WHO RESPOND TO ORAL SELINEXOR THERAPY SHOW PROLONGED SURVIVAL: UDPATED PHASE 1 RESULTS
EHA Library. Kuruvilla J. 06/13/15; 103169; S485
John Kuruvilla
Contributions
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Abstract
Abstract: S485
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room A7
Background
The nuclear export protein XPO1 (CRM1) is overexpressed in all types of malignant lymphoma including DLBCL. Selinexor is a selective inhibitor of nuclear export (SINE) that inhibits XPO1 to force nuclear retention & activation of >10 tumor suppressor proteins such as p53, IkBa, FOXO & p21. Selinexor also reduces levels of c-myc, BCL2 & other oncoproteins. Current therapy for DLBCL leads to cures in > 50% of patients (pts) after 1-2 lines of therapy. Pts with relapsed/refractory DLBCL have a very poor prognosis with expected median survival <1 year.
Aims
We previously reported efficacy & safety of selinexor in pts with relapsed/ refractory Non-Hodgkin’s Lymphoma (NHL) (J. Kuruvilla et al. ASH 2014). Here we correlate response to selinexor with progression-free (PFS) & overall (OS) survival of pts with heavily pretreated DLBCL.
Methods
Selinexor was administered orally (3–80 mg/m2) for 8 or 10 doses in a 28-day cycle in this phase 1 study (NCT01607892). Response evaluation was performed in cycle 1 and 2 & then every 2 cycles. Comparison of survival rates was done by Kaplan Meier analysis using 10-weeks timepoint as landmark. All pts had heavily pretreated DLBCL (prior R-CHOP & additional therapies) with documented progressive disease on study entry.
Results
In 31 (of 33) pts with heavily pretreated DLBCL, the median number of prior therapies was 3 (range 1-11). The most common adverse effects (Grade 1/2) occurring after cycle 1 are fatigue (43%), anorexia (38%), nausea (29%), & dysgeusia (24%). Grade 3/4 adverse events occurring in ≥ 2 pts are thrombocytopenia (62%), neutropenia (24%), anemia (24%), fatigue (10%), hyponatremia (10%), syncope (10%), & confusion (10%). These are managed with dose interruption, platelet stimulators and/or standard supportive care. Among 31 pts treated with at least 1 cycle of selinexor, the overall response rate was 39% (12/31) with a median duration of response of ~7 months. 8 pts (26%) achieved partial response (PR), & 4 pts (13%) complete response (CR) confirmed by PET scan. Selinexor showed similar activity in GCB & non-GCB subtypes of DLBCL. The overall median PFS & OS for pts on study ≥ 10 weeks were 104 days & 155 days, respectively. In order to determine if best response of CR or PR to selinexor was associated with improved clinical outcomes, the PFS & OS of responding pts were compared with those of pts with stable (SD) or progressive (PD) disease. Comparison of OS & PFS for pts with objective responses vs those with SD & PD revealed a strong correlation between response & survival (N=24): Median PFS of pts with CR/PR vs SD/PD were 329 & 49 days respectively (p<0.001). Median OS of pts with CR/PR vs SD/PD were 571 & 108 days, respectively (p<0.01). Furthermore, 4 pts with CR remained on study for 217, 505+, 525+, & 650+ days.
Summary
Selinexor monotherapy shows significant anti-cancer activity in pts with heavily pretreated relapsed / refractory DLBCL. Objective responses to selinexor are durable & correlate with improved OS & PFS compared with pts who achieve SD or PD, suggesting that these responses are associated with clinical benefit. Clinical & molecular predictors of objective response to selinexor are being evaluated. A study of selinexor monotherapy (pts randomized to high versus low dose) in pts with heavily pretreated DLBCL is ongoing & combination studies are being initiated.
Keyword(s): DLBCL, Non-Hodgkin's lymphoma
Session topic: Optimization and innovation in treating aggressive lymphomas
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room A7
Background
The nuclear export protein XPO1 (CRM1) is overexpressed in all types of malignant lymphoma including DLBCL. Selinexor is a selective inhibitor of nuclear export (SINE) that inhibits XPO1 to force nuclear retention & activation of >10 tumor suppressor proteins such as p53, IkBa, FOXO & p21. Selinexor also reduces levels of c-myc, BCL2 & other oncoproteins. Current therapy for DLBCL leads to cures in > 50% of patients (pts) after 1-2 lines of therapy. Pts with relapsed/refractory DLBCL have a very poor prognosis with expected median survival <1 year.
Aims
We previously reported efficacy & safety of selinexor in pts with relapsed/ refractory Non-Hodgkin’s Lymphoma (NHL) (J. Kuruvilla et al. ASH 2014). Here we correlate response to selinexor with progression-free (PFS) & overall (OS) survival of pts with heavily pretreated DLBCL.
Methods
Selinexor was administered orally (3–80 mg/m2) for 8 or 10 doses in a 28-day cycle in this phase 1 study (NCT01607892). Response evaluation was performed in cycle 1 and 2 & then every 2 cycles. Comparison of survival rates was done by Kaplan Meier analysis using 10-weeks timepoint as landmark. All pts had heavily pretreated DLBCL (prior R-CHOP & additional therapies) with documented progressive disease on study entry.
Results
In 31 (of 33) pts with heavily pretreated DLBCL, the median number of prior therapies was 3 (range 1-11). The most common adverse effects (Grade 1/2) occurring after cycle 1 are fatigue (43%), anorexia (38%), nausea (29%), & dysgeusia (24%). Grade 3/4 adverse events occurring in ≥ 2 pts are thrombocytopenia (62%), neutropenia (24%), anemia (24%), fatigue (10%), hyponatremia (10%), syncope (10%), & confusion (10%). These are managed with dose interruption, platelet stimulators and/or standard supportive care. Among 31 pts treated with at least 1 cycle of selinexor, the overall response rate was 39% (12/31) with a median duration of response of ~7 months. 8 pts (26%) achieved partial response (PR), & 4 pts (13%) complete response (CR) confirmed by PET scan. Selinexor showed similar activity in GCB & non-GCB subtypes of DLBCL. The overall median PFS & OS for pts on study ≥ 10 weeks were 104 days & 155 days, respectively. In order to determine if best response of CR or PR to selinexor was associated with improved clinical outcomes, the PFS & OS of responding pts were compared with those of pts with stable (SD) or progressive (PD) disease. Comparison of OS & PFS for pts with objective responses vs those with SD & PD revealed a strong correlation between response & survival (N=24): Median PFS of pts with CR/PR vs SD/PD were 329 & 49 days respectively (p<0.001). Median OS of pts with CR/PR vs SD/PD were 571 & 108 days, respectively (p<0.01). Furthermore, 4 pts with CR remained on study for 217, 505+, 525+, & 650+ days.
Summary
Selinexor monotherapy shows significant anti-cancer activity in pts with heavily pretreated relapsed / refractory DLBCL. Objective responses to selinexor are durable & correlate with improved OS & PFS compared with pts who achieve SD or PD, suggesting that these responses are associated with clinical benefit. Clinical & molecular predictors of objective response to selinexor are being evaluated. A study of selinexor monotherapy (pts randomized to high versus low dose) in pts with heavily pretreated DLBCL is ongoing & combination studies are being initiated.
Keyword(s): DLBCL, Non-Hodgkin's lymphoma
Session topic: Optimization and innovation in treating aggressive lymphomas
Abstract: S485
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room A7
Background
The nuclear export protein XPO1 (CRM1) is overexpressed in all types of malignant lymphoma including DLBCL. Selinexor is a selective inhibitor of nuclear export (SINE) that inhibits XPO1 to force nuclear retention & activation of >10 tumor suppressor proteins such as p53, IkBa, FOXO & p21. Selinexor also reduces levels of c-myc, BCL2 & other oncoproteins. Current therapy for DLBCL leads to cures in > 50% of patients (pts) after 1-2 lines of therapy. Pts with relapsed/refractory DLBCL have a very poor prognosis with expected median survival <1 year.
Aims
We previously reported efficacy & safety of selinexor in pts with relapsed/ refractory Non-Hodgkin’s Lymphoma (NHL) (J. Kuruvilla et al. ASH 2014). Here we correlate response to selinexor with progression-free (PFS) & overall (OS) survival of pts with heavily pretreated DLBCL.
Methods
Selinexor was administered orally (3–80 mg/m2) for 8 or 10 doses in a 28-day cycle in this phase 1 study (NCT01607892). Response evaluation was performed in cycle 1 and 2 & then every 2 cycles. Comparison of survival rates was done by Kaplan Meier analysis using 10-weeks timepoint as landmark. All pts had heavily pretreated DLBCL (prior R-CHOP & additional therapies) with documented progressive disease on study entry.
Results
In 31 (of 33) pts with heavily pretreated DLBCL, the median number of prior therapies was 3 (range 1-11). The most common adverse effects (Grade 1/2) occurring after cycle 1 are fatigue (43%), anorexia (38%), nausea (29%), & dysgeusia (24%). Grade 3/4 adverse events occurring in ≥ 2 pts are thrombocytopenia (62%), neutropenia (24%), anemia (24%), fatigue (10%), hyponatremia (10%), syncope (10%), & confusion (10%). These are managed with dose interruption, platelet stimulators and/or standard supportive care. Among 31 pts treated with at least 1 cycle of selinexor, the overall response rate was 39% (12/31) with a median duration of response of ~7 months. 8 pts (26%) achieved partial response (PR), & 4 pts (13%) complete response (CR) confirmed by PET scan. Selinexor showed similar activity in GCB & non-GCB subtypes of DLBCL. The overall median PFS & OS for pts on study ≥ 10 weeks were 104 days & 155 days, respectively. In order to determine if best response of CR or PR to selinexor was associated with improved clinical outcomes, the PFS & OS of responding pts were compared with those of pts with stable (SD) or progressive (PD) disease. Comparison of OS & PFS for pts with objective responses vs those with SD & PD revealed a strong correlation between response & survival (N=24): Median PFS of pts with CR/PR vs SD/PD were 329 & 49 days respectively (p<0.001). Median OS of pts with CR/PR vs SD/PD were 571 & 108 days, respectively (p<0.01). Furthermore, 4 pts with CR remained on study for 217, 505+, 525+, & 650+ days.
Summary
Selinexor monotherapy shows significant anti-cancer activity in pts with heavily pretreated relapsed / refractory DLBCL. Objective responses to selinexor are durable & correlate with improved OS & PFS compared with pts who achieve SD or PD, suggesting that these responses are associated with clinical benefit. Clinical & molecular predictors of objective response to selinexor are being evaluated. A study of selinexor monotherapy (pts randomized to high versus low dose) in pts with heavily pretreated DLBCL is ongoing & combination studies are being initiated.
Keyword(s): DLBCL, Non-Hodgkin's lymphoma
Session topic: Optimization and innovation in treating aggressive lymphomas
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 16:45 to 13.06.2015 17:00
Location: Room A7
Background
The nuclear export protein XPO1 (CRM1) is overexpressed in all types of malignant lymphoma including DLBCL. Selinexor is a selective inhibitor of nuclear export (SINE) that inhibits XPO1 to force nuclear retention & activation of >10 tumor suppressor proteins such as p53, IkBa, FOXO & p21. Selinexor also reduces levels of c-myc, BCL2 & other oncoproteins. Current therapy for DLBCL leads to cures in > 50% of patients (pts) after 1-2 lines of therapy. Pts with relapsed/refractory DLBCL have a very poor prognosis with expected median survival <1 year.
Aims
We previously reported efficacy & safety of selinexor in pts with relapsed/ refractory Non-Hodgkin’s Lymphoma (NHL) (J. Kuruvilla et al. ASH 2014). Here we correlate response to selinexor with progression-free (PFS) & overall (OS) survival of pts with heavily pretreated DLBCL.
Methods
Selinexor was administered orally (3–80 mg/m2) for 8 or 10 doses in a 28-day cycle in this phase 1 study (NCT01607892). Response evaluation was performed in cycle 1 and 2 & then every 2 cycles. Comparison of survival rates was done by Kaplan Meier analysis using 10-weeks timepoint as landmark. All pts had heavily pretreated DLBCL (prior R-CHOP & additional therapies) with documented progressive disease on study entry.
Results
In 31 (of 33) pts with heavily pretreated DLBCL, the median number of prior therapies was 3 (range 1-11). The most common adverse effects (Grade 1/2) occurring after cycle 1 are fatigue (43%), anorexia (38%), nausea (29%), & dysgeusia (24%). Grade 3/4 adverse events occurring in ≥ 2 pts are thrombocytopenia (62%), neutropenia (24%), anemia (24%), fatigue (10%), hyponatremia (10%), syncope (10%), & confusion (10%). These are managed with dose interruption, platelet stimulators and/or standard supportive care. Among 31 pts treated with at least 1 cycle of selinexor, the overall response rate was 39% (12/31) with a median duration of response of ~7 months. 8 pts (26%) achieved partial response (PR), & 4 pts (13%) complete response (CR) confirmed by PET scan. Selinexor showed similar activity in GCB & non-GCB subtypes of DLBCL. The overall median PFS & OS for pts on study ≥ 10 weeks were 104 days & 155 days, respectively. In order to determine if best response of CR or PR to selinexor was associated with improved clinical outcomes, the PFS & OS of responding pts were compared with those of pts with stable (SD) or progressive (PD) disease. Comparison of OS & PFS for pts with objective responses vs those with SD & PD revealed a strong correlation between response & survival (N=24): Median PFS of pts with CR/PR vs SD/PD were 329 & 49 days respectively (p<0.001). Median OS of pts with CR/PR vs SD/PD were 571 & 108 days, respectively (p<0.01). Furthermore, 4 pts with CR remained on study for 217, 505+, 525+, & 650+ days.
Summary
Selinexor monotherapy shows significant anti-cancer activity in pts with heavily pretreated relapsed / refractory DLBCL. Objective responses to selinexor are durable & correlate with improved OS & PFS compared with pts who achieve SD or PD, suggesting that these responses are associated with clinical benefit. Clinical & molecular predictors of objective response to selinexor are being evaluated. A study of selinexor monotherapy (pts randomized to high versus low dose) in pts with heavily pretreated DLBCL is ongoing & combination studies are being initiated.
Keyword(s): DLBCL, Non-Hodgkin's lymphoma
Session topic: Optimization and innovation in treating aggressive lymphomas
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