SEAL: Selinexor extends PFS in advanced dedifferentiated liposarcoma

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.

The investigational drug selinexor appears to be improving progression-free survival in patients with advanced dedifferentiated liposarcoma, based on phase 2 results from the randomized, placebo-controlled SEAL study.

But the statistical significance of the improvements varied depending on whether progression-free survival (PFS) was assessed by the World Health Organization criteria, which looks at two-dimensional measurements of these irregular three-dimensional objects, or RECIST v1.1 criteria, which only looks at a unidimensional measure, reported Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center, New York, at the annual meeting of the American Society of Clinical Oncology. When tumor response was based on WHO criteria, there was no difference in median PFS for the 24 patients on active therapy (1.4 months) and the 27 patients on placebo (1.8 months). By RECIST v1.1 criteria, however, median PFS was 5.6 months with selinexor.

Dedifferentiated liposarcoma is incurable, and palliative therapies are associated with an overall survival of 11-20 months in these patients. Selinexor is an oral selective inhibitor of exportin-1 which exports proteins from the nucleus into the cytoplasm. The drug appears to prevent p53 from leaving the nucleus, thereby protecting it from overexpressed MDM2, which is a negative regulator of p53, but the drug might have other potential mechanisms of action.

The double-blind study included 56 evaluable patients who had progressive dedifferentiated liposarcoma and had received at least one prior systemic therapy. Patients’ median age was 61 years and they had received a median of two prior therapies. Patients were randomized to get either 60 mg of selinexor (26 patients) or placebo (30 patients) twice weekly until their disease progressed or they were no longer able to tolerate therapy. Patients whose disease progressed on placebo (24 patients) were allowed to cross over to open-label selinexor therapy.

Treatments were unblinded for 51 of the patients, 24 on selinexor and 27 on placebo. Disease progression as confirmed by Independent Central Radiological Review using WHO criteria was the main reason for ending blinded treatment.

Grade 1/2 adverse events for selinexor versus placebo, respectively, were nausea (85% vs. 31%), anorexia (62% vs. 14%), and fatigue (58% vs. 45%). The comparable rates of grade 3/4 adverse events were hyponatremia (15% vs. 0%), anemia (15% vs. 7%), and thrombocytopenia (12% vs. 0%). Selinexor dose was reduced because of adverse events in 12 patients.

In a discussion of the study’s implications, Mark Andrew Dickson, MD, also of Memorial Sloan Kettering Cancer Center, called the adverse events profile “mostly manageable but predictable grade 1/2 adverse events ... and median progression-free survival of 5 and a half months is quite encouraging.

“Changing response assessment method midtrial in a study with progression-free survival as the primary endpoint is obviously problematic, but it also highlights how difficult it is to measure three-dimensional tumors like complex retroperitoneal liposarcomas, which move and change and grow and shrink over time,” he said. “And I would conclude that RECIST is probably the worst method of tumor assessment for sarcoma, except for all the other methods of tumor assessment.”

To illustrate the difficulty of measuring tumor response, Dr. Dickson presented examples of different tumor shapes and scenarios where one method would indicate tumor progression and the other would indicate stable disease.

“There can be differences between the two methods in how progression responds and is determined. And you can do this experiment with a number of different shapes and find scenarios where one method would call it progression at a different time than the other. So this is really critically important when we look at the results of the clinical trial, because it was designed to look at WHO PFS. And you can see that, based on that, there was no significant difference between the selinexor and placebo arm,” he said.

Additionally, he reviewed cases from the study where “either way you measure this, you can see that [the] tumor is getting smaller over time,” as well as cases where the tumor grew in patients on placebo first, but decreased in size after switching to the active therapy.

“The improvement in progression-free survival is promising and ... selinexor probably does have activity in dediff lipo compared to historical data,” said Dr. Dickson, adding that he looks forward to selinexor progressing to a randomized, phase 3 trial and “seeing those data perhaps next year.”

Dr. Gounder disclosed financial relationships with multiple drug companies including Karyopharm Therapeutics, the maker of selinexor. Dr. Dickson disclosed a consult or adviser role with Celgene and research funding from Eli Lilly.

SOURCE: Gounder M et al. ASCO 2018, Abstract 11512.