Neil Osterweil

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – Patients with advanced urothelial cancer that has progressed following platinum-based chemotherapy and immunotherapy with checkpoint inhibitors have a poor prognosis and few effective therapeutic options.

But in a phase 2 trial in 125 patients with locally advanced or metastatic urothelial cancer, the investigational agent enfortumab vedotin was associated with a 44% objective response rate, including a 12% complete response rate and 32% partial response rate. The responses were observed across all subgroups, irrespective of response to prior immunotherapy or the presence of liver metastases, reported Daniel Petrylak, MD, a professor of medical oncology and urology at Yale Cancer Center in New Haven, Connecticut.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Petrylak described how the agent is directed toward a novel target, Nectin-4, a protein expressed in about 97% of urothelial cancers and in other solid tumor types.

The study is sponsored by Seattle Genetics and Astellas Pharma. Dr. Petrylak disclosed a consulting or advisory role with Astellas and others, funding from Seattle Genetics, and financial relationships with multiple other companies.
 

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.

Neil Osterweil/MDedge News

Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.

“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.

The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.

The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.

“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.

The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.

The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.

In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).

As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.

The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.

Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.

Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.

The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.

Neil Osterweil/MDedge News

Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.

The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.

SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .

CHICAGO – Adding ribociclib to endocrine therapy significantly improved overall survival of premenopausal women with advanced hormone receptor positive, HER2-negative breast cancer, results of the randomized phase 3 MONALEESA-7 trial showed.

Neil Osterweil/MDedge News

A landmark analysis conducted at 42 months showed that the overall survival rate for women randomized to receive endocrine therapy with either a nonsteroidal aromatase inhibitor (AI) or tamoxifen plus the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib was 70%, compared with 46% for women randomized to endocrine therapy alone, reported Sara A Hurvitz, MD, of the University of California Los Angeles Jonsson Comprehensive Cancer Center

“This is the first time a statistically significant improvement in overall survival has been observed with a CDK4/6 inhibitor in combination with endocrine therapy in patients with hormone receptor-positive advanced disease,” she said at a briefing prior to her presentation of the data in an oral abstract session at the American Society of Clinical Oncology annual meeting.

“This is an important study, because it shows that the class of drugs, CDK4/6 inhibitors, which we are widely using, has been shown to delay the time to progression, delay the time to need for chemotherapy for advanced breast cancer, and really doubled the effectiveness of endocrine therapy, now also translates into a significant survival benefit for women who ER-positive metastatic breast cancer,” commented Harold J. Burstein, MD, PhD, an ASCO expert from the Dana-Farber Cancer Institute in Boston.

Neil Osterweil/MDedge News

In the trial, 672 pre- or perimenopausal women with HR+/HER2– advanced breast cancer with no prior endocrine therapy for advanced disease and no more than one line of chemotherapy for advanced disease were enrolled. The patients were stratified by the presence of liver/lung metastases, prior chemotherapy, and prior endocrine partner, tamoxifen or nonsteroidal AI, and then randomly assigned to ribociclib 600 mg/day for 3 weeks, followed by 1-week off, plus tamoxifen or AI and goserelin, or the same combination and schedule with placebo.

Of the 672 patients enrolled, a total of 335 patients assigned to ribociclib and 337 assigned to placebo received treatment. The majority of patients – 495 – received an AI, either letrozole (Femara) or anastrozole (Arimidex). Dr. Hurvitz noted that after the initiation of MONALEESA-7, the combination of a CDK4/6 inhibitor and tamoxifen was found to prolong the QT interval and increase risk for cardiac arrhythmias, and is now contraindicated.

As previously reported , results of the primary MONALEESA-7 endpoint of progression-free survival favored the combination, with a median PFS of 23.8 months, compared with 13 months for women treated with endocrine therapy alone. The hazard ratio for progression with the ribociclib-based combination was 0.553 ( P less than .0001), and the treatment benefit of the CDK4/6 inhibitor was seen across all patients subgroups and regardless of the endocrine partner.

At ASCO 2019, Dr. Hurvitz reported on the key secondary endpoint of overall survival. At a median follow-up duration of 34.6 months, with an additional 15 months beyond the initial analysis, the median OS for the ribociclib arm was not reached, compared with 40.9 months in the placebo arm. The hazard ratio for death with ribociclib was 0.712 ( P = .00973). An analysis of OS by endocrine partner subgroup showed no significant differences between AIs or tamoxifen.

At the time of the data cutoff, 35% of patients in the ribociclib arm were still on therapy.

The safety and tolerability of the combination were consistent with those previously reported, Dr. Hurvitz said.

“In an era when we are thinking about value in oncology care, a demonstration of a robust sutvival difference I think substantially adds to a value proposition for products like ribociclib that were discussed here,” Dr. Burstein said.

“Hopefully, these data will enable access to this product to more women around the world, particularly in health care systems that assess value rigorously as part of their decisions for national access to drugs,” he added.

The MONALEESA-7 trial is supported by Novartis. Dr. Hurvitz reported travel and accommodation expenses from Novartis. Dr. Burstein reported no relevant disclosures.

SOURCE: Hurvitz SA et al. ASCO 2019. Abstract LBA1008 .

CHICAGO – Adding ribociclib to endocrine therapy significantly improved overall survival of premenopausal women with advanced hormone receptor positive, HER2-negative breast cancer, results of the randomized phase 3 MONALEESA-7 trial showed.

Neil Osterweil/MDedge News

A landmark analysis conducted at 42 months showed that the overall survival rate for women randomized to receive endocrine therapy with either a nonsteroidal aromatase inhibitor (AI) or tamoxifen plus the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib was 70%, compared with 46% for women randomized to endocrine therapy alone, reported Sara A Hurvitz, MD, of the University of California Los Angeles Jonsson Comprehensive Cancer Center

“This is the first time a statistically significant improvement in overall survival has been observed with a CDK4/6 inhibitor in combination with endocrine therapy in patients with hormone receptor-positive advanced disease,” she said at a briefing prior to her presentation of the data in an oral abstract session at the American Society of Clinical Oncology annual meeting.

“This is an important study, because it shows that the class of drugs, CDK4/6 inhibitors, which we are widely using, has been shown to delay the time to progression, delay the time to need for chemotherapy for advanced breast cancer, and really doubled the effectiveness of endocrine therapy, now also translates into a significant survival benefit for women who ER-positive metastatic breast cancer,” commented Harold J. Burstein, MD, PhD, an ASCO expert from the Dana-Farber Cancer Institute in Boston.

Neil Osterweil/MDedge News

In the trial, 672 pre- or perimenopausal women with HR+/HER2– advanced breast cancer with no prior endocrine therapy for advanced disease and no more than one line of chemotherapy for advanced disease were enrolled. The patients were stratified by the presence of liver/lung metastases, prior chemotherapy, and prior endocrine partner, tamoxifen or nonsteroidal AI, and then randomly assigned to ribociclib 600 mg/day for 3 weeks, followed by 1-week off, plus tamoxifen or AI and goserelin, or the same combination and schedule with placebo.

Of the 672 patients enrolled, a total of 335 patients assigned to ribociclib and 337 assigned to placebo received treatment. The majority of patients – 495 – received an AI, either letrozole (Femara) or anastrozole (Arimidex). Dr. Hurvitz noted that after the initiation of MONALEESA-7, the combination of a CDK4/6 inhibitor and tamoxifen was found to prolong the QT interval and increase risk for cardiac arrhythmias, and is now contraindicated.

As previously reported , results of the primary MONALEESA-7 endpoint of progression-free survival favored the combination, with a median PFS of 23.8 months, compared with 13 months for women treated with endocrine therapy alone. The hazard ratio for progression with the ribociclib-based combination was 0.553 ( P less than .0001), and the treatment benefit of the CDK4/6 inhibitor was seen across all patients subgroups and regardless of the endocrine partner.

At ASCO 2019, Dr. Hurvitz reported on the key secondary endpoint of overall survival. At a median follow-up duration of 34.6 months, with an additional 15 months beyond the initial analysis, the median OS for the ribociclib arm was not reached, compared with 40.9 months in the placebo arm. The hazard ratio for death with ribociclib was 0.712 ( P = .00973). An analysis of OS by endocrine partner subgroup showed no significant differences between AIs or tamoxifen.

At the time of the data cutoff, 35% of patients in the ribociclib arm were still on therapy.

The safety and tolerability of the combination were consistent with those previously reported, Dr. Hurvitz said.

“In an era when we are thinking about value in oncology care, a demonstration of a robust sutvival difference I think substantially adds to a value proposition for products like ribociclib that were discussed here,” Dr. Burstein said.

“Hopefully, these data will enable access to this product to more women around the world, particularly in health care systems that assess value rigorously as part of their decisions for national access to drugs,” he added.

The MONALEESA-7 trial is supported by Novartis. Dr. Hurvitz reported travel and accommodation expenses from Novartis. Dr. Burstein reported no relevant disclosures.

SOURCE: Hurvitz SA et al. ASCO 2019. Abstract LBA1008 .

CHICAGO – Adding ribociclib to endocrine therapy significantly improved overall survival of premenopausal women with advanced hormone receptor positive, HER2-negative breast cancer, results of the randomized phase 3 MONALEESA-7 trial showed.

Neil Osterweil/MDedge News

A landmark analysis conducted at 42 months showed that the overall survival rate for women randomized to receive endocrine therapy with either a nonsteroidal aromatase inhibitor (AI) or tamoxifen plus the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib was 70%, compared with 46% for women randomized to endocrine therapy alone, reported Sara A Hurvitz, MD, of the University of California Los Angeles Jonsson Comprehensive Cancer Center

“This is the first time a statistically significant improvement in overall survival has been observed with a CDK4/6 inhibitor in combination with endocrine therapy in patients with hormone receptor-positive advanced disease,” she said at a briefing prior to her presentation of the data in an oral abstract session at the American Society of Clinical Oncology annual meeting.

“This is an important study, because it shows that the class of drugs, CDK4/6 inhibitors, which we are widely using, has been shown to delay the time to progression, delay the time to need for chemotherapy for advanced breast cancer, and really doubled the effectiveness of endocrine therapy, now also translates into a significant survival benefit for women who ER-positive metastatic breast cancer,” commented Harold J. Burstein, MD, PhD, an ASCO expert from the Dana-Farber Cancer Institute in Boston.

Neil Osterweil/MDedge News

In the trial, 672 pre- or perimenopausal women with HR+/HER2– advanced breast cancer with no prior endocrine therapy for advanced disease and no more than one line of chemotherapy for advanced disease were enrolled. The patients were stratified by the presence of liver/lung metastases, prior chemotherapy, and prior endocrine partner, tamoxifen or nonsteroidal AI, and then randomly assigned to ribociclib 600 mg/day for 3 weeks, followed by 1-week off, plus tamoxifen or AI and goserelin, or the same combination and schedule with placebo.

Of the 672 patients enrolled, a total of 335 patients assigned to ribociclib and 337 assigned to placebo received treatment. The majority of patients – 495 – received an AI, either letrozole (Femara) or anastrozole (Arimidex). Dr. Hurvitz noted that after the initiation of MONALEESA-7, the combination of a CDK4/6 inhibitor and tamoxifen was found to prolong the QT interval and increase risk for cardiac arrhythmias, and is now contraindicated.

As previously reported , results of the primary MONALEESA-7 endpoint of progression-free survival favored the combination, with a median PFS of 23.8 months, compared with 13 months for women treated with endocrine therapy alone. The hazard ratio for progression with the ribociclib-based combination was 0.553 ( P less than .0001), and the treatment benefit of the CDK4/6 inhibitor was seen across all patients subgroups and regardless of the endocrine partner.

At ASCO 2019, Dr. Hurvitz reported on the key secondary endpoint of overall survival. At a median follow-up duration of 34.6 months, with an additional 15 months beyond the initial analysis, the median OS for the ribociclib arm was not reached, compared with 40.9 months in the placebo arm. The hazard ratio for death with ribociclib was 0.712 ( P = .00973). An analysis of OS by endocrine partner subgroup showed no significant differences between AIs or tamoxifen.

At the time of the data cutoff, 35% of patients in the ribociclib arm were still on therapy.

The safety and tolerability of the combination were consistent with those previously reported, Dr. Hurvitz said.

“In an era when we are thinking about value in oncology care, a demonstration of a robust sutvival difference I think substantially adds to a value proposition for products like ribociclib that were discussed here,” Dr. Burstein said.

“Hopefully, these data will enable access to this product to more women around the world, particularly in health care systems that assess value rigorously as part of their decisions for national access to drugs,” he added.

The MONALEESA-7 trial is supported by Novartis. Dr. Hurvitz reported travel and accommodation expenses from Novartis. Dr. Burstein reported no relevant disclosures.

SOURCE: Hurvitz SA et al. ASCO 2019. Abstract LBA1008 .