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CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.
Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.
“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”
Mutations in IDH2 occur in approximately 12% of AML patients.
Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.
Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.
Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).
The clinical and translational papers were published simultaneously in Blood.
Study design
The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.
Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.
Four expansion arms were added, with 126 patients.
Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.
The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.
Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.
The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.
Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.
The MTD was not reached at doses up to 650 mg/day.
Baseline characteristics
Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.
The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.
Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).
There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).
The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.
SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.
Safety
The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).
The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).
“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”
“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”
Response
The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).
The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.
An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state with either 100 mg enasidenib daily or all doses.
“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”
“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”
Hematologic parameters also improved gradually.
Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.
Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”
“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”
Survival
The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.
And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.
Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.
Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.
And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.
“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.
Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.
The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.
But they did observe myeloid differentiation using FISH.
Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.
Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.
The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.
A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.
Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 
CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.
Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.
“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”
Mutations in IDH2 occur in approximately 12% of AML patients.
Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.
Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.
Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).
The clinical and translational papers were published simultaneously in Blood.
Study design
The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.
Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.
Four expansion arms were added, with 126 patients.
Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.
The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.
Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.
The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.
Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.
The MTD was not reached at doses up to 650 mg/day.
Baseline characteristics
Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.
The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.
Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).
There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).
The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.
SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.
Safety
The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).
The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).
“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”
“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”
Response
The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).
The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.
An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state with either 100 mg enasidenib daily or all doses.
“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”
“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”
Hematologic parameters also improved gradually.
Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.
Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”
“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”
Survival
The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.
And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.
Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.
Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.
And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.
“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.
Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.
The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.
But they did observe myeloid differentiation using FISH.
Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.
Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.
The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.
A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.
Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration.
CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.
Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.
“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”
Mutations in IDH2 occur in approximately 12% of AML patients.
Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.
Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.
Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).
The clinical and translational papers were published simultaneously in Blood.
Study design
The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.
Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.
Four expansion arms were added, with 126 patients.
Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.
The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.
Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.
The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.
Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.
The MTD was not reached at doses up to 650 mg/day.
Baseline characteristics
Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.
The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.
Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).
There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).
The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.
SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.
Safety
The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).
The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).
“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”
“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”
Response
The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).
The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.
An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state with either 100 mg enasidenib daily or all doses.
“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”
“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”
Hematologic parameters also improved gradually.
Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.
Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”
“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”
Survival
The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.
And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.
Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.
Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.
And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.
“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.
Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.
The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.
But they did observe myeloid differentiation using FISH.
Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.
Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.
The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.
A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.
Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration.