ONCAlert | Upfront Therapy for mRCC

Case 3: IDH Inhibitors for the Treatment of AML

Targeted Oncology
Published Online:12:27 PM, Wed July 10, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: I think we’ll stop here and, if you can please go ahead, Dr Gergis, and discuss the IDH data.

Usama Gergis, MD, MBA: Sure. I’ll present IDH data that was presented at ASH [the American Society of Hematology meeting] 2017 in the refractory/relapsed AML [acute myeloid leukemia] phase I/II design. There are 2 phases in this, the phase I escalation phase, then the expansion dosing. It was designed for patients with advanced myeloid malignancies with IDH2 mutation. The IDH2 inhibitor was given continuously for 28 days. The cumulative daily dose had a huge range of 50 mg to 650 mg. The expansion phase included patients with relapsed/refractory AML above age 60 or younger than 60, and there was a proportion of patients with upfront, untreated AML. I think there were about 30 patients, more or less, and some other patients who were ineligible for other arms. The expansion dosing had enasidenib at 100 mg po [by mouth] once a day for the AML group that had about 109 patients. Just like phase I, the early phase II studies’ key endpoints were the safety and the maximum tolerated dose.

The efficacy of enasidenib in mutated IDH2 relapsed/refractory AML, so they highlighted 2 boxes. According to the second box, the complete remission [CR]—42 patients out of 214, so that’s approximately 20% for the AML group and 19% for all patients. CR and CRi [complete remission with incomplete hematologic recovery] were 38.8% for the AML group. The overall survival by the best response were those who had CR, who had the best overall survival at 19.7 months. The nonresponders had 7 months, which is not so bad for relapsed/refractory AML patients. It’s much less than that in the real world. The non-CR responses—CRi and others—had something in between at 13.8 months.

Naval G. Daver, MD: Thank you very much. Again, this brings up the point that as a single agent…because I think you have to have the perspective, as you kind of mentioned, even with chemotherapy. Gail Roboz [MD] had a big multi-arm study of elacytarabine, and if you look at it, everybody was hitting 20% or 30%. Again, above 35% or 40%, and to get that survival with a single oral agent, which is really quite safe, once you know about the differentiation, is very good.

The other thing is, this kind of changed, actually it was BLINA [blinatumomab] that started it, but this changed the paradigm for AML with responses above CRh [complete response with partial hematologic recovery] becoming meaningful. I think this is something that almost all the physicians agree with, and probably patients, too. It was really good that even the FDA felt that this was meaningful, because we always had this very high bar of platelets of 100 and ANC [absolute neutrophil count] of 1. Whereas, if I saw somebody in clinic with platelets of 60 or 70 and ANC of 0.8 staying that way for 2 months, I was very happy. I think that the CRh, especially in the setting of these non-induction cytotoxic therapies, is a very meaningful benefit. We’re seeing it used with AZA/VEN [azacitidine/venetoclax] and with gilteritinib. In fact, a lot of these patients actually are doing quite well.

With these new agents, there’s a lot of discussion about response criteria, and for 20 years we were on the train of only remission and not only remission, where only remission MRD [minimal residual disease]-negative mattered. Now we’re actually almost, with the new agents, taking a step back, because with IDH with FLT3, we’re seeing that the MRD negativity may not correlate directly with survival. They showed that in the IDH paper. I think there’s going to be a new learning curve with these new agents that is going to be different from cytotoxics. It’s very exciting and interesting data. With that, we’ll move to the next case. Thank you very much.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Naval G. Daver, MD: I think we’ll stop here and, if you can please go ahead, Dr Gergis, and discuss the IDH data.

Usama Gergis, MD, MBA: Sure. I’ll present IDH data that was presented at ASH [the American Society of Hematology meeting] 2017 in the refractory/relapsed AML [acute myeloid leukemia] phase I/II design. There are 2 phases in this, the phase I escalation phase, then the expansion dosing. It was designed for patients with advanced myeloid malignancies with IDH2 mutation. The IDH2 inhibitor was given continuously for 28 days. The cumulative daily dose had a huge range of 50 mg to 650 mg. The expansion phase included patients with relapsed/refractory AML above age 60 or younger than 60, and there was a proportion of patients with upfront, untreated AML. I think there were about 30 patients, more or less, and some other patients who were ineligible for other arms. The expansion dosing had enasidenib at 100 mg po [by mouth] once a day for the AML group that had about 109 patients. Just like phase I, the early phase II studies’ key endpoints were the safety and the maximum tolerated dose.

The efficacy of enasidenib in mutated IDH2 relapsed/refractory AML, so they highlighted 2 boxes. According to the second box, the complete remission [CR]—42 patients out of 214, so that’s approximately 20% for the AML group and 19% for all patients. CR and CRi [complete remission with incomplete hematologic recovery] were 38.8% for the AML group. The overall survival by the best response were those who had CR, who had the best overall survival at 19.7 months. The nonresponders had 7 months, which is not so bad for relapsed/refractory AML patients. It’s much less than that in the real world. The non-CR responses—CRi and others—had something in between at 13.8 months.

Naval G. Daver, MD: Thank you very much. Again, this brings up the point that as a single agent…because I think you have to have the perspective, as you kind of mentioned, even with chemotherapy. Gail Roboz [MD] had a big multi-arm study of elacytarabine, and if you look at it, everybody was hitting 20% or 30%. Again, above 35% or 40%, and to get that survival with a single oral agent, which is really quite safe, once you know about the differentiation, is very good.

The other thing is, this kind of changed, actually it was BLINA [blinatumomab] that started it, but this changed the paradigm for AML with responses above CRh [complete response with partial hematologic recovery] becoming meaningful. I think this is something that almost all the physicians agree with, and probably patients, too. It was really good that even the FDA felt that this was meaningful, because we always had this very high bar of platelets of 100 and ANC [absolute neutrophil count] of 1. Whereas, if I saw somebody in clinic with platelets of 60 or 70 and ANC of 0.8 staying that way for 2 months, I was very happy. I think that the CRh, especially in the setting of these non-induction cytotoxic therapies, is a very meaningful benefit. We’re seeing it used with AZA/VEN [azacitidine/venetoclax] and with gilteritinib. In fact, a lot of these patients actually are doing quite well.

With these new agents, there’s a lot of discussion about response criteria, and for 20 years we were on the train of only remission and not only remission, where only remission MRD [minimal residual disease]-negative mattered. Now we’re actually almost, with the new agents, taking a step back, because with IDH with FLT3, we’re seeing that the MRD negativity may not correlate directly with survival. They showed that in the IDH paper. I think there’s going to be a new learning curve with these new agents that is going to be different from cytotoxics. It’s very exciting and interesting data. With that, we’ll move to the next case. Thank you very much.

Transcript edited for clarity.
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