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Treatment with ivosidenib , a mutant isocitrate dehydrogenase 1 ( IDH1 ) inhibitor , led to durable remissions among people with relapsed or refractory , IDH1-mutated acute myeloid leukemia ( AML ), according to results from a phase I , dose-escalation and -expansion study presented at the 2018 ASCO Annual Meeting .

Daniel A . Pollyea , MD , MS , from the University of Colorado School of Medicine , reported the results , which were published simultaneously in The New England Journal of Medicine .

In February 2018 , the U . S . Food and Drug Administration ( FDA ) granted priority review to ivosidenib for the treatment of relapsed or refractory disease with an IDH1 mutation , based on earlier results from this ongoing phase I trial that were presented at the 2017 ASH Annual Meeting .

A total of 258 patients had received ivosidenib , at doses ranging from 100 mg twice-daily to 1,200 mg once-daily ; 179 ( median age = 67 years ; range = 18-87 years ) had received 500 mg once daily in continuous 28-day cycles .

The median number of prior therapies was two ( range = 1-6 ), and most participants had relapsed / refractory AML that was in second or later relapse , had relapsed following hematopoietic cell transplantation ( HCT ), or was refractory to induction or reinduction ( n = 126 ).

As of November 10 , 2017 ( data cutoff ), 17 patients ( 9.5 %) who received ivosidenib 500 mg remained on treatment , for a median treatment duration of 3.9 months ( range = 0.1-39.5 months ). The most common causes for treatment discontinuation were :

• progressive disease ( n = 92 ; 51.4 %)

• adverse event ( AE ; n = 27 ; 15.1 %)

• HCT ( n = 17 ; 9.5 %)

• death ( n = 10 ; 5.6 %)

The authors reported that the most common adverse events ( AEs ) of any grade ( occurring in ≥25 % of patients ) were : diarrhea ( 33.5 %), leukocytosis ( 31.3 %), nausea ( 31.3 %), febrile neutropenia ( 29.1 %), fatigue ( 28.5 %), and prolonged QT ( 25.7 %).

Most of these AEs were grades 1 or 2 and were considered unrelated to ivosidenib treatment . The most common grade ≥3 AEs included febrile neutropenia ( 29.1 %), anemia ( 20.1 %), and prolonged QT ( 10.1 %).

Nineteen patients ( 10.6 %) experienced IDH differentiation syndrome ( IDH-DS ), an AE that also was reported in clinical trials of the IDH2 inhibitor enasidenib . IDH-DS was grade ≥3 in nine of these patients ( 5.0 %), and six patients ( 3.4 %) discontinued ivosidenib because of IDH-DS .

“ This is what we would expect the adverse event profile to be in a cohort of patients with relapsed / refractory AML ,” Dr . Pollyea said . “ A few patients had to have study drug held , but there were no cases of dose reduction or permanent discontinuation and no deaths from IDH-DS .” He added that , even among people who developed

IDH-DS , most responded to ivosidenib , “ so the message is that supportive care and continued treatment can allow for patients to ultimately respond .”

The primary efficacy endpoint was complete remission rate ( CR ; defined as absolute neutrophil count > 0.5 × 10 9 / L and platelet count > 50 × 10 9 / L ) and CR with partial hematologic recovery ( CRh ).

The combined CR / CRh rate was 31.8 percent , which included CR in 43 patients ( 24 %). The median duration of CR / CRh was 8.2 months ( range = 5.6- 12.0 months ), and patients achieved CR / CRh within a median of 2.0 months ( range = 0.9-5.6 months ). Additional response data , including overall response ( secondary endpoint ) are presented in the TABLE .

After a median follow-up of 15.3 months ( range = 0.2-39.5 months ), median overall survival was nine months ( range = 7.1-10 months ), and 18.8 months ( range = 14.2 months to not estimable ) in patients who achieved CR / CRh .

Among the 91 patients who were platelet transfusion – dependent and 97 who were red blood cell transfusiondependent , the overall rate of transfusion independence ( defined as no transfusion for at least one 56-day period ) was 38.5 percent and 42.3 percent , respectively . Transfusion independence was observed across all response categories , the investigators noted . Among those who achieved a lower-degree response or no response at all , 17.5 percent became platelet transfusion independent and 23.7 percent red blood cell transfusion independent , “ which is obviously a big achievement with regard to quality of life .”

In a preliminary analysis of minimal residual disease in this cohort , single-agent ivosidenib 500 mg was “ able to completely

Attendees at the 2018 ASCO Annual Meeting

eradicate evidence of the IDH1 clone in 23 percent ( n = 11 / 47 ) of patients who had achieved a complete remission .” Depth of response also was associated with clinical outcomes , durability , and survival , which were improved for all patients who responded and were able to clear the IDH1 mutations , Dr . Pollyea added .

The study ’ s findings are limited by its single-arm and unblended design . Dr . Pollyea noted that , based on results of ivosidenib in this patient population , the drug is being evaluated in patients with previously untreated AML .

The authors report financial relationships with Agios , the manufacturers of ivosidenib .

REFERENCE

Pollyea DA , Dinardo CD , de Botton S , et al . Ivosidenib ( IVO ; AG-120 ) in mutant IDH1 relapsed / refractory acute myeloid leukemia ( R / R AML ): results of a phase 1 study . Abstract # 7000 . Presented at the 2018 ASCO Annual Meeting , June 2 , 2018 ; Chicago , IL .

TABLE . Efficacy Outcomes With Ivosidenib 500 mg / Day N = 179