Therapeutic targeting of isocitrate dehydrogenase mutant AML

Figures & data

Figure 1. Mutant IDH enzymes convert α-KG to 2-HG with consequent widespread dysregulation in epigenetic machinery. Altered enzyme activity is indicated with curved red arrow. CB839- glutaminase inhibitor, venetoclax-BCL2 inhibitor, AG221, AG120, IDH305- mutant IDH inhibitors. Full color available online.

Table 1. Interim results of Phase 1 studies on AG120, AG221, and IDH305.

Drug	Study phase	Disease condition	Study number of patients	Reported response rates	Toxicity profile (deaths)	Comments
AG120	Phase 1	IDH1-mutant positive advanced hematologic malignancies	N = 78 (63 with R/R AML)	ORR = 33%, CR = 16%	30-Day mortality: 12%, 60-day mortality: 21%	Safe with minimal toxicities. Durable response durations of a median of 10.2 months
IDH305	Phase 1	Advanced malignancies including R/R AML/MDS with IDH1^R132 mutation	N = 81; AML/MDS = 24	ORR = 7 (33%) AML; CR in 2 (9.5%)	Not reported	Very favorable safety profile. Durable response durations in responders
AG221	Phase 1/2	mIDH2- AML	R/R-AML n = 138 (70%); untreated AML/MDS/other 30%	74 (41%); RR-AML = 52 (41%)	Not reported	Safe with few side effects, including indirect hyperbilirubinemia and nausea. Good response rates in IDH2 AML.

ORR: objective response rate; CR: complete remission; AML: acute myeloid leukemia; MDS: myelodysplastic syndromes.

Table 2. Ongoing Phase I/II studies evaluating AG-221 and AG-120 either as monotherapy or in combination regimens in AML.

Drug	Mutation	Disease condition	Study arm intervention	Outcome measures	Phase, current status	NCI identifier
AG221	IDH2	R/R AML + IDH2 > 60 years	AG221 vs. aza+BSC/LDAC+BSC/IDAC+BSC	Efficacy-OS	3, recruiting	NCT02577406
AG221	IDH2	R/R AML + IDH2 > 18 years not eligible for intensives	AG221	Safety, tolerability, maximum tolerated dose	1/2, active	NCT01915498
AG120	IDHI1	R/R AML + IDH1 > 18 yrs	AG120	Safety, tolerability, maximum tolerated dose	1, recruiting	NCT02074839
AG120	IDHI1	R/R AML + IDH1 > 18 yrs not eligible for intensives	AG120+azacitidine vs. azacitidine	Efficacy-ORR	2, recruiting	NCT02677922
AG120 & AG221	IDH1/2	Newly diagnosed AML with IDH mutation; in combination with standard induction and consolidation therapies	AG120+ standard induction (cytarabine/daunorubicin) and consolidation; AG221+ standard induction (cytarabine/daunorubicin) and consolidation	Safety, tolerability	1b/2, recruiting	NCT02632708

AML: acute myeloid leukemia; OS: overall survival; ORR: objective response rate; BSC: best supportive care; LDAC: low dose ara-C; IDAC: intermediate dose ara-C.