The impact of IDH2 mutant allele (R140/R172) on survival outcomes with enasidenib: An update from the IDHENTIFY trial

Mutations in the isocitrate dehydrogenase 2 (IDH2) gene occur in around 8–19% of patients with acute myeloid leukemia (AML).¹ Enasidenib, an oral inhibitor of IDH2, is the only U.S. Food and Drug Administration (FDA)-approved therapy for this group of patients with relapsed or refractory (R/R) disease. We have previously outlined the IDHENTIFY trial of enasidenib versus conventional care regimens (CCR) in elderly patients with late-stage IDH2-mutated R/R AML (NCT02577406), which failed to meet its primary endpoint of increased overall survival. During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, De Botton, et al.¹ reported on the safety and efficacy analyses from the IDHENTIFY trial for patient subgroups defined by the IDH2 gene point mutations R140K and R172K. We summarize the key points below.

Co-mutational profile

Of the 319 patients enrolled, 229 (72%) had the IDH2^R140 mutation, and 88 (28%) had the IDH2^R172 mutation. IDH2 variable allele frequencies at baseline were highly variable but similar between treatment arms and IDH2 variants.

In the IDH2^R140 subgroup, the median number of baseline co-mutations was 5 (range, 1–11), with RUNX1 (59%) and SRSF2 (59%) being the most common. Moreover, this subgroup of patients was enriched with generally poor-risk mutations, including FLT3 (either the internal tandem duplication, or in the tyrosine kinase domain), NRAS, and RUNX1. In the IDH2^R172 subgroup, DNMT3A (57%) and RUNX1 (43%) were the most frequent co-mutations, with enrichment of both DNMT3A and TP53 compared to the IDH2^R140 subgroup. In addition, the median 2-hydroxyglutarate (2-HG) levels at baseline were similar between the treatment arms enasidenib (770.5 ng/mL) and CCR (791.8 ng/mL), and the mutant IDH2 variant subgroups IDH2^R140 (774.5 ng/mL) and IDH2^R172 (872.0 ng/mL).

Clinical responses

The overall response rate, complete remission rate, red blood cell transfusion independence, and hematologic improvement were all increased in patients treated with enasidenib versus CCR, in both subgroups (Figure 1).

Figure 1. Response rates for patients with IDH2^R140 or IDH2^R172 mutations treated with enasidenib or conventional care regimens*

CCR, conventional care regimens; CR, complete remission; ENA, enasidenib; HI, hematologic improvement; ORR, overall response rate; RBC-TI, red blood cell transfusion independence.
*Adapted from De Botton, et al.¹

Survival outcomes for patients with IDH2^R140 and IDH2^R172 mutations are shown in Table 1. Treatment with enasidenib conferred a significant survival benefit compared to CCR in patients with IDH2^R172. In patients with IDH2^R140, although time-to-treatment failure was improved with enasidenib treatment, the overall survival was similar between arms.

Table 1. Survival rates for patients with either IDH2^R140 or IDH2^R172 treated with enasidenib or conventional care regimens*

Safety

The median duration of treatment was substantially longer with enasidenib compared to CCR (142 days versus 36 days, respectively). The rates of common adverse events were comparable between patients in the IDH2^R140 and IDH2^R172 subgroups in both treatment arms (Table 2). The rates of enasidenib-related increases in bilirubin levels (IDH2^R140, 21%; IDH2^R172, 17%) and IDH differentiation syndrome (IDH2^R140, 14%; IDH2^R172, 14%) were comparable between treatment arms.

Table 2. Grade ≥3 treatment-related adverse events occurring in ≥10% of patients*

Conclusion

The IDH2^R140 variant was associated with poor-risk mutations and a significantly greater baseline mutational burden versus IDH2^R172. Enasidenib improved the overall response rate, complete remission, red blood cell transfusion independence, and hematologic improvement compared to CCR in both mutational subgroups, with similar safety profiles, also observed between treatments. The survival benefits provided by enasidenib were more evident in patients with the IDH2^R172 mutation than IDH2^R140. Additional research is required to investigate the influence of the distinct IDH2^R140/IDH2^R172 co-mutational profiles on treatment outcomes.