IDH1/2

ASCO 2018 | Ivosidenib induced durable responses in patients with IDH1 mutated R/R AML

In patients with advanced isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML), ivosidenib, an oral targeted inhibitor of mutant IDH1, at a dose of 500 mg daily was well tolerated and induced durable responses, and molecular remissions in some patients with complete remission (CR), according to data from a phase I dose escalation and expansion study (NCT02074839), presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting by Daniel Pollyea from the University of Colorado School of Medicine, Aurora, CO.

The phase I dose escalation and expansion study is evaluating ivosidenib monotherapy in patients with advanced hematologic malignancies with an IDH1 mutation. The efficacy and safety data obtained from the cohorts of R/R AML patients (primary efficacy population) receiving ivosidenib (500 mg once daily) with at least 6 months of follow-up were presented during this talk.

Overall, 179 R/R AML patients (median age = 67.0 years, range: 18–87) received ivosidenib 500 mg QD and 17 (9.5%) remained on treatment at the time of data cut-off (10 November 2017). The median duration of treatment for all patients was 3.9 months (range: 0.1–39.5). The primary efficacy endpoint was complete remission (CR) plus CR with partial hematologic recovery (CRh).

Key findings:
  • Safety
    • Most common adverse events occurring in ≥ 25% of patients include diarrhea (33.5%), leukocytosis (31.3%), nausea (31.3%), febrile neutropenia (29.1%), fatigue (28.5%), and electrocardiogram QT prolonged (25.7%)
    • Grade ≥ 3 leukocytosis occurred in 8% (14/179) of patients, managed with hydroxyurea
    • Grade ≥ 3 electrocardiogram QT prolonged occurred in 10% (18/179) of patients, managed with supportive care
    • IDH differentiation syndrome (IDH-DS) occurred in 10.6% (19/179) of patients, managed with supportive care
      • Grade ≥ 3 IDH-DS occurred in nine patients (5.0%)
    • Efficacy
      • CR+CRh rate: 31.8% (95% CI, 25.1–39.2)
      • Median duration of CR+CRh: 8.2 months (95% CI, 5.6–12.0)
      • Overall response rate (ORR): 41.9% (95% CI, 34.6–49.5)
    • Survival
      • Median follow-up time: 15.3 months (range: 0.2–39.5)
        • Median Overall survival (OS) in all patients: 9.0 months (95% CI, 7.1–10.0)
        • Median OS in patients that achieved CR+CRh: 18.8 months (95% CI, 14.2–NE)
      • IDH1 mutational clearance (MC)
        • Ivosidenib induced IDH1 MC in bone marrow mononuclear cells (BMMCs) in 23% of patients who achieved CR+CRh
          • Ivosidenib reduced mIDH1 variant allele frequency in both BMMCs and neutrophils in patients with best overall response of CR or CRh
        • Patients with MC had better durability of response and OS than patients without MC

The speaker concluded by stating that “in this high-risk, molecularly defined R/R AML patient population, ivosidenib induced durable remissions and was well tolerated”. Additionally, ivosidenib induced IDH1 MC in BMMCs in 23% of patients with best overall response of CR+CRh.

Eunice S. Wang from Roswell Park Comprehensive Cancer Center, Buffalo, NY, commented on the findings of this study during a talk at the ASCO meeting. She highlighted that ORR rate seen with ivosidenib “closely parallels” those seen with enasidenib, oral IDH2 inhibitor, in R/R IDH2 mutated AML patients. Eunice S. Wang noted that “ivosidenib is likely to become the new standard of care for IDH1 mutated R/R AML”. Additionally, given the development of ivosidenib and enasidenib in R/R AML patients, Eunice Wang recommended that IDH1/2 mutational status should also be considered as a standard of care for all R/R AML in order to “determine eligibility for targeted therapy”.2

References
  1. Pollyea D. A.  et al. Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/refractory acute myeloid leukemia (R/R AML): Results of a phase 1 study. J Clin Oncol 36, 2018 (suppl; abstr #7000). 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, 2018 June 1–5; Chicago, IL, USA.
  2. Wang E. S. Advancing Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes. 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, 2018 June 1–5; Chicago, IL, USA.
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