Ivosidenib monotherapy of 500 mg/24 hrs in R/R AML had acceptable tolerance and was not related to any dose-limiting toxic effects, although adverse events (AEs) were reported in 99% of the patients enrolled in Phase I clinical trial and the dose-expansion study [NCT02074839].38,39 Table 1summarizes the AEs reported in >20% patients in all the grades, as well as AE grades ≥3. Treatment-related AEs from ivosidenib were IDH differentiation syndrome (IDH-DS), prolongation of the QT interval, and leukocytosis. All these AEs are manageable and reversible, without needing permanent discontinuation of treatment. There were no deaths related to ivosidenib dose of 500 mg/24 hrs, whereas at 800 mg/24 hrs one AE-related death (cardiac tamponade) was reported as possibly associated with ivosidenib.
IDH-DS is a potentially fatal AE that produces a rapid increase in the differentiation of neutrophils after the removal of the differentiation block in the malignant myeloid clone. It was initially described in acute promyelocytic leukemia and it is a common AE of IDHmut inhibitors.43,44 IDH-DS showed similar incidence with enasidenib (ivosidenib, total: 19 [10.6%], grade ≥3: 9 [5.0%];38 enasidenib, total: 33 [11.7%]; grade ≥3: 15 [6.3%]),45 an IDH2 inhibitor, and in more than a third of the cases it could be accompanied with leukocytosis. A recent systematic analysis performed by the FDA46obtained a higher incidence of 19% of IDH-DS in clinical trials of ivosidenib and enasidenib in R/R AML using the diagnosed criteria of Montesinos et al.47 IDH-DS could be managed by discontinuation and treatment with glucocorticoids and/or hydroxyurea, and these patients had clinical responses.38,42
After the FDA approval of ivosidenib monotherapy in R/R AML with IDH1mut, an expanded-access program has been promoted by manufacturing company including adult patients and children ≥12 years of age who weigh at least approximately 100 lb [NCT03245424]. Combinations of ivosidenib with HMAs or intensive chemotherapy in R/R AML IDH1mut patients have not been evaluated yet. However, the addition of venetoclax to ivosidenib is under investigation in this subset of patients in a Phase I/II trial [NCT03471260].
The use of ivosidenib as a front-line therapy as a single agent38,48 has been analyzed in a Phase Ib clinical trial [NCT02074839] (Table 2), and it has shown a promising 42.4% CR/CRh rate among the 33 subjects. Ongoing clinical trials are testing in IDH1mut-untreated AML patients, the safety and efficacy of different combinations of ivosidenib with azacitidine [NCT03173248; NCT02677922]49–51 or intensive chemotherapy [NCT02632708]52 (Table 2). It is worth noting that a new international Phase III randomized clinical trial aiming to enroll a large number of patients will compare AZA+IVO vs AZA in newly diagnosed IDH1mut patients unfit for intensive chemotherapy [NCT03173248]. Moreover, ivosidenib is being tested as maintenance therapy after allo-HSCT in IDH1mut myeloid malignancies in a Phase I dose-escalation trial [NCT03564821].
(To view a larger version of Table 2, click here.)
Drug development and pharmacokinetics
Olutasidenib (FT-2102) is a new IDH1mut inhibitor that is being tested in an ongoing Phase I/II clinical trial in patients with IDH1mut AML (R/R or untreated) and MDS [NCT02719574] in monotherapy and combined with azacitidine. Preclinical studies in rats and human tissue showed a major excretion route through the hepatic metabolism by CYP enzymes (CPY3A4, 2C9 and 1A1). Pharmacokinetic, pharmacodynamic, and safety data have supported the selection of a 150 mg/12 hr dose, reaching a durable steady state at 2 weeks without a low threshold for QTc-prolongation risk and achieving prompt and durable 2-HG reductions.53 FT-2102 is also being tested in advanced solid tumors and gliomas with IDH1mut [NCT03684811].
The first set of data of the Phase I/II clinical trial was recently presented, including 31 patients treated with FT-2102 as a single agent with a median of 3 months (range 0.2–20 months), 22 of them with R/R AML with no prior therapy with IDH1mut inhibitors (Table 1).53 Preliminary endpoints reported were CR rate of 14%, a CRi and morphologic leukemia-free state (MLFS) of 19%, and OR of 33%.
Regarding the safety of olutasidenib, severe AEs occurring in >5% of patients of the entire cohort are included in Table 1. IDH-DS was reported in 3 patients and resolved after temporary discontinuation and treatment with dexamethasone, hydroxyurea, and supportive care. There were no deaths related to FT-2102 therapy.53
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