Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies.

Abstract

7500 Background: Mutations in the isocitrate dehydrogenase-1 gene ( IDH1) result in myeloid differentiation arrest and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), promoting leukemogenesis. We report a primary safety and efficacy analysis of the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continous) combined with venetoclax (VEN; D1-14 per 28-day cycle), with and without azacitidine (AZA; 75mg/m2 D1-7). Methods: Eligible patients age ≥18 with IDH1 mutated myeloid malignancies (high-risk MDS and AML) enrolled into one of three successive cohorts (Cohort 1: IVO+VEN 400 mg, Cohort 2: IVO+VEN 800 mg, Cohort 3: IVO+VEN 400 mg+AZA). Primary endpoints include safety and tolerability and overall response rate (ORR) by revised IWG criteria. Key secondary endpoints include survival endpoints and PK correlates. Results: 19 patients (median age 68) enrolled, 17 with AML: 9 relapsed/refractory AML (R/R; median 1 prior line of therapy), 5 treatment naïve AML, and 3 HMA-failure MDS with secondary AML. Two patients had high-risk MDS. ELN risk was favorable, intermediate, and adverse risk in 37%, 15%, and 47%. Co-mutations included NPM1 (37%), chromatin-spliceosome (32%), methylation (16%), and RAS pathway (21%). Adverse events of special interest included IDH differentiation syndrome (n=4, grade > 3 in 1) and tumor lysis syndrome (TLS; n=2), including one grade 3 TLS event in a NPM1+ patient (successfully managed without hemodialysis). In evaluable patients (n=18), composite complete remission (CRc: CR+CRi+CRh) rates were 78% overall (treatment naive: 100%, R/R: 75%), and 67%, 100%, and 67% by cohort (median time to best response: 2 months). 7 (50%) patients achieving CRc were also MRD negative by flow cytometry. 1 patient had HI without CR/CRi and 1 had a MLFS. 9 (50%) patients remain on study, 3 (17%) proceeded to SCT in CR, 2 were non-responders, and 5 (22%) experienced progressive disease following CRc occurring after a median of 3 months. After a median follow up of 3.5 months, median OS was not reached in treatment naïve patients, and 9.7 months in R/R patients. Conclusions: IVO+VEN +AZA therapy is well tolerated and highly effective for patients with IDH1 mutated AML. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03471260 . [Table: see text]

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points

“…In terms of therapeutic decision-making for elderly or unfit AML patients with known FLT3 or IDH1/2 mutations, we are often faced with the choice of venetoclax-based therapy or targeted therapy with either IDH inhibitors (enasidenib/ivosidenib) or FLT3 inhibitors (midostaurin/gilteritinib). Preliminary results from an ongoing phase Ib/II study on venetoclax plus ivosidenib with or without azacitidine in IDH1 mutated AML and high-risk MDS appear promising 56 . A total of 19 patients were enrolled of which 17 were AML (9 relapsed, 5 treatment naïve and 3 with secondary AML following MDS with progression on HMA) and 2 patients with high-risk MDS with composite CR rate of 78% overall and 100% for treatment-naive patients.…”

Emerging agents and regimens for AML

“…There is also a rationale for combining IDH inhibitors with BCL-2 inhibitors, since the accumulation of 2-HG caused by IDH mutations could decrease the mitochondrial threshold for induction of apoptosis induced by BCL-2 inhibition with venetoclax [ 46 ]. The combination therapy of ivosidenib (IVO) plus venetoclax (VEN) with or without azacitidine was found to be effective against AML harboring an IDH1 mutation in a phase Ib/II trial [ 47 ]. Patients with AML or high-risk MDS were assigned to one of three cohorts, either receiving IVO + VEN 400 mg, IVO + VEN 800 mg, or IVO + VEN 400 mg + AZA.…”

Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions

“…This concept is currently being investigated in a phase Ib/II clinical trial of a combination of venetoclax and ivosidenib, with or without azacitidine in patients with IDH1-mutated AML (NCT03471260). Preliminary results have been presented at the American Society of Clinical Oncology (ASCO 2020 meeting for the first 18 evaluable patients treated (3 cohorts with 6 patients each, ivosidenib + venetoclax 400 mg or 800 mg +/-azacytidine), showing good tolerability and promising efficacy (53). No new safety signal was observed, and the CR/CRi rate was 89% (100% with ivosidenib + venetoclax 800 mg, 67% with ivosidenib + venetoclax 400 mg, and 67% with ivosidenib + venetoclax 400 mg + azacytidine).…”