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

American Society of Clinical Oncology (ASCO) - Tập 38 Số 15_suppl - Trang 7500-7500 - 2020
Curtis A. Lachowiez1, Gautam Borthakur2, Sanam Loghavi3, Zhihong Zeng4, Tapan M. Kadia5, Lucia Masárová6, Koichi Takahashi2, George D. Tippett7, Kiran Naqvi2, Prithviraj Bose5, Elias Jabbour2, Farhad Ravandi2, Naval Daver5, Guillermo Garcia‐Manero2, Bilyana Stoilova8, Paresh Vyas9, Hagop M. Kantarjian5, Marina Konopleva2, Courtney D. DiNardo2
1M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
4University of Texas M. D. Anderson Cancer Center, Houston, TX.
5The University of Texas MD Anderson Cancer Center, Houston, TX
6The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX
7The University of Texas M.D. Anderson Cancer Center, Houston, TX
8MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
9University of Oxford and Oxford University Hospitals, Oxford, United Kingdom;

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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]

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American Society of Clinical Oncology (ASCO)

Tập 38 Số 15_suppl

7500-7500

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