Venetoclax plus MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in R/R AML

Conference Correspondent - ASH 2017


Based on preclinical evidence suggesting synergy between the oral small-molecule BCL-2 inhibitor venetoclax and the MEK inhibitor cobimetinib or the MDM2 inhibitor idasanutlin, the current open-label, phase 1b trial is evaluating the safety and preliminary efficacy of the 2 combination therapies in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).

In this study, eligible patients were aged ≥60 years with R/R or secondary AML who have received therapy for a prior antecedent hematologic disease and are not eligible for cytotoxic therapy. Patients were treated on arm A with oral venetoclax daily plus cobimetinib on days 1 through 21, and on arm B with venetoclax daily plus idasanutlin on days 1 through 5, in 28-day cycles. The data cutoff was August 21, 2017.

At data cutoff, the study population included 42 patients. Arm A included 4 cohorts: venetoclax 400 mg + cobimetinib 40 mg (n = 4), venetoclax 600 mg + cobimetinib 40 mg (n = 7), venetoclax 800 mg + cobimetinib 40 mg (n = 12), and venetoclax 400 mg + cobimetinib 60 mg (n = 7); arm B included 3 cohorts: venetoclax 400 mg + idasanutlin 200 mg (n = 3), venetoclax 600 mg + idasanutlin 200 mg (n = 8), and venetoclax 400 mg + idasanutlin 400 mg (n = 9). The median age was 71.5 years (range, 60-84 years) in arm A and 73 years (range, 64-93 years) in arm B; 15 and 13 patients, respectively, had secondary AML; and 6 patients in arm A had undergone prior hematopoietic stem-cell transplantation. Patients had received a median of 2 prior therapies in both arms. By European LeukemiaNet risk classification, about 60% of patients were in the intermediate-I/II risk group and 33% were in the adverse risk group in both arms.

In the venetoclax + cobimetinib arm, 3 dose-limiting toxicities (DLTs) were reported: 1 grade 3 diarrhea in the venetoclax 600-mg + cobimetinib 40-mg cohort, and 1 grade 3 diarrhea and 1 grade 3 decrease in ejection fraction (EF) in the venetoclax 400-mg + cobimetinib 60-mg cohort. The grade 3 decrease in EF occurred in the setting of sepsis, and was subsequently not considered related to study treatment. The venetoclax 800-mg + cobimetinib 40-mg cohort is continuing; however, the venetoclax 400-mg + cobimetinib 60-mg dose level is not continuing, due to the higher rates of grade ≥3 diarrhea (57%). In the venetoclax + idasanutlin arm, 4 DLTs were reported: 1 grade 3 generalized muscle weakness and 1 grade 3 diarrhea (venetoclax 600 mg + idasanutlin 200 mg), 1 grade 3 acute coronary syndrome, and 1 grade 4 elevated bilirubin (venetoclax 400 mg + idasanutlin 400 mg).

In both combination cohorts, the most common adverse events (AEs; any grade, ≥30%) were diarrhea, nausea, and vomiting. Grade ≥3 AEs, occurring in ≥30% of patients, in the venetoclax + cobimetinib cohort (n = 30) were diarrhea (37%), febrile neutropenia (37%), fatigue (7%), pneumonia/lung infection (33%), sepsis/septic shock (10%), and hypokalemia (7%); in the venetoclax + idasanutlin cohort (n = 24), they were diarrhea (8%), febrile neutropenia (29%), pneumonia/lung infection (25%), sepsis/septic shock (38%), hypokalemia (8%), fatigue (8%), and nausea (4%).

In the venetoclax + cobimetinib cohort (n = 30), the preliminary efficacy analysis showed antileukemic responses in 6 patients (20%), including 3 complete remissions (CRs), 1 CRp, 1 CRi, and 1 morphologic leukemia-free response (MLFS). For the venetoclax + idasanutlin arm (n = 24), antileukemic responses were achieved by 8 patients (33%), including 1 CR, 1 CRp, 2 CRi, 1 partial response (5%), and 1 MLFS; 6 of these responses were achieved by the venetoclax 600-mg + idasanutlin 200-mg or 150-mg cohorts (n = 12). Based on baseline mutation profiling, 5 of 8 patients who had an IDH1/2 mutation at baseline achieved a response.

These preliminary results indicate that the 2 novel combination therapies of venetoclax plus cobimetinib or idasanutlin were associated with gastrointestinal toxicity that may be managed with appropriate risk mitigation measures in R/R AML, and showed early evidence of clinical activity in patients with R/R AML.

Daver N, et al. 2017 ASH. Abstract 813.