Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial

• Published in: Clinical lymphoma, myeloma and leukemia Vol. 24; no. 6; pp. 364 - 374
• Main Authors: Konopleva, Marina Y., Dail, Monique, Daver, Naval G., Garcia, Jacqueline S., Jonas, Brian A., Yee, Karen W.L., Kelly, Kevin R., Vey, Norbert, Assouline, Sarit, Roboz, Gail J., Paolini, Stefania, Pollyea, Daniel A., Tafuri, Agostino, Brandwein, Joseph M., Pigneux, Arnaud, Powell, Bayard L., Fenaux, Pierre, Olin, Rebecca L., Visani, Giuseppe, Martinelli, Giovanni, Onishi, Maika, Wang, Jue, Huang, Weize, Dunshee, Diana R., Hamidi, Habib, Ott, Marion G., Hong, Wan-Jen, Andreeff, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2024
• Subjects: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Azetidines - administration & dosage; Azetidines - pharmacology; Azetidines - therapeutic use; B-cell lymphoma-2; Biomarker; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Drug Resistance, Neoplasm - drug effects; Female; Humans; Leukemia, Myeloid, Acute - drug therapy; Male; Middle Aged; Mitogen-activated protein kinase pathway; Piperidines - pharmacology; Piperidines - therapeutic use; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Targeted therapy; Treatment Outcome; Biomarker; PR; Targeted therapy; BCL-xL; MLFS; ven-idasa; BCL-2; SD; R/R; CRc; MEK1/2; TLS; CRi; ven-cobi; HSCT; AML; CRp; Cmax; AE; OS; MR; CI; MAPK; B-cell lymphoma-2; CR; pS6; PD; RP2D; SAE; sAML; VAF; PK; MTD; Mitogen-activated protein kinase pathway; AHD; pERK
• ISSN: 2152-2650; 2152-2669; 2152-2669
• DOI: 10.1016/j.clml.2024.01.007

•Ven-cobi showed limited efficacy, similar to venetoclax alone, in R/R AML.•Ven-cobi had additional toxicity versus venetoclax alone in patients with R/R AML.•High MCL-1 levels and TP53/signaling mutations may promote ven-cobi resistance.•These findings may optimize future trials of BCL-2/MAPK inhibitor combinations.
Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies.
This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle.
Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway.
Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.
Treatment options for patients who have acute myeloid leukemia (AML) which has come back (relapsed) or stopped responding to treatment (refractory) are limited. In this study, 30 patients with relapsed/refractory AML received 2 drugs (venetoclax and cobimetinib). Venetoclax-cobimetinib had limited responses with unwanted side effects, compared with venetoclax alone. However, these findings will help future trials of similar drug combinations.