Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML
Authors: Daver Naval , Pollyea Daniel A. , Yee Karen W.L. , Fenaux Pierre , Brandwein Joseph M. , Vey Norbert , Martinelli Giovanni , Kelly Kevin R , Roboz Gail J. , Garcia Jacqueline S. , Pigneux Arnaud , Kshirsagar Smita , Dail Monique , Wang Jue , Mobasher Mehrdad , Chen Lin-Chi , Hong Wan-Jen , Konopleva Marina , Andreeff Michael 
Published: April 2021

Abstract
Introduction: Effective treatment options for patients (pts) with R/R AML are limited and novel therapies are needed. Previous pre-clinical data have shown that venetoclax (VEN) plus cobimetinib (cobi) or idasanutlin (idasa) may be synergistic. MEK and MDM2 inhibition have been shown to down-regulate MCL-1, overcoming a resistance pathway to BCL-2 inhibition in AML (Han, ASH 2016; Pan, ASH 2014). We report preliminary results from a dose-escalation study evaluating VEN plus cobi or idasa in pts with R/R AML. This is the first study evaluating novel-novel oral combinations with VEN in pts with AML.
Methods: This open-label, multicenter study evaluates the safety, tolerability and efficacy of VEN + cobi or idasa in pts ≥60 yrs old with R/R or secondary AML who have received therapy for a prior antecedent hematological disease and are not eligible for cytotoxic therapy (NCT02670044). Two-dimensional dose escalation is being used to establish the maximum tolerated dose (MTD) for each combination. Pts on Arm A received VEN PO daily + cobi PO on Days 1-21, and pts on Arm B received VEN PO daily + idasa PO on Days 1-5 in 28-day cycles. Dose limiting toxicities (DLTs) were assessed for the first cycle.
Results: As of 25 April 2017, 42 pts were treated in the dose-escalation stage. Arm A included 4 cohorts: VEN 400 mg + cobi 40 mg (n=4), VEN 600 mg + cobi 40 mg (n=7), VEN 800 mg + cobi 40 mg (n=4) and VEN 400 mg + cobi 60 mg (n=7); Arm B included 3 cohorts: VEN 400 mg + idasa 200 mg (n=3), VEN 600 mg + idasa 200 mg (n=8) and VEN 400 mg + idasa 400 mg (n=9). Median age was 72 (range 60-93) yrs and median number of prior therapies was 2 (range 1-10). 19% (8/42) were ECOG 2, 62% (26/42) of pts were refractory to last therapy and 48% (20/42) of pts had secondary AML. According to ELN risk classification, 29% were intermediate-I, 34% intermediate-II and 34% were adverse risk.
Most common AEs in both arms are summarized in Table 1. In the VEN + cobi arm, the majority of deaths on study were due to progressive disease (PD); 3 deaths were due to AEs of sepsis, pneumonia and respiratory failure. Three DLTs were reported: 1 diarrhea (Gr 3) in VEN 600 mg + cobi 40 mg and 1 diarrhea (Gr 3) and 1 decrease in ejection fraction (EF) (Gr 3) in VEN 400 mg + cobi 60 mg. The Gr 3 decrease in EF occurred in the setting of sepsis and was subsequently not considered related to study treatment. Due to the higher rates of Gr ≥3 diarrhea (57%) in VEN 400 mg + cobi 60 mg, this dose level will no longer be evaluated in this study. The VEN 800 mg + cobi 40 mg cohort is ongoing. In the VEN + idasa arm, the most common cause of death was PD; 1 death was due to an AE of sepsis. Four DLTs were reported: 1 generalized muscle weakness (Gr 3) and 1 diarrhea (Gr 3) in VEN 600 + idasa 200 mg and 1 acute coronary syndrome (Gr 3) and 1 elevated bilirubin (Gr 4) in VEN 400 mg + idasa 400 mg. Additional dose cohorts evaluating VEN + idasa are ongoing.
When compared to monotherapy data at the same dose, preliminary PK analyses suggest that VEN exposure is slightly lower, while cobi and idasa exposures are similar.
Preliminary efficacy for the VEN + cobi arm showed 2 CRs (9%), 1 CRp (4.5%) and 1 CRi (4.5%) for an overall response rate (ORR) of 18% (4/22); duration of response (DOR) ranged from 1 to 5 mo, with 1 response ongoing at data cut-off. For the VEN + idasa arm, 1 CR (5%), 1 CRp (5%), 1 CRi (5%) and 1 PR (5%) were achieved for an ORR of 20% (4/20); DOR ranged from 1.3 to 6.7 mo, with 1 response ongoing at data cut-off. In the VEN 600 mg + idasa 200 mg cohort, the ORR was 38% (3/8) with 1 CR, 1 CRp, and 1 CRi. Of the pts who did not achieve a response by IWG criteria, anti-leukemic activity was seen in an additional 7 pts who achieved ≥ 50% bone marrow blast reduction from baseline (3/22 [14%] pts on VEN + cobi and 4/20 [20%] pts on VEN + idasa).
Baseline mutation profiling was available in 32 of 42 pts and is summarized for responders in Table 2. Of the 9 pts who had an IDH1/2 mutation at baseline, 44% (4/9) achieved a response (1 on VEN + cobi and 3 on VEN + idasa). Of the 3 pts with known p53 mutations on the VEN + idasa cohorts, none achieved a response.
Conclusions: Preliminary results show that VEN plus cobi or idasa can be administered with appropriate risk mitigation measures for GI toxicity and early evidence of clinical activity in R/R AML pts. Dose finding is ongoing and the MTD for both combinations has not yet been determined. Preliminary ORR for the VEN 600 mg + idasa 200 mg cohort was encouraging at 38%. Safety, PK and efficacy data will be updated at the time of presentation.

Disclosures
Daver: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Yee: Oncoethix: Research Funding; Novartis Canada: Honoraria; Astex: Research Funding; Karyopharm: Research Funding; Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kelly: Abbvie: Honoraria; Pharmacyclics: Honoraria; Amgen: Honoraria; Jannsen: Honoraria. Roboz: Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Kshirsagar: Genentech, Inc: Other: Services via contractor. Dail: Genentech, Inc.: Employment. Wang: Genentech: Employment. Mobasher: Roche: Equity Ownership; Genentech: Employment. Chen: 4. F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Hong: Genentech: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership.