Abstract
Afuresertib (GSK2110183) is a potent pan-AKT inhibitor that demonstrated synergy with bortezomib in preclinical models of multiple myeloma (MM) and single agent activity in heavily pretreated patients in a first-time-in-human study. We therefore sought to evaluate the safety and preliminary efficacy of afuresertib in combination with bortezomib and dexamethasone in the context of a phase 1b study.
The objectives of the study were to define the maximum tolerated dose (MTD) and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of afuresertib in combination with bortezomib and dexamethasone in patients with relapsed/refractory MM. This two part study included a dose escalation phase (part1) and a currently ongoing expansion phase (part2). Patients with bortezomib-refractory disease were allowed in part1, but were excluded in part2. Afuresertib was given orally, continuously, once daily (QD) until progression or unacceptable toxicity, while bortezomib (IV or SC) + oral dexamethasone were given on days 1, 4, 8 and 11 every 21 days for a maximum of 8 cycles. Continued daily afuresertib therapy was allowed after 8 cycles for those benefitting from and tolerating treatment.
A total of 67 patients have been enrolled in the study at the time of data cut off: 34 in part1, 10 in the PK/PD cohort, and 23 in part2. Patients had received a median of 3.5 prior lines of therapy (range 1-10); 88% of patients had previously received proteasome inhibitors, 96% had received immunomodulatory drugs, and 85% had received both. Afuresertib doses explored in part1 were 75, 100, 125, 150 and 175 mg in combination with bortezomib (1.0 or 1.3mg/m2) and dexamethasone (20 or 40mg). The MTD was established at 150 mg afuresertib + 1.3mg/m2 bortezomib + 40mg dexamethasone. Dose-limiting toxicities (DLTs) were: Grade 2 ALT elevation in 1/6 patients at 100mg and G3 erythema multiforme at 125mg (1/6). Additional three patients experienced DLTs at 175mg dose: G3 rash (1/6), G2 rash (1/6), and G3 diarrhea, G3 thrombocytopenia, G3 rash (1/6). All DLTs were reversible. The most common (>20%) adverse events (AEs) were diarrhea (54%), fatigue (51%), thrombocytopenia (39%), nausea (39%), dyspepsia (36%), constipation (36%), hyperglycemia (30%), vomiting (28%), anemia (25%), and dizziness (21%). Most AEs were grade 1-2, and reversible. The most frequent G3-4 AEs (>10%) were as follows: thrombocytopenia (28%), diarrhea (13%), rash and other skin related toxicities (13%), anemia (10%). Preliminary pharmacokinetic analysis showed that concentration-time profiles were approximately proportional to dose and did not reveal any drug-drug interaction. Pre- and post-dose bone marrow biopsies from patients dosed at MTD exhibited changes in AKT phosphorylation indicative of target engagement in 5/7 pairs, as measured by immunohistochemistry. Analysis of substrate phosphorylation downstream of AKT is ongoing. Responses were evaluated based on serum M-protein or free light chain serum levels (FLC) according to IMWG criteria (Rajkumar 2011). Confirmed overall response rate (ORR) in part1 (34 pts) was 41% (1CR, 3VGPR, 10PR), and 3 additional patients had MRs (accounting for Clinical Benefit Rate, CBR=50%). Part2 is ongoing, and from 23 (of 40 planned) patients enrolled so far the ORR is 61% (3VGPR and 11PR); MRs were recorded in 4 additional patients (CBR=78%). Complete progression free survival (PFS) data are not available at this time due to limited follow-up.
Afuresertib administered in combination with bortezomib and dexamethasone is safe and well tolerated at doses where target engagement was demonstrated. This combination has demonstrated significant clinical activity in patients with relapsed and relapsed/refractory MM.
Voorhees:GlaxoSmithKline: Consultancy, Research Funding. Stewart:Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Chari:Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Rosenzwieg:Celgene: Speakers Bureau. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Smith:GlaxoSmithKline: Employment, Equity Ownership. Antal:GlaxoSmithKline: Employment. Santiago-Walker:GlaxoSmithKline: Employment. Gauvin:GlaxoSmithKline: Employment. Opalinska:GlaxoSmithKline: Employment. Trudel:GlaxoSmithKline: Research Funding.
Author notes
Asterisk with author names denotes non-ASH members.
