Afuresertib Plus Bortezomib/Dexamethasone Active in Relapsed/Refractory Multiple Myeloma
NEW ORLEANS—The novel pan-AKT inhibitor, afuresertib, demonstrated significant clinical activity when combined with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma, investigators concluded at the 55th American Society of Hematology Annual Meeting and Exposition.
In fact, “responses in bortezomib-refractory patients suggest that afuresertib may be able to overcome bortezomib resistance in some cases,” said Peter M. Voorhees, MD, of the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
The study sought to define the maximum tolerated dose (MTD) and to evaluate the pharmacokinetics, pharmacodynamics, and clinical activity of afuresertib (GSK2110183) administered in combination with bortezomib and dexamethasone. The two-part study included a dose-escalation phase (part 1) and an expansion phase (part 2). Patients with bortezomib-refractory disease were allowed in part 1; however they were excluded in part 2.
Afuresertib doses explored in part 1 were 75, 100, 125, 150, and 175 mg in combination with bortezomib (1.0 or 1.3 mg/m2) and dexamethasone (20 or 40 mg). Dose-limiting toxicities (DLTs) were grade 2 ALT elevation (one of six patients) at 100 mg and grade 3 erythema multiforme at 125 mg (one of six patients). Two other patients experienced DLTs at the 175 mg dose, including grade 3 rash (one of six patients), and grade 3 diarrhea, grade 3 thrombocytopenia, and grade 3 rash (one of six patients). All DLTs were reversible. The MTD was established at 150 mg afuresertib with 1.3 mg/m2 bortezomib and 40 mg dexamethasone.
Afuresertib was given orally once daily continuously until progression or unacceptable toxicity; bortezomib (intravenous or subcutaneous) plus oral dexamethasone was administered on days 1, 4, 8, and 11 every 21 days for a maximum of eight cycles. “Continued daily afuresertib therapy was allowed after eight cycles for those benefitting from and tolerating treatment,” Dr. Voorhees reported.
A total of 81 patients were enrolled in the study, 34 in part 1, 10 in the PK/PD cohort, and 37 in part 2. Patients received a median of three prior lines of therapy (range, 1-10 lines of therapy); 82% of patients had previously received proteasome inhibitors, 96% had received immunomodulatory drugs, 79% had received both, and 63% had undergone autologous transplant. In part 2, mean age of the patients was 66 years (range, 35-83 years), and 59% were male.
Of the 81 patients enrolled, 29 (36%) remain on treatment.
The most common (> 20%) nonhematologic adverse events (AEs) were fatigue (51%), diarrhea (49%), nausea (37%), constipation (33%), dyspepsia (32%), hyperglycemia (28%), vomiting (27%), peripheral neuropathy (22%), insomnia (20%), and rash (20%), Dr. Voorhees reported. Most AEs were grade 1/2, and reversible. Hematologic toxicities observed were thrombocytopenia (38%), anemia (25%), neutropenia (11%), and febrile neutropenia (2%). The most frequent grade 3/4 AEs were thrombocytopenia (27%), diarrhea (14%), rash (7%), and anemia (10%).
Serious adverse events, recorded in 31 patients, were infections, acute renal injury, skin disorders, gastrointestinal, bone-related events, and vascular events. There was one on-study death, septic shock in a 61-year-old woman. The discontinuation rate for AEs was 23%.
Pharmacokinetic analysis showed that concentration-time profiles were approximately proportional to dose. Afuresertib's pharmacokinetic profile does not appear to be affected by bortezomib or dexamethasone. Bortezomib's pharmacokinetic profile is not affected by afuresertib; however, dexamethasone exposure is increased by 30% to 50%.
Afuresertib was found to lead to increased phospho-AKT levels in myeloma cells, “demonstrating achievement of target inhibition at [the] 150 mg daily dose,” he said.
Responses were evaluated based on serum M-protein or free light chain serum levels according to International Myeloma Working Group criteria. In part 1, confirmed overall response rate (ORR) was 50% (one complete response, three very good partial responses [VGPRs], 13 PRs), and two additional patients had molecular responses, for a clinical benefit rate (CBR) of 56%.
In part 2, ORR was 65% (eight VGPRs and 14 PRs) and CBR, 73% (three molecular responses). By prior bortezomib exposure, ORR was 62% in 13 treatment-naïve patients, 61% in 44 relapsed patients, and 43% in 23 refractory patients. One patient in whom prior exposure was unknown did not respond.
“Afuresertib can be given safely in combination with bortezomib and dexamethasone,” Dr. Voorhees said. “Gastrointestinal and dermatology AEs are common but manageable.” He added that further studies are planned to confirm the clinical efficacy of afuresertib with active myeloma drugs.