Preliminary Results By Age Group of Treatment with CPX-351 Plus Venetoclax in Adults with Newly Diagnosed AML: Subgroup Analysis of the V-FAST Phase 1b Master Trial

Introduction: CPX-351 (United States: Vyxeos ^®; Europe: Vyxeos ^® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML, after 5 years of follow-up CPX-351 significantly improved median overall survival and remission rates versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the BCL-2 inhibitor venetoclax (VEN). Interim results from the V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) study have demonstrated the safety and preliminary efficacy of CPX-351 in combination with VEN or midostaurin. Herein, we report the preliminary results of a subgroup analysis of adults with newly diagnosed AML treated with CPX-351 + VEN, based on age, to provide insights into the tolerability of this novel combination in younger versus older adults with AML.

Methods: V-FAST is an ongoing, open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (venetoclax, midostaurin, enasidenib). Each combination arm had a dose-exploration phase (3+3 design; n ≤12) and a subsequent expansion phase (n = 20) to determine the recommended phase 2 dose (RP2D), safety, and initial efficacy of that treatment combination. Eligible patients included adults aged 18 to ≤75 years with newly diagnosed AML who were deemed fit for intensive chemotherapy and had an ECOG performance status of 0 to 2. Patients assigned to treatment with CPX-351 + VEN were to have wild type FLT3 and IDH2 based on molecular testing. The RP2D of this treatment arm was determined to be dose level 1, in which patients received CPX-351 100 units/m ² (daunorubicin 44 mg/m ² + cytarabine 100 mg/m ²) on Days 1, 3, and 5 + VEN 400 mg on Days 1 to 14 of the first induction. At this dose level, 1 of 6 patients in the dose-exploration phase experienced 2 dose-limiting toxicities (grade 4 neutropenia [Day 16] and grade 4 thrombocytopenia [Day 18]) that extended beyond 49 days; no dose adjustments were required and the study enrolled an additional 21 patients at this dose level. For this subgroup analysis, patients were grouped by age: 18 to ≤59 years (younger) and 60 to ≤75 years (older).

Results: A total of 21 patients received CPX-351 + VEN and had sufficient data to be included in the analysis, comprising 14 patients aged 18 to ≤59 years and 7 patients aged 60 to ≤75 years. Patient baseline characteristics are shown in Table 1. The most common TEAEs of any grade in younger adults were neutropenia, febrile neutropenia, and constipation; the most common TEAEs in older adults were febrile neutropenia, thrombocytopenia, and nausea (Table 2). The most common grade ≥3 TEAEs in both age groups included febrile neutropenia, thrombocytopenia, neutropenia, and leukopenia (Table 2). TEAEs categorized as serious events included febrile neutropenia (n = 3 [younger]; n = 1 [older]), sepsis (n = 2 [younger]), ischemic stroke (n = 1 [older]), skin infection (n = 1 [older]), and AML (n = 1 [younger]). Six evaluable patients in the younger age group and 1 in the older age group died during the study due to primary causes of relapse/progression (n = 4), adverse event (n = 2), and other (n = 1; sepsis and multiorgan failure after early termination from treatment). Median platelet and neutrophil recovery times were similar between age groups (Table 3) and consistent with the previously reported safety profile of CPX-351 monotherapy. Complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) evaluable younger adults and 4/6 (67%) evaluable older adults, including 5/14 (36%) and 3/6 (50%) who achieved CR.

Conclusions: This analysis of preliminary results by age group from the V-FAST study supports the conclusion that the combination of CPX-351 + VEN is equally feasible with a manageable safety profile in both younger and older adult patients with newly diagnosed AML. Promising remission rates were also reported for both age groups.

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