Efficacy and Safety of CPX-351 Versus 7+3 in a Phase 3 Exploratory Analysis in Patients with High-Risk/Secondary Acute Myeloid Leukemia (AML) with Prior Hypomethylating Agent Exposure Who Achieved Remission
Authors: Lin Tara L. , Ryan Daniel H. , Ritchie Ellen K. , Strickland Stephen A. , Hogge Donna E. , Solomon Scott R. , Kolitz Jonathan E. , Schiller Gary J. , Wieduwilt Matthew J. , Ryan Robert J. , Faderl Stefan , Cortes Jorge E. 
Published: November 2019

Introduction: Patients (pts) with newly diagnosed, secondary AML (sAML) may have previously received hypomethylating agent (HMA) therapy for an antecedent hematologic malignancy (eg, myelodysplastic syndrome [MDS]). Outcomes for pts with MDS who progress following HMA therapy are typically poor, with remission rates &lt;30% and median overall survival (OS) of ~6 months (Prébet T, et al. J ClinOncol. 2011; Jabbour E, et al. Cancer 2010). CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of cytarabine [C] and daunorubicin [D] at a synergistic 5:1 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a large randomized, open-label, multicenter, phase 3 study (NCT01696084) in older pts with newly diagnosed, high-risk/sAML, induction followed by consolidation with CPX-351 significantly improved OS (9.56 vs 5.95 months; hazard ratio [HR] = 0.69; 1-sided P = 0.003) versus conventional 7+3, with a safety profile comparable to that of 7+3. An exploratory subgroup analysis of the phase 3 study was performed to compare outcomes in pts with any prior HMA exposure who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 versus 7+3.
Methods: Pts were randomized 1:1 to receive 1-2 induction cycles with CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-minute infusion on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day continuously for 7 days [2nd induction: 5 days] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR+CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Pts could receive hematopoietic cell transplantation (HCT) at the discretion of the treating physician. This exploratory subgroup analysis included pts with any prior HMA exposure who achieved CR+CRi to study treatment.
Results: A total of 309 pts were enrolled in the study, including 133 (43%) pts who had received prior HMA therapy. Among pts with any prior HMA exposure, 23/62 (37%) receiving CPX-351 and 20/71 (28%) receiving 7+3 (odds ratio [OR] = 1.50 [95% CI: 0.73-3.12]) achieved CR+CRi and were included in this analysis. Baseline characteristics for these pts were generally balanced between treatment arms; 9% and 5% of pts in the CPX-351 and 7+3 arms, respectively, were classified as having therapy-related AML, 78% and 90% had antecedent MDS, and 13% and 5% had antecedent chronic myelomonocytic leukemia.
In pts with any prior HMA exposure who achieved CR+CRi to CPX-351 or 7+3, median OS was longer with CPX-351 (14.72 vs 10.17 months; HR = 0.55 [95% CI: 0.26-1.15]; Figure 1). More of the pts with prior HMA exposure who achieved CR+CRi and received CPX-351 underwent HCT versus those who received 7+3 (57% vs 35%; relative risk = 1.39 [95% CI: 0.73-2.67]), and OS landmarked from the HCT date was longer with CPX-351 versus 7+3 (not reached vs 14.09 months; HR = 0.43 [95% CI: 0.12-1.51]; Figure 2). In pts without prior HMA exposure, 50/91 (55%) receiving CPX-351 and 32/85 (38%) receiving 7+3 (OR = 2.02 [95% CI: 1.11-3.69]) achieved CR+CRi; among those who achieved CR+CRi to CPX-351 versus 7+3, median OS was also longer with CPX-351 (26.32 vs 10.43 months).
The most common treatment-emergent adverse events (TEAEs) in pts with any prior HMA exposure who achieved CR+CRi were febrile neutropenia (CPX-351: 83%; 7+3: 75%), nausea (48%; 55%), fatigue (48%; 45%), diarrhea (43%; 70%), constipation (43%; 50%), peripheral edema (39%; 65%), and dizziness (13%; 50%). The most common grade ≥3 TEAEs were febrile neutropenia (CPX-351: 83%; 7+3: 75%) and fatigue (22%; 0%). The most common serious TEAEs were febrile neutropenia (CPX-351: 13%; 7+3: 10%), ejection fraction decreased (9%; 10%), and subdural hemorrhage (0%; 10%). There was no early mortality by Day 60 in either arm.
Conclusions: Pts with prior HMA exposure for an antecedent hematologic malignancy typically have poor outcomes and are a challenging subgroup of AML. Among pts in this study who had any prior HMA exposure and achieved CR+CRi, CPX-351 increased median OS, the rate of HCT, and median OS landmarked from the HCT date versus 7+3. The safety profile for CPX-351 in this subgroup was consistent with the overall study population and the known safety profile of 7+3.

Disclosures
Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ryan:University of Rochester: Patents & Royalties; AbbVie: Equity Ownership. Ritchie:Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Celgene, Incyte, Novartis, Pfizer: Consultancy. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Kolitz:Astellas: Research Funding; Boeringer-Ingelheim: Research Funding; Roche: Research Funding. Schiller:Astellas: Research Funding; Amgen: Other, Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; FujiFilm: Research Funding; Eli Lilly and Company: Research Funding; Daiichi Sankyo: Research Funding; Constellation Pharmaceutical: Research Funding; Celgene: Research Funding, Speakers Bureau; Agios: Research Funding, Speakers Bureau; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Amgen, Leadiant, Merck, Servier: Research Funding. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Faderl:Jazz Pharmaceutics: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding.