Background CPX-351. Lancet J, et al. J Clin Oncol. 2017;35(suppl): Abstract 7035.

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1 Overall Survival (OS) With Versus in Older Adults With Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia (taml): Subgroup Analysis of a Phase 3 Study Abstract 7035 Lancet JE, Rizzieri D, Schiller GJ, Stuart RK, Kolitz JE, Solomon SR, Newell LF, Erba HP, Uy GL, Ryan R, Chiarella M, Louie AC, Cortes JE

2 Background Older acute myeloid leukemia (AML) patients (aged 60 years), particularly those with secondary AML (eg, therapy-related AML[tAML] or AML with myelodysplasia-related changes), often have poor prognosis. 1-3 taml, which may occur as a late complication of cytotoxic or radiation therapy for a prior malignant disease, is associated with lower remission rates than standard induction chemotherapy and inferior overall survival (OS) compared with de novo AML. 1 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that is designed to achieve synergistic antileukemia activity 4 A 5:1 molar ratio of cytarabine: Daunorubicin provides synergistic leukemia cell killing in vitro 4 The synergistic drug ratio is maintained in human plasma for 24 hours after administration, and drug exposure persists for approximately 7 days 5 Selective uptake of liposome by bone marrow leukemia cells has been demonstrated in xenograft models 6 DSPC, desaturated phosphatidylcholine; DSPG, distearoyl phosphatidylglycerol 1. Granfelt Ostgard LS, et al. J Clin Oncol. 2015;33(31): Appelbaum FR, et al. Blood. 2006;107(9): Juliusson G, et al. Blood. 2009;113(18): Tardi P, et al. Leuk Res. 2009;33(1): Feldman EJ, et al. J Clin Oncol. 2011;29(8): Lim WS, et al. Leuk Res. 2010;34(9):

3 Objective The objective of this exploratory post hoc analysis of the phase III trial in elderly adults with newly diagnosed, highrisk AML was to evaluate the efficacy and safety of versus cytarabine/daunorubicin () in the subgroup of patients with taml

4 Study Design This was a randomized, open-label, multicenter, phase III trial (ClinicalTrials.gov Identifier: NCT ). 1 Patients were randomized 1:1 to receive 1 to 2 cycles of induction therapy with or chemotherapy and were stratified by age (60-69 and years) and AML subtype : 100 units/m 2 (cytarabine 100 mg/m 2 + daunorubicin 44 mg/m 2 ) on days 1, 3, and 5 (days 1 and 3 for second induction) : cytarabine 100 mg/m 2 /day for 7 days (5 days for second induction) + daunorubicin 60 mg/m 2 on days 1, 2, and 3 (days 1 and 2 for second induction) Patients with documented complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation Patients who achieved a CR or CRi could be considered for allogenic stem cell transplantation based on institutional criteria 1. Lancet JE, et al. J Clin Oncol. 2016;34(suppl). Abstract 7000.

5 Study Enrollment Criteria Patients 60 to 75 years of age with a pathologic diagnosis of AML according to World Heath Organization 2006 criteria ( 20% blasts in peripheral blood or bone marrow) 1 Confirmation of high-risk secondary AML based on prior cytotoxic treatment, a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia, or de novo AML with cytogenetic changes linked to MDS Ability to tolerate intensive AML chemotherapy Eastern Cooperative Oncology Group performance status of 0, 1, or 2 Adequate renal and hepatic function; cardiac ejection fraction 50% No acute promyelocytic leukemia t(15;17) or favorable cytogenetics at screening No prior treatment intended as induction therapy for AML; hydroxyurea was permitted No active secondary malignancies or central nervous system leukemia Phase III Study Design (n = 153) Key eligibility Previously untreated years of age Able to tolerate intensive therapy ECOG PS 0-2 Primary endpoint: Overall survival Stratifications: Therapy-related AML AML with history of MDS with and without prior HMA therapy AML with history of CMML de novo AML with MDS karyotype years of age years of age Induction (1-2 cycles) Patients in CR or CRi: Consolidation (1-2 cycles) Follow-up: Death or 5 years (n = 156) ECOG PS, Eastern Cooperative Oncology Group performance status; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; HMA, hypomethylating agent; CMML, chronic myelomonocytic leukemia; CR, complete remission; CRi, complete remission with incomplete platelet or neutrophil recovery 1. Swerdlow SH, et al. Who Classification of Tumours of Haematopoletic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.

6 Results Patients A total of 309 patients were enrolled in the trial, and 304 patients received treatment with either (n = 153) or (n = 151) Of these, 62 (20%) patients had a diagnosis of taml and received study treatment (, n = 30;, n = 32); baseline demographic and clinical characteristics for this patient subgroup were similar between treatment arms Characteristic, n (%) Baseline Demographic and Clinical Characteristics for Patients with taml (Safety Population*) (n = 32) Median age (range), y 69 (61-72) 67.5 (60-75) Sex, n (%) Male 14 (47) 17 (53) Female 16 (53) 15 (47) ECOG PS, n (%) 0 6 (20) 8 (25) 1 22 (73) 17 (53) 2 2 (7) 7 (22) Prior therapy type, n (%) Non-anthracycline chemotherapy alone 6 (20) 10 (31) Radiation alone 10 (33) 6 (19) Non-anthracycline chemotherapy + radiation 8 (27) 12 (38) Non-anthracycline + anthracycline chemotherapy 1 (3) 2 (6) Non-anthracycline + anthracycline chemotherapy + radiation 5 (17) 2 (6) *Data presented are for the safety population, which includes all enrolled patients who received study treatment.

7 Efficacy In the overall study population, was associated with a significant OS benefit versus (primary endpoint of the study; 9.56 vs 5.95 months, respectively; hazard ratio [HR] = 0.69 [95% confidence interval (CI) = 0.52, 0.90]; 1-sided P =.003) 1 Kaplan-Meier estimates of survival were higher for versus at 1 year (42% vs 28%, respectively) and at 2 years (31% vs 12%) Kaplan-Meier Curve for OS in Patients With taml (ITT population*) Events/N Median Survival (95% CI) 18/ (7.43, NR) 29/ (2.92, 8.48) also resulted in significantly higher CR + CRi rate (48% vs 33% with ; 1-sided P =.008) The significant OS benefit observed for versus was preserved among the subgroup of patients with taml (HR = 0.49 [95% CI = 0.27, 0.88]) ITT, intent to treat; CI, confidence interval; NR, not reached *Data presented are for the ITT population, which includes all enrolled patients with taml. 1. Lancet JE, et al. J Clin Oncol. 2016;34(suppl). Abstract 7000.

8 Best Response and Transplantation Rates in Patients With taml (ITT Population a ) taml patients treated with versus those treated with were more likely to achieve remission (47% vs 36%, respectively) and to proceed to stem cell transplantation (37% vs 27%) For those patients who received a transplant, median OS landmarked from the date of transplantation was not yet reached in the arm versus 6.57 months in the arm (HR = 0.19 [95% CI = 0.04, 0.97]) Patients (%) CR+ CRI (n = 33) HSCT OR (95% CI): 1.53 (0.56, 4.20) 1.54 (0.53, 4.49) (n = 33) CR, complete remission; CRi, complete remission with incomplete platelet or neutrophil recovery; HSCT, hematopoietic stem cell transplantation; OR, odds ratio; *Data presented are for the ITT population, which includes all enrolled patients with taml.

9 Outcomes in Patients with taml by Type of Prior Therapy (ITT Population*) Outcomes Median OS, mo n n HR (95% CI) Prior chemotherapy alone (0.31, 2.59) Prior radiation alone (0.08, 1.03) Prior chemotherapy and radiation (0.19, 1.12) CR + CRi rate, n (%) OR (95% CI) Prior chemotherapy alone 7 2 (29) 13 5 (39) 0.40 (0.047, 3.424) Prior radiation alone 10 5 (50) 6 2 (33) 1.79 (0.211, ) Prior chemotherapy and radiation 13 7 (54) 14 5 (36) 2.05 (0.433, 9.699) HSCT rate, n (%) OR (95% CI) Prior chemotherapy alone 7 3 (43) 13 4 (31) 4.67 (0.341, ) Prior radiation alone 10 3 (30) 6 1 (17) 2.00 (0.227, ) Prior chemotherapy and radiation 13 5 (39) 14 4 (29) 1.55 (0.315, 7.578) *Data presented for the ITT population, which includes all enrolled patients with taml.

10 Safety and Tolerability The overall safety and tolerability profile of was comparable to that of Among the subpopulation with taml, was associated with lower 30-day morality and 60-day morality The most frequently reported serious treatment-emergent adverse events (TEAEs) in the taml subgroup were febrile neutropenia (: n = 6 [20%]; : n = 0) and respiratory failure (: n = 2 [7%]; : n = 3 [9%] No more than 1 patient experienced any specific grade 5 TEAEs Number of patients Early Mortality Rates in Patients With taml (Safety Population*) (n = 33) Death 30 days (n = 33) Deaths 60 days a Data presented are for the safety population, which includes all enrolled patients with taml who received study treatment. b Investigators were requested to indicate whether there was evidence of persistent/progressive leukemia prior to death. Although the extend of its contribution is uncertain, persistent/progressive AML was present in higher proportion of patients in the arm prior to 60-day early mortality (n = 5 [16%]) compared with the arm (n = 0 [0%]) and, consequently, may have been a greater contributor to early death among patients in the arm.

11 Summary of and Safety Profiles in Patients With taml (Safety Population a ) Safety parameter, n (%) (n = 33) Safety parameter, n (%) (n = 33) TEAEs reported in 20% of patients in either treatment arm Mucosal inflammation 7 (23) 6 (19) Febrile neutropenia 21 (70) 23 (72) Constipation 7 (23) 5 (16) Rash 15 (50) 7 (22) Insomnia 7 (23) 5 (16) Headache 13 (43) 9 (28) Pruritus 7 (23) 2 (6) Nausea 12 (40) 20 (63) Cough 6 (20) 7 (22) Diarrhea 11 (37) 22 (69) Vomiting 5 (17) 9 (28) Decreased appetite 10 (33) 11 (34) Hypotension 5 (17) 8 (25) Epistaxis 10 (33) 6 (19) Edema 3 (10) 7 (22) Peripheral edema 7 (23) 13 (41) Grade 3 or 4 TEAE 24 (80) 29 (91) Fatigue 7 (23) 10 (31) Serious TEAE 18 (60) 12 (38) Chills 7 (23) 9 (28) Discontinuation due to a TEAE 1 (3) 0 Dyspnea 7 (23) 8 (25) TEAE leading to death 3 (10) 5 (16) Pneumonia 7 (23) 7 (22) a Data presented are for the safety population, which includes all enrolled patients with taml who received study treatment.

12 Conclusions was associated with significantly improved OS compared with in this exploratory post hoc analysis of older patients with newly diagnosed taml has a safety profile that is generally consistent with the known safety profile of chemotherapy and has demonstrated lower rates of early mortality These results are consistent with the overall phase III study population, 1 as well as with other reports of in high-risk AML populations. 2,3 Although this analysis was limited by the small subpopulation of enrolled patients with taml, the outcomes suggest that may represent a new therapeutic option for high-risk AML patients, including those with taml. 1. Lancet JE, et al. J Clin Oncol. 2016;34(suppl): Abstract Lancet JE, et al. Blood. 2014;123(21): Cortes JE, et al. Cancer. 2015;121(2):