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In newly-diagnosed secondary AML patients, VYXEOS demonstrated superior overall survival, higher CR and CR+CRi rates, and a better chance to reach HSCT vs 7+31,2,a

Discussion of the pivotal Phase 3 trial

Dr. Bayard Powell, section chief of Hematology and Oncology at Wake Forest Baptist Health, reviews the VYXEOS Phase 3 trial in detail and explains what the efficacy and safety data mean for adult sAML patients

Results of the Phase 3 trial were also published in the Journal of Clinical Oncology2

‌aCytarabine 100 mg/m2 and daunorubicin 60 mg/m2.

VYXEOS demonstrated superior overall survival vs 7+3, reducing the risk of death by 31%b in sAML patients facing a poor prognosis (primary endpoint)1

Kaplan-Meier curve for overall survival, ITT population1

VYXEOS overall survival KM curve VYXEOS overall survival KM curve

Hazard ratio=0.69 (0.52, 0.90)
P=0.005

Median survival (95% CI)

VYXEOS: 9.6 months (6.6, 11.9)  
7+3: 5.9 months (5.0, 7.8)

‌bHazard ratio was adjusted for age and AML subtype.

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VYXEOS demonstrated a statistically significant improvement in CR and CR+CRi vs 7+31,2

Percentage of sAML patients who achieved CR and CR+CRi1,2

Overall response rate with VYXEOS treatment

CR, n/N:

VYXEOS: 58/153
7+3: 41/156
P=0.036c

CR+CRi, n/N:

VYXEOS: 73/153
7+3: 52/156
P=0.016c

a
b
P value is 2-sided.
Reaching CR is an important milestone for patients hoping to achieve prolonged survival and the opportunity for HSCT—consider a treatment that provided a significantly better chance for remission1,3

OS in sAML patients who achieved CR or CRi4

This subgroup analysis was exploratory and not powered to determine statistical significance. No efficacy conclusions about OS following CR or CRi can be drawn from this analysis

OS in sAML patients who achieved CR or CRi4

VYXEOS OS in patients with CR or CRi KM curve

Events/N:

VYXEOS: 35/73
7+3/5+2: 38/52

Median survival (95% CI)

VYXEOS: 25.4 (13, NR)
7+3/5+2: 10.4 (7.8, 15.2)

Limitations of subanalysis4

  • Results should be interpreted with caution, as this was an exploratory analysis of a specific subgroup
  • The treatment effect of this nonrandomized subgroup was possibly confounded by unbalanced baseline characteristics
  • This analysis was potentially biased, as it included only responders who achieved CR or CRi
  • Of the patients who achieved CR or CRi, 55% of patients in the VYXEOS arm underwent HSCT (n=40/73) compared to 46% of patients in the 7+3 arm (n=24/52)
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Chemotherapy followed by HSCT provides an opportunity for prolonged survival5

More sAML patients received HSCT following treatment with VYXEOS vs 7+31

Overall rate of HSCT1,d

Overall rate of HSCT for treatment with VYXEOS

‌dInduction failure, first CR, or as salvage after relapse.

A greater proportion of sAML patients who achieved first CR with VYXEOS subsequently underwent HSCT6

Rate of HSCT during first CR1,6

Rate of HSCT during first CR with VYXEOS
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Exploratory post hoc analyses of overall survival following HSCT in the Phase 3 trial

These subgroup analyses were exploratory and not powered to determine statistical significance. No efficacy conclusions about OS following HSCT can be drawn from these analyses

Analysis 1: Kaplan-Meier curve for OS landmarked from time of transplant, ITT population2,e

OS from time of HSCT after treatment with VYXEOS

Median survival (95% CI)

VYXEOS: (n=18/52) Not reached
7+3: (n=26/39) 10.3 months (6.2, 16.7)

Limitations of subanalysis

  • Results should be interpreted with caution, as this analysis was not prespecified and was conducted in a small, nonrandomized subgroup (n=91)2,7
  • The treatment effect of this nonrandomized subgroup was possibly confounded by unbalanced baseline characteristics
    • A higher proportion of patients proceeding to HSCT in the VYXEOS arm (75%) were in CR/CRi as compared with the 7+3 arm (62%)7
    • To address this limitation, Analysis 2 (right)(below) evaluated only those patients in each treatment arm who were in CR/CRi at the time they received HSCT8

Analysis 2: Kaplan-Meier curve for OS landmarked from time of transplant in patients in CR/CRi at time of HSCT8

OS in from time of HSCT in CR/CRi patients who received VYXEOS

Median survival (95% CI)

VYXEOS: (n=13/39) Not reached (15.6, NR)
7+3: (n=16/24) 11.7 months (4.6, 24.3)

Limitations of subanalysis

  • Results should be interpreted with caution, as this analysis was not prespecified and was conducted in a small, nonrandomized subgroup (n=63)8
  • The treatment effect of this nonrandomized subgroup was possibly confounded by unbalanced baseline characteristics

‌eLancet JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684-2692. Reprinted with permission. © 2018 American Society of Clinical Oncology. All rights reserved.

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Study Design1

The Phase 3 study was a randomized, multicenter, open-label, active-controlled superiority study of VYXEOS versus cytarabine and daunorubicin (7+3) in patients 60 to 75 years of age with newly-diagnosed t-AML or AML-MRC. There were 153 patients randomized to VYXEOS and 156 patients randomized to the 7+3 arm. Twenty percent had t-AML, 54% had AML with an antecedent hematological disorder, and 25% had de novo AML with MDS-related cytogenetic abnormalities. Efficacy was established on the basis of overall survival from the date of randomization to death from any cause.

VYXEOS 44 mg/100 mg per m2 (daunorubicin/cytarabine) was given intravenously on Days 1, 3, and 5 for first induction and on Days 1 and 3 for those needing a second induction. For consolidation, the VYXEOS dose was 29 mg/65 mg per m2 (daunorubicin/cytarabine) on Days 1 and 3. In the 7+3 arm, first induction was cytarabine 100 mg/m2/day on Days 1-7 by continuous infusion + daunorubicin 60 mg/m2/day on Days 1-3. For second induction and consolidation, cytarabine was dosed on Days 1-5 and daunorubicin on Days 1 and 2. Patients could receive up to 2 cycles of induction and 2 cycles of consolidation in each arm. Subsequent induction was highly recommended for patients who did not achieve a response and was mandatory for patients achieving >50% reduction in percent blasts.

Learn more about the Phase 3 study design

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INDICATION

VYXEOS (daunorubicin and cytarabine) liposome for injection 44 mg/100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

IMPORTANT SAFETY INFORMATION

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.

Contraindications

VYXEOS is contraindicated in patients with a history of serious hypersensitivity reactions to cytarabine, daunorubicin, or any component of the formulation.

Warnings and Precautions

Hemorrhage

Serious or fatal hemorrhage events, including fatal CNS hemorrhages, associated with prolonged thrombocytopenia, have occurred with VYXEOS. The overall incidence (grade 1-5) of hemorrhagic events was 74% in the VYXEOS arm and 56% in the control arm. The most frequently reported hemorrhagic event was epistaxis (36% in VYXEOS arm and 18% in control arm). Grade 3 or greater events occurred in 12% of VYXEOS-treated patients and in 8% of patients in the control arm. Fatal treatment-emergent CNS hemorrhage not in the setting of progressive disease occurred in 2% of patients in the VYXEOS arm and in 0.7% of patients in the control arm. Monitor blood counts regularly and administer platelet transfusion support as required.

Cardiotoxicity

VYXEOS contains daunorubicin, which has a known risk of cardiotoxicity. This risk may be increased in patients with prior anthracycline therapy, preexisting cardiac disease, previous radiotherapy to the mediastinum, or concomitant use of cardiotoxic drugs. Assess cardiac function prior to VYXEOS treatment and repeat prior to consolidation and as clinically required. Discontinue VYXEOS in patients with impaired cardiac function unless the benefit of initiating or continuing treatment outweighs the risk. VYXEOS is not recommended in patients with cardiac function that is less than normal.

Total cumulative doses of non-liposomal daunorubicin greater than 550 mg/m2 have been associated with an increased incidence of drug-induced congestive heart failure. The tolerable limit appears lower (400 mg/m2) in patients who received radiation therapy to the mediastinum. Calculate the lifetime cumulative anthracycline exposure prior to each cycle of VYXEOS. VYXEOS is not recommended in patients whose lifetime anthracycline exposure has reached the maximum cumulative limit.

Hypersensitivity Reactions

Serious or fatal hypersensitivity reactions, including anaphylactic reactions, have been reported with daunorubicin and cytarabine. Monitor patients for hypersensitivity reactions. If a mild or moderate hypersensitivity reaction occurs, interrupt or slow the rate of infusion with VYXEOS and manage symptoms. If a severe or life-threatening hypersensitivity reaction occurs, discontinue VYXEOS permanently, treat the symptoms, and monitor until symptoms resolve.

Copper Overload

VYXEOS contains copper. Consult with a hepatologist and nephrologist with expertise in managing acute copper toxicity in patients with Wilson’s disease treated with VYXEOS. Monitor total serum copper, serum non-ceruloplasmin-bound copper, 24-hour urine copper levels, and serial neuropsychological examinations during VYXEOS treatment in patients with Wilson’s disease or other copper-related metabolic disorders. Use only if the benefits outweigh the risks. Discontinue in patients with signs or symptoms of acute copper toxicity.

Tissue Necrosis

Daunorubicin has been associated with severe local tissue necrosis at the site of drug extravasation. Administer VYXEOS by the intravenous route only. Do not administer by intramuscular or subcutaneous route.

Embryo-Fetal Toxicity

VYXEOS can cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid becoming pregnant while taking VYXEOS. If VYXEOS is used during pregnancy or if the patient becomes pregnant while taking VYXEOS, apprise the patient of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of VYXEOS.

MOST COMMON ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) were hemorrhagic events (74%), febrile neutropenia (70%), rash (56%), edema (55%), nausea (49%), mucositis (48%), diarrhea (48%), constipation (42%), musculoskeletal pain (43%), fatigue (39%), abdominal pain (36%), dyspnea (36%), headache (35%), cough (35%), decreased appetite (33%), arrhythmia (31%), pneumonia (31%), bacteremia (29%), chills (27%), sleep disorders (26%), and vomiting (25%).

Please see full Prescribing Information, including BOXED Warning.

AML=acute myeloid leukemia; AML-MRC=AML with myelodysplasia-related changes; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete recovery; HSCT=hematopoietic stem cell transplant; ITT=intent to treat; MDS=myelodysplastic syndromes; NR=not reached; OS=overall survival; sAML=secondary AML; t-AML=therapy-related AML.

References: 1. VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684-2692. 3. Walter RB, Kantarjian HM, Huang X, et al. Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study. J Clin Oncol. 2010;28(10):1766-1771. 4. Faderl S, Uy GL, Schiller GJ, et al. Outcomes in older patients with newly diagnosed, high-risk/secondary AML (sAML) who achieve remission with CPX-351 versus 7+3 induction. Poster presented at: International Symposium on Acute Leukemias (ISAL) XVII; February 24-27; Munich, Germany. 5. Wang ES. Treating acute myeloid leukemia in older adults. Hematology Am Soc Hematol Educ Program. 2014;2014(1):14-20. 6. Lin TL, Medeiros BC, Uy GL, et al. Outcomes by number of induction cycles with CPX-351 vs 7+3 chemotherapy in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (sAML). Poster presented at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL. 7. Data on file. VYX-2019-019. Palo Alto, CA: Jazz Pharmaceuticals. 8. Data on file. VYX-2019-018. Palo Alto, CA: Jazz Pharmaceuticals.

INDICATION

VYXEOS (daunorubicin and cytarabine) liposome for injection 44 mg/100 mg is indicated for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

Important Safety Information

WARNING: DO NOT INTERCHANGE WITH OTHER DAUNORUBICIN AND/OR CYTARABINE-CONTAINING PRODUCTS

VYXEOS has different dosage recommendations than daunorubicin hydrochloride injection, cytarabine injection, daunorubicin citrate liposome injection, and cytarabine liposome injection. Verify drug name and dose prior to preparation and administration to avoid dosing errors.