You are using an outdated browser. Please upgrade your browser to improve your experience and security.

VYXEOS demonstrated superior overall survival and higher HSCT rates vs 7+31,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.

Overall survival

Kaplan-Meier curve for overall survival, ITT population1

Kaplan-Meier curve for overall survival with VYXEOS® (daunorubicin and cytarabine) vs 7+3, ITT population Kaplan-Meier curve for overall survival with VYXEOS® (daunorubicin and cytarabine) vs 7+3, ITT population

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

Median survival (95% CI)

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

Prespecified exploratory subgroup analysis of overall survival by age in the Phase 3 trial2

Limitations of subanalysis2

  • Results should be interpreted with caution, as this is an exploratory analysis of a specific subgroup
Kaplan-Meier curve for overall survival with VYXEOS® (daunorubicin and cytarabine) in patients aged 60-69 vs 7+3, ITT population

Median survival (95% Cl)

VYXEOS (n=96): 9.6 months (6.2, 12.6)   
7+3 (n=102): 6.9 months (4.6, 8.8)

Lancet 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.

Kaplan-Meier curve for overall survival with VYXEOS® (daunorubicin and cytarabine) in patients aged 70-75 vs 7+3, ITT population

Median survival (95% Cl)

VYXEOS (n=57): 8.9 months (4.7, 12.2)   
7+3 (n=54): 5.6 months (3.3, 7.5)

Lancet 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.

Patients receiving consolidation following successful induction had longer overall survival with VYXEOS vs those receiving 7+3/5+23,b

Outcomes in an exploratory post hoc analysis using data from the Phase 3 trial3

Limitations of subanalysis3

  • Results should be interpreted with caution, as this is an exploratory analysis of a specific subgroup
  • This analysis is potentially biased as it only includes responders who went on to receive consolidationc
  • The treatment effect of this nonrandomized subgroup is possibly confounded by unbalanced baseline characteristics
Kaplan-Meier curve for overall survival with VYXEOS® (daunorubicin and cytarabine) in patients receiving consolidation with VYXEOS vs 7+3, ITT population

Events/N:

VYXEOS: 25/49
7+3/5+2: 25/32

Median survival (95% CI)

VYXEOS: 25.4 (12.4, NR)
7+3/5+2: 8.5 (5.7, 15.2)

a
5+2 regimen for consolidation was cytarabine 100 mg/m2/day given on Days 1 through 5 and daunorubicin 60 mg/m2/day given on Days 1 and 2.3
One subject on VYXEOS entered into consolidation without a response.3
up icon

Overall response

Percentage of patients who achieved CR and CR+CRi1,4

Percentage of patients who achieved a response with VYXEOS® (daunorubicin and cytarabine) vs 7+3

CR+CRi, n/N:

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

CR, n/N:

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

a
b
c
P value is 2-sided.
up icon

Rate of HSCT

Overall rate of HSCT1,e

Percentage of patients receiving stem cell transplant after treatment with VYXEOS® (daunorubicin and cytarabine) vs 7+3

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

Rate of HSCT during first CR1,5

Percentage of patients receiving stem cell transplant after treatment with VYXEOS® (daunorubicin and cytarabine) vs 7+3

Prespecified exploratory subgroup analysis of transplant rate by age in the Phase 3 trial6

Limitations of subanalysis6

  • Results should be interpreted with caution, as this is an exploratory analysis of a specific subgroup
  • This analysis was limited by the small patient number and that no statistical analysis was conducted on rate of HSCT by age group
Patients aged 60-69

Data presented are for the subgroup of patients aged 60-69 years in the ITT population.

Patients aged 70-75

Data presented are for the subgroup of patients aged 70-75 years in the ITT population.

up icon

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,f

Kaplan-Meier curve for overall survival following HSCT with VYXEOS (daunorubicin and cytarabine) vs 7+3

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

Kaplan-Meier curve for overall survival following HSCT in patients in CR/CRi at time of HSCT with VYXEOS (daunorubicin and cytarabine) vs 7+3

Median survival (95% CI)

VYXEOS: (n=13/39) Not reached (15.6, not reached)
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

‌fLancet 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.

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 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

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. Kolitz JE, Strickland SA, Cortes JE, et al. Outcomes in older patients with newly diagnosed, high-risk/secondary acute myeloid leukemia (sAML) who received consolidation in a phase 3 study of CPX-351 versus conventional 7+3/5+2 cytarabine and daunorubicin. Poster presented at: 6th Annual Meeting of the Society of Hematologic Oncology; September 12-15, 2018; Houston, TX. 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. 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. 6. Lancet JE, Uy GL, Cortes JE, et al. Analysis of survival after allogeneic transplantation by age strata for patients treated with CPX-351 liposome for injection versus cytarabine and daunorubicin 7+3 in patients aged 60-75 years with untreated high-risk acute myeloid leukemia. Poster presented at: 43rd Annual Meeting of the European Society for Blood and Marrow Transplantation; March 26-29, 2017; Marseille, France. 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.