CADTH Reimbursement Review

Table 5: Details of the ANDROMEDA Study

Criteria

Description

Design and population

Study design

Phase III, randomized, open-label, active-controlled, multi-centre

Locations

109 sites in 22 countries (Australia, Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, the Netherlands, Poland, Spain, South Korea, Sweden, Turkey, UK, and US)

Study duration

October 10, 2017, to ongoing

Patient enrolment: May 3, 2018, to August 15, 2019

Data cut-off date

February 14, 2020 (date of last observation for last patient recorded as part of the database for primary analysis)

Number of patients randomized (randomization ratio)

N = 388 (1:1)

Main inclusion criteria

• Age ≥ 18 years

• Histopathological diagnosis of systemic AL amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent in Congo red-stained tissue specimens or characteristic electron microscopy appearance

• Measurable disease

  • Serum M-protein ≥ 0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at a central laboratory)

  • Serum free light chain ≥ 50 mg/L with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains ≥ 50 mg/L

• Involvement in ≥ 1 organ(s)

• Eastern Cooperative Oncology Group Performance Score of 0 to 2

• Pre-treatment clinical laboratory values meeting the following criteria during the screening phase:

  • Absolute neutrophil count ≥ 1.0 × 109/L

  • Hemoglobin level ≥ 8.0 g/dL (≥ 5 mmol/L); red blood cell transfusion allowed until 7 days before randomization

  • Platelet count ≥ 50 × 109/L; platelet transfusions are acceptable without restriction during the screening period

  • Alanine aminotransferase level ≤ 2.5 times the ULN

  • Aspartate aminotransferase ≤ 2.5 times the ULN

  • Total bilirubin level ≤ 1.5 × ULN except for patients with Gilbert syndrome, in which case direct bilirubin ≤ 2 × ULN

  • Estimated glomerular filtration rate ≥ 20 mL/min/1.73 m2 measured using the Chronic Kidney Disease Epidemiology Collaboration equation

Main exclusion criteria

• Prior therapy for AL amyloidosis or multiple myeloma including medications that target CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid) maximum exposure before randomization

• Previous or current diagnosis of symptomatic multiple myeloma, including the presence of lytic bone disease, plasmacytomas, ≥ 60% plasma cells in the bone marrow, or hypercalcemia

(continued)

• Evidence of significant cardiovascular conditions

  • NT-ProBNP > 8,500 ng/L

  • New York Heart Association class IIIB or IV heart failure

  • Heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzyme elevation and electrocardiogram changes) or uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy

  • Inpatient admission to a hospital for unstable angina or myocardial infarction within the last 6 months before first dose or percutaneous cardiac intervention with recent stent within 6 months or coronary artery bypass grafting within 6 months

  • For patients with congestive heart failure, cardiovascular-related hospitalizations within 4 weeks before randomization

  • History of sustained ventricular tachycardia or aborted ventricular fibrillation or an atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker or implantable cardioverter defibrillator is indicated but not placed

  • Screening 12-lead electrocardiogram showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 500 ms; patients who have a pacemaker are included regardless of calculated QTc interval

  • Supine systolic blood pressure < 90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 20 mm Hg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

• Planned autologous stem cell transplant during the first 6 cycles treatment

• History of malignancy other than AL amyloidosis within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator and with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years)

• Prior therapy for AL amyloidosis or multiple myeloma, including anti-CD38 medications (except for 160 mg dexamethasone, or equivalent corticosteroid, maximum exposure before randomization)

Drugs

Comparator

CyBorD: Cyclophosphamide (1.3 mg/m2 orally or intravenously), bortezomib (1.3 mg/m2 of body surface area), dexamethasone (40 mg orally or intravenously once weekly), for 6 cycles of 28 days each

Intervention

DCyBorD:

Cyclophosphamide (1.3 mg/m2 orally or intravenously), bortezomib (1.3 mg/m2 of body surface area), dexamethasone (40 mg orally or intravenously once weekly), for 6 cycles of 28 days each

plus

Daratumumab 1,800 mg per 15 mL administered SC, weekly in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter until disease progression or the start of subsequent therapy, or for a maximum of 24 cycles from start of the trial

Duration

Phase

Safety run-in (non-randomized)

2 years (n = 28) daratumumab SC weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years; CyBorD was given weekly for 6 cycles; patients received a median of 16 (range = 1 to 23) treatment cycles

Screening

Up to 28 days before treatment initiation

Open-label

CyBorD: 24 weeks

DCyBorD: 24 weeks for CyBorD and up to 24 months for daratumumab SC monotherapy

Follow-up

Ongoing

Outcomes

Primary end point

Hematologic CR assessed by an independent review committee

Secondary and exploratory end points

Secondary end points:

• MOD-PFS/MOD-EFS

• Organ response rate

• Overall survival

• Hematologic CR at 6 months

• Hematologic VGPR-or-better rate

• Time to hematologic response

• Duration of hematologic response

• Time to next treatment

• Time to organ response

• Duration of organ response

• Time to organ progression

• Improvement in fatigue

Exploratory end points:

• Hematologic PFS

• Minimal residual disease

• Health-related quality of life

• Medical resource utilization

Safety:

• AEs

• Grade 3 or 4 AEs

• TEAE

• Discontinuation due to TEAE

• Death within 30 days of last dose of study treatment

• Systemic administration-related reactions

Notes

Publications

Kastritis et al. (2021)7

AE = adverse event; AL = light chain; CR = complete response; CyBorD = cyclophosphamide, bortezomib, and dexamethasone; DCyBorD = daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone; EFS = event-free survival; MOD = major organ deterioration; NT-ProBNP = N-terminal pro-B-type natriuretic peptide; PFS = progression-free survival; SC = subcutaneous; TEAE = treatment-emergent adverse event; ULN = upper limit of normal; VGPR = very good partial response.

Source: Clinical Study Report for Darzalex.8