Literature Scan
a high risk of thrombosis recurrence
and serious bleeding complications,”
the authors wrote. These results suggest
that apixaban can be considered in this
population, offering “important advan-
tages over parenteral agents, including
route of administration, convenience,
and cost.”
AVERT enrolled patients who had a
newly diagnosed cancer or progressive can-
cer following complete or partial remission
and who were initiating a new course
of chemotherapy. All participants had
an increased risk of VTE (defined as a
Khorana score ≥2). Patients were ex-
cluded if they had conditions putting
them at increased risk for clinically
significant bleeding; hepatic disease
associated with coagulopathy; renal
insufficiency; or a diagnosis of basal-
cell or squamous-cell skin carcinoma,
acute leukemia, or myeloproliferative
neoplasm.
After stratifying for age, sex, and
participating center, the investigators
randomized 574 participants to re-
ceive thromboprophylaxis with either
apixaban 2.5 mg twice daily (n=291)
or placebo (n=283). The treatment
period was 180 days and the first
dose of study drug was administered
within 24 hours after the initiation of
chemotherapy.
Participants’ baseline character-
istics were well balanced, the authors
reported. The mean age was 61
years and the most common types
of primary cancer were gynecologic
(25.8%), lymphoma (25.3%), and
pancreatic (13.6%).
The median duration of treatment
was 157 days in the apixaban group
(interquartile range [IQR] = 78-168)
and 155 days in the placebo group
(IQR=83-168), and the median
duration of follow-up was 183 days
in each group (range not reported).
“The rate of adherence to the trial
regimen was high in both groups, at
83.6 percent in the apixaban group
and 84.1 percent in the placebo
group,” the researchers noted.
Three patients in the apixaban
group and eight in the placebo group
did not receive treatment, so 288 and
275 patients in each group, respec-
tively, were included.
During follow-up, the primary
efficacy endpoint (defined as major
VTE [including proximal deep-
vein thrombosis or pulmonary
embolism] within the first 180 days
after randomization) occurred in 12
apixaban-treated patients (4.2%) and
28 placebo-treated patients (10.2%;
TABLE ). This translated to a signifi-
cantly lower risk of VTE with apixa-
ban (hazard ratio [HR] = 0.41; 95% CI
0.26-0.65; p<0.001).
In the modified intention-to-
treat analysis, which included all
randomized patients who had received
at least one dose of apixaban or placebo,
major bleeding (the primary safety end-
point) occurred in 10 apixaban-treated
patients (3.5%) and five placebo-treated
patients (1.8%; HR=2.00; 95% CI 1.01-
3.95; p=0.046). Most episodes of VTE
were grade 2 in severity, meaning the
episode required treatment but was not
considered to be a clinical emergency
(n=8 [80%] in the apixaban group and
Kd
TABLE.
Efficacy and Safety Clinical Outcomes
Apixaban
(n=288) Placebo
(n=275)
Venous thromboembolism 12 (4.2%) 28 (10.2%)
Deep vein thrombosis 7 (2.4%) 12 (4.4%)
Pulmonary embolism
ASH Clinical News
p Value
0.41 (0.26-0.65) <0.001
5 (1.7%) 16 (5.8%) Major bleeding episode 10 (3.5%) 5 (1.8%) 2.00 (1.01-3.95) 0.046
Clinically relevant nonmajor bleeding 21 (7.3%) 15 (5%) 1.28 (0.89-1.84) N/A
Once-Weekly Dosing Is Now FDA Approved
The FDA granted Priority Review to KYPROLIS ® , which was the fi rst hematology product approved under the FDA Oncology
Center of Excellence Real-Time Oncology Review Pilot Program. 1
SUPERIOR OUTCOMES
SUPERIOR PFS KYPROLIS ® once-weekly 70 mg/m 2 with dexamethasone (Kd) vs
KYPROLIS ® twice-weekly 27 mg/m 2 with dexamethasone* (Kd):
• EXTENDED PFS by 47%: 11.2 months in once-weekly arm vs 7.6 months in twice-weekly arm; HR = 0.69
(95% CI: 0.54-0.88); P = 0.0014 2
*Kd27 is not an FDA-approved dose for KYPROLIS ® .
INCREASED DEPTH OF RESPONSE:
• 4x AS MANY PATIENTS ACHIEVED ≥ CR: 7.1% in once-weekly arm (n = 17) vs 1.7% in twice-weekly arm (n = 4) 2,†
A subgroup analysis of ORR.
†
COMPARABLE SAFETY: Overall safety was comparable between the once-weekly and twice-weekly groups 2
Select adverse events of interest:
• The incidence of cardiac failure was 3.8% in the once-weekly arm (n = 9) vs 5.1% in the twice-weekly arm (n = 12) 2,3
• The incidence of pulmonary hypertension was 1.7% in the once-weekly arm (n = 4) vs 1.3% in the twice-weekly arm (n = 3) 3
PATIENTS WERE ABLE TO STAY ON THERAPY LONGER: Patients stayed on treatment for 31% longer
in the once-weekly arm (median 38 weeks) vs the twice-weekly arm (median 29.1 weeks) 2
CI = confi dence interval; CR = complete response; HR = hazard ratio; Kd = KYPROLIS ® and dexamethasone; ORR = overall response rate;
PFS = progression-free survival.
Kd once-weekly vs twice-weekly study design: Phase 3, randomized, multicenter, open-label study (N = 478) in patients with relapsed and refractory
multiple myeloma who had received 2 to 3 lines of therapy, KYPROLIS ® and dexamethasone 70 mg/m 2 once weekly (n = 240) versus KYPROLIS ® and
dexamethasone 27 mg/m 2 twice weekly (n = 238). The primary endpoint was PFS. Secondary endpoints included ORR and safety. 2
INDICATION AND IMPORTANT SAFETY INFORMATION FOR KYPROLIS
INDICATION
Tumor Lysis Syndrome
KYPROLIS ® (carfi lzomib) is indicated in combination with dexamethasone or
• Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have
with lenalidomide plus dexamethasone for the treatment of patients with
occurred. Patients with a high tumor burden should be considered at
relapsed or refractory multiple myeloma who have received one to three
greater risk for TLS. Adequate hydration is required prior to each dose in
Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering
lines of therapy.
drugs in patients at risk for TLS. Monitor for evidence of TLS during
IMPORTANT SAFETY INFORMATION FOR KYPROLIS
treatment and manage promptly, and withhold until resolved.
Cardiac Toxicities
• New onset or worsening of pre-existing cardiac failure (e.g., congestive
heart failure, pulmonary edema, decreased ejection fraction), restrictive
cardiomyopathy, myocardial ischemia, and myocardial infarction including
fatalities have occurred following administration of KYPROLIS. Some
events occurred in patients with normal baseline ventricular function.
Death due to cardiac arrest has occurred within one day of administration.
• Monitor patients for signs or symptoms of cardiac failure or ischemia.
Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for
Grade 3 or 4 cardiac adverse events until recovery, and consider whether
to restart at 1 dose level reduction based on a benefi t/risk assessment.
• While adequate hydration is required prior to each dose in Cycle 1, monitor
all patients for evidence of volume overload, especially patients at risk for
cardiac failure. Adjust total fl uid intake as clinically appropriate.
• For patients ≥ 75 years, the risk of cardiac failure is increased. Patients
with New York Heart Association Class III and IV heart failure, recent
myocardial infarction, conduction abnormalities, angina, or arrhythmias
may be at greater risk for cardiac complications and should have a
comprehensive medical assessment prior to starting treatment with
KYPROLIS and remain under close follow-up with fl uid management.
Acute Renal Failure
• Cases of acute renal failure, including some fatal renal failure events, and
renal insuffi ciency adverse events (including renal failure) have occurred.
Acute renal failure was reported more frequently in patients with advanced
relapsed and refractory multiple myeloma who received KYPROLIS
monotherapy. Monitor renal function with regular measurement of the
serum creatinine and/or estimated creatinine clearance. Reduce or
withhold dose as appropriate.
Learn more at KYPROLIS-HCP.com
26
Hazard Ratio
(95% CI)
Pulmonary Toxicity
• Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure,
and acute diffuse infi ltrative pulmonary disease such as pneumonitis and
interstitial lung disease have occurred. Some events have been fatal. In
the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension
• Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac
imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until
resolved or returned to baseline and consider whether to restart based on
a benefi t/risk assessment.
Dyspnea
• Dyspnea was reported in patients treated with KYPROLIS. Evaluate
dyspnea to exclude cardiopulmonary conditions including cardiac failure
and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until
resolved or returned to baseline. Consider whether to restart based on a
benefi t/risk assessment.
Hypertension
• Hypertension, including hypertensive crisis and hypertensive emergency,
has been observed, some fatal. Control hypertension prior to starting
KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension
cannot be adequately controlled, withhold KYPROLIS and evaluate.
Consider whether to restart based on a benefi t/risk assessment.
Venous Thrombosis
• Venous thromboembolic events (including deep venous thrombosis
and pulmonary embolism) have been observed. Thromboprophylaxis
is recommended for patients being treated with the combination of
KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone.
The thromboprophylaxis regimen should be based on an assessment of
the patient’s underlying risks.