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Monitoring and Management of Adverse Events Associated With Ribociclib Combination Therapy in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

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Monitoring and Management of Adverse Events Associated With Ribociclib Combination Therapy in Patients With
Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Michele Britto, RN
NorthShore University Health System, Evanston, IL

Introduction
• The cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor ribociclib in
combination with an aromatase inhibitor (AI) is indicated as a first-line
treatment option in postmenopausal women with hormone receptor–positive
(HR+), human epidermal growth factor receptor 2–negative (HER2−)
advanced breast cancer (ABC)1
• In the Phase 3 MONALEESA-2 trial, first-line ribociclib plus the nonsteroidal
AI letrozole had a manageable safety profile and significantly prolonged
progression-free survival (PFS) vs placebo plus letrozole in postmenopausal
women with HR+, HER2− ABC2
–– With a median follow-up of 26 months, median PFS was 25.3 months in
the ribociclib group vs 16.0 months in the placebo group (P=9.63 × 10−8)3
• Effective management of adverse events (AEs) during anticancer therapy is
critical for treatment success, and oncology nurses should ensure patients
receive appropriate care
Objective
• To provide an overview of the typical safety profile of ribociclib plus letrozole
therapy, including the key aspects of AE management most relevant to
oncology nurses
Overview of Ribociclib Safety Profile
• AEs reported in ≥20% of patients treated with ribociclib plus letrozole from
the first planned interim PFS analysis of MONALEESA-2 are shown in Table 12
Table 1. Adverse Events in ≥20% of Patients Treated With Ribociclib
Plus Letrozole in MONALEESA-2
Ribociclib 600 mg + letrozole 2.5 mg
(n=334)
Placebo + letrozole 2.5 mg
(n=330)
Patients, % Any grade Grade 3/4 Any grade Grade 3/4
Neutropeniaa 74.3 59.3 5.2 0.9
Nausea 51.5 2.4 28.5 0.6
Infections 50.3 4.2 42.4 2.4
Fatigue 36.5 2.4 30.0 0.9
Diarrhea 35.0 1.2 22.1 0.9
Alopecia 33.2 0 15.5 0
Leukopenia 32.9 21.0 3.9 0.6
Vomiting 29.3 3.6 15.5 0.9
Arthralgia 27.2 0.9 28.8 0.9
Constipation 24.9 1.2 19.1 0
Headache 22.2 0.3 19.1 0.3
Hot flush 21.0 0.3 23.6 0
aIncludes the preferred terms neutropenia, decreased neutrophil count, and granulocytopenia.
• The most common any-grade and Grade 3/4 AE in patients treated with ribociclib
was neutropenia; febrile neutropenia was rare (1.5% in the ribociclib group)2
• Most symptomatic AEs were Grade 1/22
• Discontinuation of study treatment due to AEs occurred in 7.5% and 2.1% of
patients in the ribociclib and placebo groups, respectively2
• Other AEs of interest that occurred with ribociclib treatment in MONALEESA-2
included QT interval prolongation and liver enzyme elevations2,4
–– 3.3% of patients in the ribociclib group and 0.3% in the placebo group had
≥1 postbaseline average QT measurement >480 ms
–– QT interval prolongation occurred most often during the first treatment
cycle and was reversible with dose modification
–– Grade 3/4 increased alanine aminotransferase (ALT) and increased
aspartate aminotransferase (AST) were reported in 9.3% and 5.7% of
patients, respectively, in the ribociclib group vs 1.2% and 1.2% of patients,
respectively, in the placebo group
Figure 2. Grading and recommended management of neutropenia.
Figure 3. CDK4/6 inhibitors and chemotherapy induce distinct forms
of neutropenia.
Figure 4. Grading and recommended management of QT
interval prolongation.
Figure 5. Schematic of a normal and prolonged QT interval.
Figure 6. Grading and recommended management of symptomatic AEs.
Figure 7. Grading and recommended management of liver
enzyme elevations.
Cycle 1
Ribociclib Day 1
600 mg (PO, QD,
3 weeks on/1 week o)
Aromatase inhibitor
Per applicable prescribing
information (PO, QD)
Baseline
Mid-cycle Mid-cycle
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Cycle 6
Day 1
Ribociclib QD
×3 weeks
Ribociclib QD
×3 weeks
Ribociclib QD
×3 weeks
Ribociclib QD
×3 weeks
Ribociclib QD
×3 weeks
Aromatase inhibitor
Symptomatic AEs monitored continuously
= CBC, LFT, and serum electrolytesa = ECGb
Ribociclib QD
×3 weeks
Recommended
starting dose
Figure 1. Treatment schedule and recommended monitoring for select adverse events in patients treated with ribociclib.
Management of Adverse Events Associated With Ribociclib Combination Treatment
ONS 43rd Annual Congress • May 17–20, 2018 • Washington, DC
Monitoring and Management of Adverse Events Associated With Ribociclib Combination Therapy in Patients With
Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer
Michele Britto, RN
NorthShore University Health System, Evanston, IL
CBC, complete blood count; ECG, electrocardiogram; LFT, liver function test; PO, orally; QD, once daily. Additional evaluations should be conducted as clinically indicated. aSerum electrolyte measurements are recommended at baseline and at the beginning of the first 6 cycles , but are not required mid-cycle. bRibociclib should be initiated only in patients with corrected
QT interval (Fridericia's formula) <450 ms at baseline. Correct any electrolyte abnormality before starting ribociclib.
• The standard dose of ribociclib plus letrozole and recommended monitoring
for postmenopausal women with HR+, HER2− ABC receiving treatment is
shown in Figure 11
Neutropenia QT interval prolongation Symptomatic AEs
Liver enzyme elevations
R
P T
Repolarization
Depolarization
Q S
Normal QT interval
Prolonged QT interval
• Median time to onset of Grade ≥3 neutropenia was 29 days; median time to
resolution to Grade <3 was 15 days5
• The 3-weeks-on/1-week-off treatment schedule allows for mitigation
of neutropenia6
• Guidance for neutropenia management is included in the ribociclib package
insert (Figure 2)1,7; growth factor support is not required for neutropenia
except with concurrent fever8
• The mechanisms of CDK4/6 inhibitor–induced neutropenia and
chemotherapy-induced neutropenia are different (Figure 3)9
• Guidance for QT interval prolongation management is included in the
ribociclib package insert (Figure 4)1,7
• An electrocardiogram measures electrical impulse traveling through the heart
as 5 waves labeled P, Q, R, S, and T (Figure 5)10
• The most common symptomatic AEs (≥25%) in patients receiving ribociclib
were gastrointestinal events (ie, nausea, diarrhea, and vomiting), fatigue,
alopecia, and arthralgia2
• Gastrointestinal events occurred more often in earlier treatment cycles than
later treatment cycles5
–– Median time to onset of nausea was 8 days and vomiting was 29 days in
the ribociclib group
–– Median duration of the first episode of nausea was 19 days and vomiting
was 3 days in the ribociclib group
• In addition to dose modifications, patients with nausea and vomiting
in MONALEESA-2 were treated with oral serotonin antagonists,
prochlorperazine/prochlorperazine maleate, and promethazine/
promethazine hydrochloride5
• Guidance for management of symptomatic AEs is included in the ribociclib
package insert (Figure 6)1
• The ribociclib package insert recommends conducting liver function tests
before initiating ribociclib treatment, every 2 weeks for the first 2 treatment
cycles, and at the beginning of each of the subsequent 4 cycles (Figure 1)1
• Median time to onset of Grade ≥3 ALT/AST elevations was 57 days; median
time to resolution to Grade ≤2 ALT/AST elevations was 24 days1
• Guidance for management of ALT/AST elevations is included in the ribociclib
package insert (Figure 7)1,7
ANC, absolute neutrophil count; CTCAE, Common Terminology Criteria for Adverse Events; LLN, lower limit of normal; PI,
package insert. aGrade 3 neutropenia with a single episode of fever >38.3°C or >38°C for > 1 hour and/or concurrent infection.1
CDK4/6, cyclin-dependent kinases 4 and 6. In the left panel, the antiproliferative effects of CDK4/6 inhibitors are
mediated through reversible bone marrow suppression resulting from cell-cycle arrest at the G1–S phase. In contrast,
in the right panel, the antiproliferative effects of chemotherapy are mediated through irreversible bone marrow toxicity
resulting from DNA damage and apoptotic pathways.
CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram; QTc, corrected QT interval;
PI, package insert. aIn case of QT interval prolongation at any time on ribociclib treatment, more frequent ECG
monitoring is recommended. bIncluding torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms
of serious arrhythmia.
The time between the start of the Q wave and end of
the T wave corresponds to the time it takes the heart to
contract and refill with blood.10 Prolongation of the QT
interval is observed with many oncology medications and,
in rare cases, can lead to fatal arrhythmias.11
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; PI, package insert.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events;
PI, package insert; ULN, upper limit of normal. aGrading criteria for increased ALT or AST. bIf patients develop Grade ≥2 ALT/
AST increase along with total bilirubin >2.0 × ULN irrespective of baseline grade, discontinue ribociclib.
Discussion and Conclusions
• Ribociclib plus letrozole is safe and effective in postmenopausal women
with HR+, HER2− ABC
• Ribociclib plus letrozole treatment is associated with predictable and
manageable safety events
• Oncology nurses play an important role in effectively managing AEs
through patient assessment and patient education
• Ongoing Phase 3 studies are investigating the efficacy and safety of
ribociclib in combination with fulvestrant in men and postmenopausal
women with ABC who progressed on prior endocrine therapy
(MONALEESA-3) and in combination with tamoxifen or a nonsteroidal
AI in pre/perimenopausal women with ABC receiving concurrent ovarian
suppression (MONALEESA-7)12,13
Acknowledgments: Assistance with preparation of this poster was provided under
the direction of the authors by MedThink SciCom (Cary, NC) with support from Novartis
Pharmaceuticals Corporation. Ribociclib was discovered by Novartis Institutes for
BioMedical Research in collaboration with Astex Pharmaceuticals.

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