Ribociclib in Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On July 18, 2018, the indication for ribociclib (Kisqali) in combination with an aromatase inhibitor was expanded to include pre/perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy.1,2 Ribociclib was previously approved for postmenopausal women in combination with an aromatase inhibitor in this setting. Ribociclib was simultaneously approved in combination with fulvestrant (Faslodex) for postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy or following disease progression on endocrine therapy.1,2

Ribociclib is not indicated for concomitant use with tamoxifen.

Supporting Efficacy Data

The efficacy of ribociclib in combination with an aromatase inhibitor for pre/perimenopausal women was based on the double-blind phase III MONALEESA-7 trial, in which patents were randomized to receive ribociclib plus either a nonsteroidal aromatase inhibitor or tamoxifen and goserelin (Zoladex) vs placebo plus either a nonsteroidal aromatase inhibitor or tamoxifen and goserelin.2,3 Results from the prespecified analysis in the nonsteroidal aromatase inhibitor–only subgroup of 495 women, including 248 in the ribociclib group and 247 in the placebo group, who received no prior endocrine therapy for advanced disease showed progression-free survival (Response Evaluation Criteria in Solid Tumors, v1.1) of 27.5 months with ribociclib vs 13.8 months with placebo (hazard ratio = 0.569, 95% confidence interval [CI] = 0.436–0.743). In the subgroup analysis, objective response rates were 50.5% vs 36.2% among 391 patients with measurable disease.

OF NOTE

Ribociclib carries warnings/precautions for QT interval prolongation, increased QT prolongation with concomitant use of tamoxifen, hepatobiliary toxicity, neutropenia, and embryofetal toxicity.

The efficacy of ribociclib in combination with fulvestrant was demonstrated in the double-blind phase III MONALEESA-3 trial, in which 726 postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer who had received no or one line of prior endocrine treatment were randomized 2:1 to receive ribociclib plus fulvestrant (n = 484) or placebo plus fulvestrant (n = 242).2,4 Median progression-free survival was 20.5 months in the ribociclib group vs 12.8 months in the placebo group (HR = 0.593, P < .0001). Among 560 patients with measurable disease, objective response rates were 40.9% vs 28.7%.

How It Is Used

The recommended dose of ribociclib in the current indications is 600 mg (three 200-mg tablets) taken orally once daily for 21 consecutive days followed by 7 days off treatment in 28-day cycles. When given with ribociclib, the recommended dose of the aromatase inhibitor being used should be obtained from the prescribing information for that particular agent. When given with ribociclib, the recommended dose of fulvestrant is 500 mg on days 1, 15, 29, and once monthly thereafter. Pre/perimenopausal women receiving the combination of ribociclib plus an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone–releasing hormone agonist according to current clinical practice standards.

The product labeling for ribociclib provides detailed instructions on dose modifications for the following conditions: neutropenia; aspartate transaminase (AST) or alanine transaminase (ALT) elevations from baseline without an increase in total bilirubin above 2 the upper limit of normal (ULN); combined elevations in AST or ALT with total bilirubin increase in the absence of cholestasis; QT prolongation with QTcF > 480 and > 500 ms; other grade 3 or 4 toxicities; moderate and severe hepatic impairment; severe renal impairment; and concomitant use with strong CYP3A inhibitors. Labeling also provides detailed information on the concomitant use or avoidance of concomitant use with strong CYP3A inducers, CYP3A substrates, and drugs known to prolong the QT interval.

Safety Profile

Among patientsreceiving ribociclib in clinical trials, the most common adverse events of any grade (incidence ≥ 20%) have been neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough.

In MONALEESA-7, the most common adverse events of any grade occurring in at least 20% of the ribociclib group and at ≥ 2% higher incidence vs the placebo group were neutropenia (78% vs 7%), infections (35% vs 24%), leukopenia (29% vs 3%), arthralgia (33% vs 29%), nausea (31% vs 20%), and alopecia (21% vs 13%). The most common grade 3 or 4 adverse events were neutropenia (65% vs 2%), leukopenia (13% vs < 1%), and increased ALT level (5% vs 1%). Adverse events led to discontinuation of ribociclib and a nonsteroidal aromatase inhibitor in 3% and ribociclib alone in 3% and to discontinuation of placebo and a nonsteroidal aromatase inhibitor in 2% and placebo alone in > 1%. The most common causes of treatment discontinuation in the ribociclib group were increased ALT level (2%), increased AST level (2%), and drug-induced liver injury (1%). The most common grade 3 or 4 laboratory abnormalities in the ribociclib group were neutropenia (63%) and leukopenia (36%).

Expanded Indication for Ribociclib in Breast Cancer

  • The indication for ribociclib (Kisqali) in combination with an aromatase inhibitor was expanded to include pre/perimenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer as initial endocrine-based therapy.
  • The recommended dose of ribociclib in the current indications is 600 mg (three 200-mg tablets) taken orally once daily for 21 consecutive days followed by 7 days off treatment in 28-day cycles.

In MONALEESA-3, the most common adverse events of any grade reported at a frequency of at least 25% in the ribociclib group and ≥ 2% higher vs the placebo group were neutropenia (69% vs 2%), nausea (45% vs 28%), infections (42% vs 30%), diarrhea (29% vs 20%), leukopenia (27% vs < 1%), vomiting (27% vs 13%), and constipation (25% vs 12%). The most common grade 3 or 4 adverse events in the ribociclib group were neutropenia (53% vs 0%), leukopenia (12% vs 0%), increased ALT level (9% vs < 1%), increased AST level (6% vs < 1%), and infections (5% vs 2%). Adverse events led to discontinuation of both ribociclib and fulvestrant in 8% of patients and ribociclib alone in 9% and to discontinuation of fulvestrant and placebo in 4% and placebo alone in 2%. The most common causes of discontinuation of treatment in the ribociclib group were increased ALT level (5%), increased AST level (3%), and vomiting (1%). The most common grade 3 or 4 laboratory abnormalities in the ribociclib group were neutropenia (53%) and leukopenia (25%).

Ribociclib carries warnings/precautions for QT interval prolongation, increased QT prolongation with concomitant use of tamoxifen, hepatobiliary toxicity, neutropenia, and embryofetal toxicity.

Electrocardiograms (ECGs) and electrolytes should be monitored prior to initiation of treatment, and ECGs should be repeated at approximately day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated. Electrolytes should be monitored at the beginning of each cycle for 6 cycles and as clinically indicated. Use of ribociclib with drugs known to prolong the QT interval or strong CYP3A inhibitors should be avoided. Liver function tests should be monitored before initiating treatment, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Complete blood cell counts should be monitored before initiating treatment, every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. Patients should not breastfeed while receiving ribociclib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm613803.htm. Accessed August 21, 2018.

2. Kisqali (ribociclib) tablets prescribing information, Novartis Pharmaceuticals Corporation, July 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/-label/2018/209092s001lbl.pdf. Accessed August 21, 2018.

3. Tripathy D, Im SA, Colleoni M, et al: Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol 19:904-915, 2018.

4. Slamon DJ, Neven P, Chia S, et al: Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465-2472, 2018.

REPORT ADVERSE EVENTS

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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