IMPORTANT SAFETY INFORMATION


QT interval prolongation. KISQALI has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, KISQALI may require...

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Indications. KISQALI is a kinase inhibitor indicated in combination with: an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy

Efficacy

NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®)
Ribociclib (KISQALI®) is a recommended option in HR+/HER2- mBC for postmenopausal women with an AI, postmenopausal women with fulvestrant, and premenopausal women with an LHRH agonist + an AI—based on evidence from a dedicated trial in the first-line setting.1,2

The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Trial Designs

MONALEESA-7 Study Description

MONALEESA-7 was a randomized, double-blind, placebo-controlled, multicenter, phase III trial in premenopausal women with HR+/HER2- mBC who received no prior endocrine therapy for advanced or metastatic disease. Patients (N=672) were stratified by the presence of liver and/or lung metastases, prior chemotherapy for advanced disease, and endocrine combination partner. Patients were randomized (1:1) to receive either KISQALI 600 mg (3 weeks on, 1 week off), an NSAI (letrozole 2.5 mg or anastrozole 1 mg once daily on a continuous basis) or tamoxifen 20 mg (once daily on a continuous basis), and goserelin 3.6 mg (monthly subcutaneous injection) or placebo (3 weeks on, 1 week off), an NSAI (letrozole 2.5 mg or anastrozole 1 mg once daily on a continuous basis) or tamoxifen 20 mg (once daily on a continuous basis), and goserelin 3.6 mg (monthly subcutaneous injection). The primary end point was PFS using RECIST v1.1; secondary end points included OS, ORR, QOL, and safety. The efficacy and safety results presented are from a prespecified subgroup analysis of 495 patients who had received KISQALI or placebo with an NSAI plus goserelin.1,3

MONALEESA-3 Study Description

MONALEESA-3 was a randomized, double-blind, placebo-controlled, multicenter, phase III trial in postmenopausal women with HR+/HER2- mBC who received no or only 1 prior line of endocrine therapy for advanced or metastatic disease. Patients (N=726) were stratified by the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Patients were randomized (2:1) to receive either KISQALI 600 mg (3 weeks on, 1 week off) and fulvestrant 500 mg (intramuscular injection on Days 1, 15, 29, and once monthly thereafter) or placebo (3 weeks on, 1 week off) and fulvestrant 500 mg (intramuscular injection on Days 1, 15, 29, and once monthly thereafter). The primary end point was PFS using RECIST v1.1; secondary end points included OS, ORR, QOL, and safety.1,4,5

MONALEESA-2 Study Description

MONALEESA-2 was a randomized, double-blind, placebo-controlled, multicenter, phase III trial in postmenopausal women with HR+/HER2- mBC who received no prior therapy for advanced disease. Patients (N=668) were stratified by the presence of liver and/or lung metastases and randomized 1:1 to receive either KISQALI 600 mg (3 weeks on, 1 week off) and letrozole 2.5 mg (continuously) or placebo (3 weeks on, 1 week off) and letrozole 2.5 mg (continuously). The primary end point was PFS using RECIST v1.1; secondary end points included OS, ORR, QOL, and safety; exploratory end points included tumor size reduction and DOR.1,6,7

Progression-free Survival

Largest body of first-line evidence for a CDK4/6 inhibitor regardless of menopausal status or combination1,8

 

THE FIRST AND ONLY TRIAL of a CDK4/6 inhibitor dedicated to premenopausal women (n=495)1,3,8

For nearly 20 years, few clinical trials have been solely dedicated to premenopausal women with metastatic breast cancer8

                       
mPFS

27.5

months
PREMENOPAUSAL
First line
KISQALI + NSAI + goserelin
(95% CI: 19.1-NR) vs 13.8 months with placebo + NSAI + goserelin (95% CI: 12.6-17.4), HR=0.569 (95% CI: 0.436-0.743)1
  • mPFS results based on a prespecified subgroup analysis of 495 patients who received KISQALI® (ribociclib) tablets or placebo with an NSAI + goserelin1
THE LARGEST TRIAL to evaluate a CDK4/6 inhibitor + fulvestrant as initial therapy in postmenopausal women (N=726)1,8
                       
mPFS

20.5

months
POSTMENOPAUSAL
First line and second line
KISQALI + fulvestrant (ITT)
(95% CI: 18.5-23.5) vs 12.8 months with placebo + fulvestrant (95% CI: 10.9-16.3), HR=0.593 (95% CI: 0.480-0.732); P<0.00011
THE LARGEST FIRST-LINE TRIAL to evaluate a CDK4/6 inhibitor + AI in postmenopausal women (N=668)1,8,9
                       
mPFS

25.3

months
POSTMENOPAUSAL
First line
KISQALI + letrozole (ITT)
vs 16.0 months with placebo + letrozole9
  • mPFS results based on a subsequent preplanned OS analysis9
44% reduction in risk of progression or death with KISQALI + letrozole vs placebo + letrozole (HR=0.556 [95% CI: 0.429-0.720]; P<0.0001) (primary end point, interim analysis).1

Overall Survival

Statistically significant overall survival—the KISQALI difference5

The only CDK4/6 inhibitor to show a statistically significant improvement in overall survival in premenopausal women5

P = 0.00973
  • OS was a key secondary end point in MONALEESA-75
  • HR=0.712 (95% CI: 0.535-0.948)5
  • KISQALI is not indicated for concomitant use with tamoxifen1

OVERALL SURVIVAL (ITT)5

OS KM curve showing median OS not reached for KISQALI + ET + goserelin vs 40.9 months with placebo + ET + goserelin OS KM curve showing median OS not reached for KISQALI + ET + goserelin vs 40.9 months with placebo + ET + goserelin
  • Results reported at 42 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error
The only CDK4/6 inhibitor proven in a clinical trial to help premenopausal women with HR+/HER2- mBC live longer5

KISQALI + NSAI—Consistent improvement in overall survival5

OVERALL SURVIVAL (NSAI)5

NSAI arm OS KM curve showing median OS not reached for KISQALI + NSAI + goserelin vs 40.7 months with placebo + NSAI + goserelin NSAI arm OS KM curve showing median OS not reached for KISQALI + NSAI + goserelin vs 40.7 months with placebo + NSAI + goserelin

Hazard ratio is based on unstratified Cox model.

  • Results reported at 42 months were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

KISQALI is not indicated for use with tamoxifen1

OVERALL SURVIVAL (TAMOXIFEN)5

Tamoxifen arm OS KM curve. KISQALI is not indicated for concomitant use with tamoxifen Tamoxifen arm OS KM curve. KISQALI is not indicated for concomitant use with tamoxifen

Increased QT prolongation with concomitant use of tamoxifen. KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was ≥10 ms higher in the tamoxifen + placebo subgroup compared with the NSAI + placebo subgroup. In the placebo arm, an increase of >60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of >60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the KISQALI and tamoxifen combination and in 18/245 (7%) of patients receiving KISQALI plus an NSAI.

IMPORTANT SAFETY INFORMATION
QT interval prolongation. KISQALI has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction, or discontinuation. Across clinical trials in patients with advanced or metastatic breast cancer treated with KISQALI in combination with an aromatase inhibitor or fulvestrant (“KISQALI treatment groups”), 14 of 1054 patients (1%) had >500 ms postbaseline QTcF value, and 59 of 1054 (6%) had a >60 ms increase from baseline in QTcF intervals. These ECG changes were reversible with dose interruption and most occurred within the first 4 weeks of treatment. No cases of torsades de pointes were reported. In MONALEESA-2, on the KISQALI + letrozole treatment arm, there was 1 (0.3%) sudden death in a patient with grade 3 hypokalemia and grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.

Please see additional Important Safety Information below.

 

Quality of Life

QOL preserved in women across all 3 MONALEESA trials5,10,11

MONALEESA-710

  • During treatment, QOL was maintained from baseline and similar in both arms
  • There was no significant difference in the TTD of global health status/QOL ≥10% (HR=0.759 [95% CI: 0.561-1.028])
  • At disease progression or EOT, overall QOL worsened in both arms

MONALEESA-35

  • During treatment, QOL was maintained from baseline and similar in both arms
  • There was no significant difference in the TTD of global health status/QOL ≥10% (HR=0.795 [95% CI: 0.602-1.050])
  • At disease progression or EOT, overall QOL worsened in both arms

MONALEESA-211

  • During treatment, QOL was maintained from baseline and similar in both arms
  • There was no significant difference in the TTD of global health status/QOL ≥10% (HR=0.944 [95% CI: 0.720-1.237])
  • At disease progression or EOT, overall QOL worsened in both arms

*The EORTC QLQ-C30 was used to assess the secondary QOL PRO end point. The EORTC QLQ-C30 is a standard QOL PRO tool that includes 5 functional scales: physical, role, emotional, cognitive, and social; 3 symptom scales: fatigue, nausea and vomiting, and pain; 6 single items: dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties.5,10,11

IMPORTANT SAFETY INFORMATION (continued)
QT interval prolongation (continued). Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI only in patients with QTcF values <450 ms. Repeat ECG at approximately Day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorus, and magnesium) prior to the initiation of treatment, at the beginning of each of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting therapy with KISQALI.

Avoid the use of KISQALI in patients who already have or who are at significant risk of developing QT prolongation, including patients with:
  • long QT syndrome
  • uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
  • electrolyte abnormalities

Avoid using KISQALI with drugs known to prolong the QT interval and/or strong CYP3A inhibitors, as this may lead to prolongation of the QTcF interval.

 Please see additional Important Safety Information below.

 For Information about the safety profile, continue to the next page

AI=aromatase inhibitor; CDK=cyclin-dependent kinase; CT=computed tomography; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group performance status; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT=end of treatment; ET=endocrine therapy; HER2-=human epidermal growth factor receptor 2-negative; HR=hazard ratio; HR+=hormone receptor-positive; ITT=intent to treat; LHRH=luteinizing hormone-releasing hormone; mBC=metastatic breast cancer; mPFS=median progression-free survival; NR=not reached; NSAI=nonsteroidal aromatase inhibitor; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PRO=patient-reported outcome; QOL=quality of life; RECIST=Response Evaluation Criteria In Solid Tumors; TTD=time to deterioration.

References: 1. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 15, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Tripathy D, Im S-A, 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. 2018;19(7):904-915. 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. 2018;36(24):2465-2472. 5. Data on file. Novartis Pharmaceuticals Corp; 2019. 6. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. 7. Janni W, Alba E, Bachelot T, et al. First-line ribociclib plus letrozole in postmenopausal women with HR+, HER2– advanced breast cancer: tumor response and pain reduction in the phase 3 MONALEESA-2 trial. Breast Cancer Res Treat. 2018;169(3):469-479. 8. ClinicalTrials.gov. Search results for fulvestrant; combination advanced breast cancer studies; recruiting; not yet recruiting; active, not recruiting, completed, enrolling by invitation, suspended, terminated, withdrawn, unknown status; phase 3; breast cancer; CDK; NCT01942135; NCT02102490. Search conducted July 2018. 9. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. 10. Beck JT, Wheatley-Price P, Nevin P, et al. Patient-reported outcomes with ribociclib-based therapy in hormone receptor-positive, HER2-negative advanced breast cancer: results from the Phase III MONALEESA-2, -3, and -7 trials. Poster presented at: San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Poster P6-18-14. 11. Verma S, O'Shaughnessy J, Burris HA, et al. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. 

 
Indication
KISQALI® (ribociclib) tablets is a kinase inhibitor indicated in combination with:
  • an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or
  • fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy

The KISQALI® (ribociclib) FEMARA® (letrozole) Co-Pack tablets is indicated as initial endocrine-based therapy for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

IMPORTANT SAFETY INFORMATION
QT interval prolongation. KISQALI and the KISQALI FEMARA Co-Pack have been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction, or discontinuation. Across clinical trials in patients with advanced or metastatic breast cancer treated with KISQALI in combination with an aromatase inhibitor or fulvestrant (“KISQALI treatment groups”), 14 of 1054 patients (1%) had >500 ms postbaseline QTcF value, and 59 of 1054 (6%) had a >60 ms increase from baseline in QTcF intervals. These ECG changes were reversible with dose interruption and most occurred within the first 4 weeks of treatment. No cases of torsades de pointes were reported. In MONALEESA-2, on the KISQALI + letrozole treatment arm, there was 1 (0.3%) sudden death in a patient with grade 3 hypokalemia and grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.

Assess ECG prior to initiation of treatment. Initiate treatment with KISQALI or the KISQALI FEMARA Co-Pack only in patients with QTcF values <450 ms. Repeat ECG at approximately Day 14 of the first cycle, at the beginning of the second cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorus, and magnesium) prior to the initiation of treatment, at the beginning of each of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting therapy with KISQALI or the KISQALI FEMARA Co-Pack therapy.

Avoid the use of KISQALI or the KISQALI FEMARA Co-Pack in patients who already have or who are at significant risk of developing QT prolongation, including patients with:
  • long QT syndrome
  • uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina, and bradyarrhythmias
  • electrolyte abnormalities

Avoid using KISQALI or the KISQALI FEMARA Co-Pack with drugs known to prolong the QT interval and/or strong CYP3A inhibitors, as this may lead to prolongation of the QTcF interval.

Increased QT Prolongation With Concomitant Use of Tamoxifen. KISQALI is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was ≥10 ms higher in the tamoxifen + placebo subgroup compared with the NSAI + placebo subgroup. In the placebo arm, an increase of >60 ms from baseline occurred in 6 of 90 patients (7%) receiving tamoxifen, and in no patients receiving an NSAI. An increase of >60 ms from baseline in the QTcF interval was observed in 14 of 87 (16%) patients in the KISQALI and tamoxifen combination and in 18 of 245 (7%) patients receiving KISQALI plus an NSAI.

Hepatobiliary toxicity. Across clinical trials in patients with advanced or metastatic breast cancer, increases in transaminases were observed. Across all trials, grade 3 or 4 increases in alanine aminotransferase (ALT) (10% vs 2%) and aspartate aminotransferase (AST) (7% vs 2%) were reported in the KISQALI and placebo arms, respectively.

Among the patients who had grade ≥3 ALT/AST elevation, the median time to onset was 85 days and median time to resolution to grade ≤2 was 22 days for the KISQALI treatment groups.

In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than 3 times the ULN and total bilirubin greater than 2 times the upper limit of normal (ULN), with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 (1%) patients and all patients recovered after discontinuation of KISQALI. No cases occurred in MONALEESA-7.

Perform liver function tests (LFTs) before initiating therapy with KISQALI or the KISQALI FEMARA Co-Pack. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation. Recommendations for patients who have elevated AST/ALT grade ≥3 at baseline have not been established.

Neutropenia. Across clinical trials in patients with advanced or metastatic breast cancer, neutropenia was the most frequently reported adverse reaction (AR) (74%), and a grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients in the KISQALI treatment groups. Among the patients who had grade 2, 3, or 4 neutropenia, the median time to grade ≥2 was 16 days. The median time to resolution of grade ≥3 (to normalization or grade <3) was 12 days in the KISQALI treatment groups. Febrile neutropenia was reported in 1% of patients in the KISQALI treatment groups. Treatment discontinuation due to neutropenia was 0.8%.

Perform complete blood count (CBC) before initiating therapy with KISQALI or the KISQALI FEMARA Co-Pack. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction, or discontinuation.

Embryofetal toxicity. Based on findings from animal studies and the mechanism of action, KISQALI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of KISQALI to pregnant rats and rabbits during organogenesis caused embryofetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve. Letrozole caused embryofetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a milligrams per square meter basis. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI or the KISQALI FEMARA Co-Pack and for at least 3 weeks after the last dose.

Adverse reactions. Across clinical trials of patients with advanced or metastatic breast cancer, the most common ARs reported in the KISQALI treatment groups (pooled incidence ≥20%) were neutropenia (74% vs 5%), nausea (45% vs 27%), infections (41% vs 30%), fatigue (33% vs 30%), diarrhea (30% vs 22%), leukopenia (30% vs 3%), vomiting (27% vs 16%), alopecia (24% vs 12%), headache (24% vs 22%), constipation (24% vs 16%), rash (21% vs 9%), and cough (21% vs 16%). The most common grade 3/4 ARs (reported at a pooled frequency >5%) were neutropenia (59% vs 1%), leukopenia (16% vs 3%), abnormal LFTs (9% vs 2%), and lymphopenia (5% vs 1%).

Laboratory abnormalities. Across clinical trials of patients with advanced or metastatic breast cancer, the most common laboratory abnormalities reported in the KISQALI-containing arm vs placebo arm (all grades, pooled incidence ≥20% and ≥5% higher than placebo arm) were leukocyte count decrease (94% vs 30%), neutrophil count decrease (93% vs 25%), hemoglobin decrease (66% vs 38%), lymphocyte count decrease (61% vs 26%), AST increase (47% vs 38%), ALT increase (44% vs 36%), creatinine increase (38% vs 13%), and platelet count decrease (31% vs 9%). The most common grade 3/4 laboratory abnormalities (incidence >5%) were neutrophil count decrease (59% vs 2%), leukocyte count decrease (32% vs 1%), lymphocyte count decrease (15% vs 4%), ALT increase (10% vs 2%), and AST increase (7% vs 2%).

Please see full Prescribing Information.