IMPORTANT SAFETY INFORMATION


Interstitial lung disease/pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors...

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Indications. KISQALI® (ribociclib) 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

Premenopausal Patients

Overall Survival and PFS (First Line)

LIFE CHANGING DATA for premenopausal patients—the longest median overall survival ever reported in HR+/HER2- mBC1-3

At a median follow-up of 54 months—NEARLY 5 YEARS MEDIAN OVERALL SURVIVAL

  • Median OS was 58.7 months with KISQALI + NSAI + goserelin (95% CI: 48.5-NR) vs 47.7 months with NSAI + goserelin (95% CI: 41.2-55.4); HR=0.798 (95% CI: 0.615-1.035)meaning a ~1-year increase in mOS
  • Results from the 54-month analysis are not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

At a median follow-up of 35 months—the only CDK4/6 inhibitor with significant overall survival proven in combination with an AI

  • Superiority was established for overall survival in the ITT population: P=0.00973 (HR=0.71 [95% CI: 0.54-0.95])
    • In the subgroup of women who received tamoxifen, an increased risk for QT prolongation was observed. KISQALI is not indicated for concomitant use with tamoxifen
  • Consistent overall survival benefit with KISQALI + NSAI + goserelin
    • 30% reduction in risk of death (HR=0.699 [95% CI: 0.501-0.976])

OVERALL SURVIVAL (KISQALI + NSAI + goserelin subgroup)3

Median overall survival results for KISQALI + NSAI + goserelin in premenopausal women
  • Median PFS (primary analysis): 27.5 months with KISQALI + NSAI + goserelin (95% CI: 19.1-NR) vs 13.8 months with NSAI + goserelin (95% CI: 12.6-17.4); HR=0.569 (95% CI: 0.436-0.743)3

Hazard ratios are based on unstratified Cox model.

Time to Chemotherapy

Median time to chemotherapy delayed over 4 years1

At a median follow-up of 54 months

34% REDUCTION IN RISK OF PROGRESSING TO CHEMOTHERAPY
(HR=0.659 [95% CI: 0.509-0.851])

TIME TO CHEMOTHERAPY (KISQALI + NSAI + goserelin subgroup)

Time to chemotherapy in Premeno women with mBC
  • Time to chemotherapy was an exploratory end point and was defined as the time from randomization to the beginning of the first chemotherapy after discontinuing study treatment2
  • There was no prespecified statistical procedure controlling for type 1 error

 

Quality of Life

Quality of life improved4

At a median follow-up of 35 months

31% REDUCTION IN RISK OF QUALITY-OF-LIFE DETERIORATION
(HR=0.69 [95% CI: 0.52-0.91])

More quality time

Quality of life improved
PATIENT-REPORTED OUTCOMES7
Overall quality of life preserved
throughout treatment for both arms
Median TTD ≥10% from baseline for global health status/QOL score: 24.0 vs 19.4 months NR vs 22.4 months (HR=0.721 [95% CI: 0.484-1.074])
Pain scores preserved
from baseline
No clinically meaningful change (>5 points from baseline) in both arms. At EOT, scores increased in both arms

 

QOL was preserved from baseline in both treatment arms.7
  • TTD ⩾10% in global HRQoL was significantly delayed with KISQALI + ET + goserelin vs ET + goserelin. Median TTD: 35.8 vs 23.3 months (HR= 0.67 [95% CI, 0.52–0.860])
  • There was no prespecified procedure controlling for type 1 error
  • KISQALI is not indicated for pain reduction

 

TIME TO DETERIORATION: PATIENT-REPORTED OUTCOMES (KISQALI + NSAI + goserelin subgroup)

Quality of life for Premeno women with mBC
Quality of life improved4
  • TTD ≥10% in global HRQOL was significantly delayed with KISQALI + NSAI + goserelin vs NSAI + goserelin
  • There was no prespecified procedure controlling for type 1 error
  • QOL was assessed at baseline and throughout treatment
The EORTC QLQ-C30 questionnaire was used to assess the QOL patient-reported outcomes.4,5
  • Measures include 5 functional scales (physical, role, emotional, cognitive, social), 3 symptom scales (fatigue, nausea and vomiting, pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties)
  • EORTC QLQ-C30 was completed at baseline and ≥1 postbaseline time point by 90% and 83% of patients in the KISQALI and placebo arms, respectively5

 

For information about postmenopausal patients, continue to the next page >

CDK4/6=cyclin-dependent kinase 4 and 6; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT=end of treatment; ET=endocrine therapy; HR=hazard ratio; HRQOL=health-related quality of life; ITT=intent to treat; mBC=metastatic breast cancer; mOS=median overall survival; mTTC=median time to chemotherapy; mTTD=median time to deterioration; NR=not reached; NSAI=nonsteroidal aromatase inhibitor; OS=overall survival; PFS=progression-free survival; QOL=quality of life; TTC=time to chemotherapy; TTD=time to deterioration.

References: 1. Data on file. Novartis Pharmaceuticals Corp; 2020. 2. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. 3. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 4. Harbeck N, Franke F, Villanueva-Vazquez R, et al. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020;12:1758835920943065. 5. Fayers PM, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 Scoring Manual (3rd edition). 2001. 

 

Indications
KISQALI® (ribociclib) 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 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
Interstitial lung disease/pneumonitis. Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with KISQALI and other CDK4/6 inhibitors.

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”), 1.1% of KISQALI-treated patients had ILD/pneumonitis of any grade, 0.3% had grade 3 or 4, and 0.1% had a fatal outcome. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis, which may include hypoxia, cough, and dyspnea. In patients who have new or worsening respiratory symptoms suspected to be due to ILD or pneumonitis, interrupt treatment with KISQALI immediately and evaluate the patient. Permanently discontinue treatment with KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with KISQALI in the postmarketing setting.

If signs or symptoms of SCARs occur, interrupt KISQALI until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.

If SCARs is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life-threatening cutaneous reactions during KISQALI treatment.

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 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 (MRHD) 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 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.