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

Efficacy

Overall Survival and PFS

KISQALI—more life

SUPERIOR OVERALL SURVIVAL RESULTS IN A BROAD RANGE OF WOMEN1-3

 
First treatment for advanced disease
De novo patients
Late adjuvant relapse
(DFI >12 months)
Early adjuvant relapse
(DFI ≤12 months)
First CDK4/6i
after progression
on ET for advanced disease
KISQALI + fulvestrant
postmenopausal women
KISQALI + NSAI/tamoxifen + goserelin
premenopausal women
 

 

KISQALI + fulvestrant—postmenopausal (N=726)1,2,4

  • OS benefit demonstrated vs placebo: HR=0.724 (95% CI: 0.568-0.924), P=0.00455; PFS benefit demonstrated vs placebo: HR=0.593 (95% CI: 0.480-0.732), P<0.0001. QOL benefit demonstrated vs placebo: HR=0.795 (95% CI: 0.602-1.050)
  • Randomized 2:1 to receive either KISQALI® (ribociclib) (600 mg) or placebo orally once daily (3 weeks on, 1 week off) + fulvestrant 500 mg, administered intramuscularly on Days 1, 15, and 29, and once monthly thereafter
  • Included first-line (de novo or progression >12 months after completion of [neo]adjuvant ET) patients, early adjuvant relapsers (progression ≤12 months after completion of or during [neo]adjuvant ET), and second-line (progression following ET in the metastatic setting) patients

 

KISQALI + an NSAI/tamoxifen + goserelin—premenopausal (N=672)1,3-5

  • OS benefit demonstrated vs placebo (ITT: HR=0.712 [95% CI: 0.535-0.948], P=0.00973; NSAI: HR=0.699 [95% CI: 0.501-0.976]; tamoxifen: HR=0.791 [95% CI: 0.454-1.377]). PFS benefit demonstrated vs placebo (NSAI arm only): HR=0.569 (95% CI: 0.436-0.743). PFS results based on a prespecified subgroup analysis of 495 patients who had received KISQALI or placebo with an NSAI + goserelin. QOL benefit demonstrated vs placebo: HR=0.759 (95% CI: 0.561-1.028)
  • Randomized 1:1 to receive either KISQALI (600 mg) or placebo orally once daily (3 weeks on, 1 week off) + NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg orally once daily (continuous) + goserelin 3.6 mg administered subcutaneously once every 28 days
  • Patients had no prior ET for metastatic disease
  • KISQALI is not indicated for concomitant use with tamoxifen4

 

Consistently superior overall survival

Overall survival significantly improved in postmenopausal women1

P=0.0045   28% REDUCTION IN RISK OF DEATH (HR=0.724 [95% CI: 0.568-0.924])

OVERALL SURVIVAL (ITT)1

 

Median OS not reached with KISQALI + fulvestrant vs 40.0 months with placebo + fulvestrant Median OS not reached with KISQALI + fulvestrant vs 40.0 months with placebo + fulvestrant
  • 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

PFS results (primary end point)1,2,4

  • First line: 33.6-month mPFS with KISQALI + fulvestrant vs 19.2 months in the placebo arm (HR=0.546; 95% CI: 0.415-0.718)
  • ITT (primary analysis): 20.5 months mPFS (95% CI: 18.5-23.5) with KISQALI + fulvestrant vs 12.8 months (95% CI: 10.9-16.3) in the placebo arm (HR=0.593 [95% CI=0.480-0.732], P<0.0001)

Overall survival significantly improved in premenopausal women1

P=0.00973   29% REDUCTION IN RISK OF DEATH (HR=0.712 [95% CI: 0.535-0.948])

OVERALL SURVIVAL (ITT)1,6

 

Median OS not reached in the KISQALI + ET + goserelin arm vs 40.9 months in the placebo arm Median OS not reached in the KISQALI + ET + goserelin arm vs 40.9 months in the placebo arm
  • 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

PFS results (primary end point)4

  • NSAI population: 27.5-month mPFS (95% CI: 19.1-NR) in the KISQALI arm vs 13.8 months (95% CI: 12.6-17.4) in the placebo arm (HR=0.569 [95% CI: 0.436-0.743])
  • Efficacy results based on a prespecified subgroup analysis of 495 patients who had received KISQALI or placebo with an NSAI + goserelin and were not powered to show statistical significance
    • KISQALI is not indicated for concomitant use with tamoxifen

 

KISQALI + NSAI—Consistent improvement in overall survival

 

OVERALL SURVIVAL (NSAI)1,6

 

Median OS not reached in the KISQALI + ET + goserelin arm vs 40.7 months in the placebo arm Median OS not reached in the KISQALI + ET + goserelin arm vs 40.7 months in the placebo arm
  • 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

 

OVERALL SURVIVAL (tamoxifen)1,4,6

 

Median OS not reached in both the KISQALI + tamoxifen arm and the tamoxifen + placebo arm Median OS not reached in both the KISQALI + tamoxifen arm and the tamoxifen + placebo arm

Time to Chemotherapy

Median time to chemotherapy consistently not reached with KISQALI

Time to chemotherapy in postmenopausal women1

30% REDUCTION IN RISK OF PROGRESSING TO CHEMOTHERAPY (HR=0.696 [95% CI: 0.551-0.879])

TIME TO CHEMOTHERAPY (ITT)1

 

Median TTC not reached in the KISQALI + fulvestrant arm vs 29.5 months in the placebo arm Median TTC not reached in the KISQALI + fulvestrant arm vs 29.5 months in the placebo arm
  • 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 treatment
  • There was no prespecified statistical procedure controlling for type 1 error rate

 

Time to chemotherapy delayed in premenopausal women

40% REDUCTION IN RISK OF PROGRESSING TO CHEMOTHERAPY (HR=0.596 [95% CI: 0.459-0.774])

TIME TO CHEMOTHERAPY (ITT)1

 

Median TTC not reached in the KISQALI + ET + goserelin arm vs 36.9 months in the placebo arm Median TTC not reached in the KISQALI + ET + goserelin arm vs 36.9 months in the placebo arm
  • 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 treatment
  • There was no prespecified statistical procedure controlling for type 1 error rate
  • KISQALI is not indicated for concomitant use with tamoxifen4

 

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.

Please see additional Important Safety Information below.

 

Quality of Life

Quality of life consistently preserved with KISQALI

The EORTC QLQ-C30—a validated tool used worldwide to assess quality of life in cancer patients1,5,7

EORTC QLQ-C30 MEASURES

5 functional scales
  • - Physical
  • - Role
  • - Emotional
  • - Cognitive
  • - Social
3 symptom scales
  • - Fatigue
  • - Nausea and vomiting
  • - Pain
6 single items
  • - Dyspnea
  • - Insomnia
  • - Appetite loss
  • - Constipation
  • - Diarrhea
  • - Financial difficulties

 

  • The EORTC QLQ-C30 questionnaire was used to assess the quality of life (QOL) patient-reported outcomes (PRO) end point, which was defined as the time to deterioration of the global health status/QOL scale score of the EORTC by ≥10%
  • Pain scores were assessed using the EORTC QLQ-C30 scale (TTD ≥10%), and clinically meaningful reductions in pain were defined as >5-point change from baseline

 

Quality of life preserved in both postmenopausal and premenopausal women1,2,5

PATIENT-REPORTED OUTCOMES

 
KISQALI + fulvestrant
postmenopausal women
(first line)
KISQALI + NSAI/tamoxifen + goserelin
premenopausal women
Overall quality of life preserved
throughout treatment
Pain scores preserved
from baseline

 

  • KISQALI is not approved for concomitant use with tamoxifen4

 

KISQALI + fulvestrant—postmenopausal women (first line)1,2,5

  • There was no significant difference between the arms in median TTD of global health status/QOL by ≥10%. Overall QOL worsened in both arms at end of trial
  • Clinically meaningful reductions in pain were observed at cycles 11 and 22 in the KISQALI arm vs cycles 3-25 in the placebo arm. General reductions in pain were observed in both arms throughout treatment
    • KISQALI is not indicated for pain reduction
  • These results are from the primary analysis conducted after observing 361 local PFS events


KISQALI + an NSAI/tamoxifen + goserelin—premenopausal women

  • 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
  • These results are from the primary analysis conducted after observing 319 local PFS events

 

3 CATEGORY 1 FIRST-LINE RECOMMENDATIONS

National Comprehensive Cancer Network® (NCCN®)


Ribociclib (KISQALI®) is a recommended option in HR+/HER2- mBC for postmenopausal women with fulvestrant, postmenopausal women with an AI, and premenopausal women with an LHRH agonist + an AI—based on evidence from a dedicated trial in the first-line setting.8

NCCN 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.

 

For information about safety profile, continue to the next page >

AI=aromatase inhibitor; CDK4/6i=cyclin-dependent kinase 4 and 6 inhibitor; DFI=disease-free interval; 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; mOS=median overall survival; mPFS=median progression-free survival; mTTC=median time to chemotherapy; NR=not reached; NSAI=nonsteroidal aromatase inhibitor; OS=overall survival; PFS=progression-free survival; PRO=patient-reported outcome; QOL=quality of life; TTD=time to deterioration.

References: 1. Data on file. Novartis Pharmaceuticals Corp; 2019. 2. 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. 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 randomized phase 3 trial. Lancet Oncol. 2018;19(7):904-915. 4. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018. 5. Beck JT, Wheatley-Price P, Neven P, et al. Patient-reported outcomes with ribociclib-based therapy in hormone receptor-positive, HER2-negative advanced breast cancer: results from the phase 3 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. 6. 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. 7. Fayers PM, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 Scoring Manual (3rd edition). 2001. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed September 24, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.

 
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 

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.

QT interval prolongation. KISQALI® (ribociclib) and the KISQALI® (ribociclib) FEMARA® (letrozole) 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 (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-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.