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—KISQALI + Fulvestrant in Postmenopausal

 

Overall Survival

The longest median overall survival ever reported with a CDK4/6 inhibitor + fulvestrant

MONALEESA-3: KISQALI + fulvestrant in 1L/2L postmenopausal patients

At a median follow-up of 56 months

Median overall survival results for KISQALI + fulvestrant in postmenopausal women: 53.7 months 1-year increase
Hazard ratios are based on stratified Cox model.

KISQALI® (ribociclib) is the only CDK4/6 inhibitor with statistically significant overall survival data reported in a trial dedicated to first- and second-line postmenopausal patients with fulvestrant2-5

  • Results from the 56-month analysis were not prespecified and were observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error

At a median follow-up of 39 months

Statistically significant improvement in overall survival in the ITT population6:

  • Median overall survival with KISQALI + fulvestrant was not reached (95% CI: 42.5-NR) vs 40.0 months with placebo + fulvestrant (95% CI: 37.0-NR); P=0.00455 (HR=0.724 [95% CI: 0.568-0.924])
  • PFS (primary analysis): At a median follow-up of 20 months, mPFS was 20.5 months (95% CI: 18.5-23.5) with KISQALI + fulvestrant vs 12.8 months (95% CI: 10.9-16.3) with placebo + fulvestrant (HR=0.593 [95% CI: 0.480-0.732]; P<0.0001)

 

Dr Dennis Slamon discusses overall survival, time to chemotherapy, and quality of life data for KISQALI in postmenopausal women with HR+/HER2- mBC.

Postmenopausal Patients With Liver Metastases

Overall survival improved in postmenopausal women with liver metastases

At a median follow-up of 39 months

Overall survival in postmenopausal patients with liver metastases taking KISQALI + fulvestrant: 36.1 months 1-year increase
Hazard ratios are based on stratified Cox model.
  • Results are exploratory in nature; as such, there was no prespecified statistical procedure controlling for type 1 error
  • In patients with visceral metastases: Median OS was 41.0 months with KISQALI + fulvestrant (95% CI: 38.5-NR) vs 39.4 months with fulvestrant (95% CI: 30.6-42.2); HR=0.804 (95% CI: 0.596-1.083). Median PFS was 16.6 months with KISQALI + fulvestrant (95% CI: 13.4-19.9) vs 10.6 months with fulvestrant (95% CI: 5.5-12.9); HR=0.616 (95% CI: 0.487-0.779)7
  • In patients with liver metastases: Median PFS was 12.8 months with KISQALI + fulvestrant (95% CI: 9.3-18.6) vs 3.6 months with fulvestrant (95% CI: 2.1-5.8); HR=0.466 (95% CI: 0.332-0.656)7
  • 27% (197/726) of patients had liver metastases in MONALEESA-36,7
  • Safety profiles were consistent with the overall population: neutropenia (60.2%), nausea (46.6%), and diarrhea (34.6%) were the most common in the postmenopausal trial. The rates of grade 3/4 ALT/AST elevations in the KISQALI arm (13%) were similar to those seen in the overall safety population (12%)7

Time to Chemotherapy

Median time to chemotherapy delayed 4 years

At a median follow-up of 56 months 

Median time to chemotherapy 48.1 months with KISQALI + fulvestrant
Hazard ratios are based on stratified Cox model.
  • 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 preserved
MONALEESA-3: KISQALI + fulvestrant in 1L/2L postmenopausal patients At a median follow-up of 39 months, median TTD ≥10% was 35.9 months vs 33.1 months (HR=0.81 [95% CI: 0.62-1.06])
Medians reported as KISQALI vs placebo.

Quality of life was assessed using the EORTC QLQ-C30 questionnaire—a validated tool used worldwide to assess quality of life in patients with cancer.8

  • Quality of life was a secondary end point measured by patient-reported outcomes and was assessed at baseline and throughout treatment
  • Time to deterioration was defined as a decline of at least 10% of the global health status/QOL scale score
  • There was no prespecified statistical procedure controlling for type 1 error
  • The EORTC QLQ-C30 incorporates 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status/QOL scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and perceived financial impact of the disease9

Study design: MONALEESA-3 was a randomized, double-blind, placebo-controlled phase III study of KISQALI + fulvestrant (n=484) vs placebo + fulvestrant (n=242) for the treatment of postmenopausal patients with HR+/HER2- mBC who have received no or only 1 line of prior ET for advanced disease. OS was a secondary end point; PFS was the primary end point.6,10

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

1L=first line; 2L=second line; AI=aromatase inhibitor; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CDK=cyclin-dependent kinase; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; ET=endocrine therapy; HR=hazard ratio; ITT=intent to treat; mBC=metastatic breast cancer; mOS=median overall survival; mTTC=median time to chemotherapy; NR=not reached; OS=overall survival; PFS=progression-free survival; QOL=quality of life; TTD=time to deterioration.

References: 1. Slamon DJ, Neven P, Chia S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021;32(8):1015-1024. 2. Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514-524. 3. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. 4. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. 5. Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy–MONARCH 2: a randomized clinical trial. JAMA Oncol. 2020;6(1):116-124. 6. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 7. Data on file. Novartis Pharmaceuticals Corp; 2020. 8. Fasching PA, Beck JT, Chan A, et al. Ribociclib plus fulvestrant for advanced breast cancer: health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020;54:148-154. 9. Fayers PM, Aaronson NK, Bjordal K, et al. EORTC QLQ-C30 Scoring Manual (3rd edition). 2001. 10. 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.

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.