Letrozole and Ribociclib for Breast Cancer

INDICATIONS AND USAGE KISQALI FEMARA CO-PACK, a co-packaged product containing ribociclib, a kinase inhibitor, and letrozole, an aromatase inhibitor, is indicated: for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. ( 1 ) as initial endocrine-based therapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer therapy. ( 1 ) 1.1 Early Breast Cancer KISQALI ® FEMARA ® CO-PACK is indicated for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 1.2 Advanced or Metastatic Breast Cancer KISQALI ® FEMARA ® CO-PACK indicated as initial endocrine-based therapy for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

DOSAGE AND ADMINISTRATION KISQALI FEMARA CO-PACK tablets are taken in combination orally with or without food. ( 2 ) Early Breast Cancer KISQALI recommended starting dose: 400 mg orally (two 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. ( 2.1 ) Advanced or Metastatic Breast Cancer KISQALI recommended starting dose: 600 mg orally (three 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. ( 2.1 ) KISQALI dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability. ( 2.2 ) FEMARA: 2.5 mg (one tablet) continuously for a 28-day cycle. ( 2.1 ) 2.1 Recommended Dosage Important Administration Instructions The KISQALI FEMARA CO-PACK is comprised of ribociclib tablets co-packaged with letrozole tablets, to provide a 28-day treatment regimen. KISQALI FEMARA CO-PACK can be taken with or without food [ see Clinical Pharmacology (12.3) ]. Pre/perimenopausal women, or men, treated with KISQALI FEMARA CO-PACK should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. Patients should take their doses of KISQALI FEMARA CO-PACK at approximately the same time each day, preferably in the morning. If the patient vomits after taking the dose or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. Early Breast Cancer KISQALI: The recommended dosage of KISQALI is 400 mg (two 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. In patients with early breast cancer, treatment with KISQALI should continue for 3 years or until disease recurrence or unacceptable toxicity occurs. Advanced or Metastatic Breast Cancer KISQALI: The recommended dosage for KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. Refer to the Full Prescribing Information for the recommended dosage for each product. 2.2 Dose Modifications Dose Modifications for Adverse Reactions The recommended dose modifications of KISQALI for adverse reactions are listed in Table 1. Dose modifications are not recommended for FEMARA when administered with KISQALI for the adverse reactions of KISQALI, including neutropenia, hepatobiliary toxicity, or QT prolongation [see Dosage and Administration (2)] . Table 1: Recommended Dose Modification of KISQALI FEMARA CO-PACK for Adverse Reactions Level KISQALI FEMARA Dose Number of tablets Dose Number of tablets Early breast cancer Starting dose 400 mg/day two 200 mg tablets 2.5 mg/day one 2.5 mg tablet Dose reduction 200 mg/day * one 200 mg tablet 2.5 mg/day one 2.5 mg tablet Advanced or metastatic breast cancer Starting dose 600 mg/day three 200 mg tablets 2.5 mg/day one 2.5 mg tablet First dose reduction 400 mg/day two 200 mg tablets 2.5 mg/day one 2.5 mg tablet Second dose reduction 200 mg/day* one 200 mg tablet 2.5 mg/day one 2.5 mg tablet *If dose reduction below 200 mg/day is required, discontinue KISQALI. Tables 2, 3, 4, 5, 6, and 7 summarize recommendations for dose interruption, reduction, or discontinuation of KISQALI in the management of specific adverse reactions. Dose modification of KISQALI FEMARA CO-PACK is recommended based on individual patient safety and tolerability. Table 2: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis Grade 1 (asymptomatic) Grade 2 (symptomatic) Grade 3 (severe symptomatic) or 4 (life-threatening) ILD/Pneumonitis [see Warnings and Precautions (5.1)] No dose interruption or adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Dose interruption until recovery to Grade ≤ 1 then consider resuming KISQALI at the next lower dose level*. If Grade 2 recurs, discontinue KISQALI. Discontinue KISQALI. Abbreviation: ILD, interstitial lung disease. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. *An individualized benefit-risk assessment should be performed when considering resuming KISQALI. Table 3: Dose Modification and Management for Cutaneous Adverse Reactions, Including SCARs Grade 1 (< 10% body surface area (BSA) with active skin toxicity, no signs of systemic involvement) Grade 2 (10%-30% BSA with active skin toxicity, no signs of systemic involvement) Grade 3 (severe rash not responsive to medical management; > 30% BSA with active skin toxicity, signs of systemic involvement present; SJS*) Grade 4 (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life threatening consequences; TEN**) Cutaneous adverse reactions, including SCARs [see Warnings and Precautions (5.2)] No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Interrupt KISQALI until the etiology of the reaction has been determined. If the etiology is a SCAR, permanently discontinue KISQALI. If the etiology is not a SCAR, interrupt dose until recovery to Grade ≤ 1, then resume KISQALI at same dose level. If the cutaneous adverse reaction still recurs at Grade 3, resume KISQALI at the next lower dose level. Permanently discontinue KISQALI. Abbreviations: BSA, body surface area; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. *SJS (Grade 3 and 4) is defined as skin sloughing covering < 10% BSA and 10%-30% BSA, respectively, with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment). **TEN (Grade 4) is defined as skin sloughing covering ≥ 30% BSA with associated symptoms (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment). Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Table 4: Dose Modification and Management of KISQALI for QT Prolongation QTcF* prolongation Early breast cancer Advanced or metastatic breast cancer > 480 ms and ≤ 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms Resume at the same dose Reduce to the next lower dose level If QTcF > 480 ms recurs, interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. > 500 ms Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. If QTcF > 500 ms recurs, discontinue KISQALI. Permanently discontinue KISQALI if QTcF interval prolongation is either > 500 ms or > 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia. Note: If dose reduction below 200 mg/day is required, discontinue KISQALI. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment in all patients. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. In case of QTcF prolongation at any given time during treatment, monitor ECG more frequently, and as clinically indicated. * QTcF = QT interval corrected by Fridericia’s formula. Table 5: Dose Modification and Management of KISQALI for Hepatobiliary Toxicity Grade 1 (> ULN – 3 x ULN) Grade 2 (> 3 to 5 x ULN) Grade 3 (> 5 to 20 x ULN) Grade 4 (> 20 x ULN) AST and/or ALT elevations from baseline*, WITHOUT increase in total bilirubin above 2 x ULN [see Warnings and Precautions (5.4)] No dose adjustment is required. Baseline* at < Grade 2: Dose interruption until recovery to ≤ baseline grade

WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis: Patients treated with CDK 4/6 inhibitors should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Interrupt and evaluate patients with new or worsening respiratory symptoms suspected to be due to ILD/pneumonitis. Permanently discontinue KISQALI in patients with recurrent symptomatic or severe ILD/pneumonitis. ( 2.2 , 5.1 ) Severe Cutaneous Adverse Reactions (SCARs): Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur with KISQALI treatment. Permanently discontinue KISQALI in patients with SCARs or other life-threatening cutaneous reactions. ( 2.2 , 5.2 ) QT Interval Prolongation: Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with KISQALI. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles, and as clinically indicated. Avoid using KISQALI with drugs known to prolong QT interval and/or strong CYP3A inhibitors. ( 2.2 , 5.3 , 7.1 , 7.4 ) Hepatobiliary Toxicity: Increases in serum transaminase and bilirubin levels have been observed. Perform liver function tests (LFTs) before initiating treatment with KISQALI FEMARA CO-PACK. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2, 5.4 ) Neutropenia: Perform complete blood count (CBC) before initiating therapy with KISQALI FEMARA CO-PACK. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. ( 2.2, 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm when administered to pregnant women. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during therapy. ( 5.6 , 8.1 , 8.3 ) 5.1 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. In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus a non-steroidal aromatase inhibitor (NSAI), 1.5% of patients had ILD/pneumonitis (Grade 1-2). In patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-7), 1.2% of KISQALI-treated patients had ILD/pneumonitis (any grade, 0.3% had Grade 3-4). Additional cases of ILD/pneumonitis have occurred in the postmarketing setting, some resulting in death [see Adverse Reactions (6.2)] . 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 KISQALI immediately and evaluate the patient. Permanently discontinue KISQALI in patients with severe ILD/pneumonitis or any recurrent symptomatic ILD/pneumonitis [see Dosage and Administration (2.2)] . Refer to the Full Prescribing Information for KISQALI ® . 5.2 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), can occur in patients treated with KISQALI [see Adverse Reactions (6.2)] . If signs or symptoms of SCARs occur, interrupt KISQALI until the etiology of the reaction has been determined [see Dosage and Administration (2.2)] . Early consultation with a dermatologist is recommended to ensure greater diagnostic accuracy and appropriate management. If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs during KISQALI treatment. 5.3 QT Interval Prolongation KISQALI has been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)] . Avoid KISQALI in patients who are at significant risk of developing Torsades de Pointes (TdP), including those with: congenital long QT syndrome; uncontrolled or significant cardiac disease, recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism; electrolyte abnormalities; taking drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval. Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2), Drug Interactions (7.4)] . In patients with early breast cancer (NATALEE) who received 400 mg KISQALI plus NSAI, 8 out of 2494 patients (0.3%) had > 500 ms post-baseline QTcF interval value and 50 out of 2494 patients (2%) had > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7) who received 600 mg KISQALI plus NSAI, 7 out of 574 patients (1%) had a > 500 ms post-baseline QTcF value, and 29 out of 574 patients (5%) had a > 60 ms QTcF increase from baseline. QTcF prolongation was reversible with dose interruption. The majority of QTcF prolongation occurred within the first four weeks of KISQALI. There were no reported cases of Torsades de Pointes. In MONALEESA-2, in the KISQALI plus letrozole treatment arm, there was one (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 [see Adverse Reactions (6)] . Perform ECG in all patients prior to starting KISQALI FEMARA CO-PACK. Initiate treatment with KISQALI FEMARA CO-PACK only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle, and as clinically indicated. Monitor serum electrolytes (including potassium, calcium, phosphorous, and magnesium) prior to the initiation of KISQALI FEMARA CO-PACK, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting KISQALI FEMARA CO-PACK [see Dosage and Administration (2.2)] . 5.4 Hepatobiliary Toxicity In patients with early and advanced or metastatic breast cancer, drug-induced liver injury and increases in transaminases occurred with KISQALI. In patients with early breast cancer (NATALEE) treated with KISQALI, drug-induced liver injury was reported in 9 patients (0.4%), of which 5 were Grade ≥ 3, and 8 had resolved as of the data cutoff. There were 8 (0.3%) clinically confirmed Hy’s Law cases (including 4 out of 9 drug-induced liver injury mentioned above), 6 of which had resolved within 303 days and 2 of which were improving, all after discontinuation of KISQALI. Grade 3 or 4 increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 8% and 4.7% respectively; including Grade 4 increases in ALT (1.5%) and AST (0.8%). In patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7), treated with KISQALI Grade 3 or 4 increases in ALT and AST occurred in 11% and 8%, respectively. Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 111 days for the KISQALI plus aromatase inhibitor treatment arm. The median time to resolution to Grade ≤ 2 was 22 days in the KISQALI plus aromatase inhibitor treatment arm. In MONALEESA-2, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis (Hy’s Law) occurred in 4 (1%) patients and all pat

DRUG INTERACTIONS Ribociclib CYP3A4 Inhibitors: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, reduce KISQALI dose. ( 2.2, 7.1 ) CYP3A4 Inducers: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inducers. ( 7.2 ) CYP3A Substrates: The dose of CYP3A substrates with narrow therapeutic indices may need to be reduced when given concurrently with KISQALI FEMARA CO-PACK. ( 7.3 ) Drugs Known to Prolong QT Interval: Avoid concomitant use of drugs known to prolong QT interval, such as anti-arrhythmic medicines. ( 7.4 ) 7.1 Drugs That May Increase Ribociclib Plasma Concentrations CYP3A4 Inhibitors Coadministration of a strong CYP3A4 inhibitors increases ribociclib exposure [see Clinical Pharmacology (12.3)] . Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation [see Warnings and Precautions (5.3)] . Avoid concomitant use of strong CYP3A inhibitors with KISQALI and consider alternative concomitant medications with less potential for CYP3A inhibition. In patients with early breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 200 mg once daily. In patients with advanced or metastatic breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily [see Dosage and Administration (2.2)] . 7.2 Drugs That May Decrease Ribociclib Plasma Concentrations CYP3A4 Inducers Coadministration of a strong CYP3A4 inducers decreases the plasma exposure of ribociclib [see Clinical Pharmacology (12.3)] . Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A. 7.3 Effect of KISQALI on Other Drugs CYP3A Substrates Coadministration of sensitive CYP3A4 substrates with multiple doses of KISQALI increases the substrate exposure [see Clinical Pharmacology (12.3)] . For CYP3A substrates where minimal increases in the concentration may increase CYP3A substrate adverse reactions, monitor for increased adverse reactions of the CYP3A substrate during treatment with KISQALI. The dose of a sensitive CYP3A substrate may need to be reduced as KISQALI can increase its exposure. 7.4 Drugs That Prolong the QT Interval Avoid coadministration of KISQALI with products with a known potential to prolong QT interval, such as antiarrhythmic drugs that are known to prolong the QT interval. If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)] .

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3)] Hepatobiliary Toxicity [see Warnings and Precautions (5.4)] Neutropenia [see Warnings and Precautions (5.5)] In patients with early breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, leukocytes decreased, neutrophils decreased, hemoglobin decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, creatinine increased, platelets decreased, headache, nausea, and fatigue. ( 6 ) In patients with advanced or metastatic breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, nausea, fatigue, platelets decreased, diarrhea, headache, alopecia, vomiting, back pain, constipation, cough, rash, creatinine increased, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in WARNINGS AND PRECAUTIONS reflect exposure to KISQALI plus non-steroidal aromatase inhibitor (NSAI) in 2526 patients with early breast cancer (NATALEE), of whom 51% completed 36 months of KISQALI treatment. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were lymphocytes decreased (97%), leukocytes decreased (95%), neutrophils decreased (94%), hemoglobin decreased (47%), alanine aminotransferase increased (45%), aspartate aminotransferase increased (44%), infections (37%), creatinine increased (33%), platelets decreased (28%), headache (23%), nausea (23%), and fatigue (22%). In additions, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to KISQALI in 582 patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7), of whom 80% were exposed for 6 months or longer and 65% were exposed for greater than one year. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (94%), neutrophils decreased (94%), hemoglobin decreased (72%), lymphocytes decreased (59%), alanine aminotransferase increased (53%), aspartate aminotransferase increased (53%), infections (46%), nausea (46%), fatigue (36%), platelets decreased (34%), diarrhea (33%), headache (29%), alopecia (29%), vomiting (29%), back pain (25%), constipation (25%), cough (24%), rash (22%), creatinine increased (20%), and abdominal pain (20%). NATALEE: KISQALI in Combination with a Non-steroidal Aromatase Inhibitor as Adjuvant Treatment Adults with HR-positive, HER2-negative Stage II and III Early Breast Cancer at High Risk of Recurrence The safety of KISQALI was evaluated in NATALEE, a clinical trial of 5101 patients who received KISQALI plus NSAI or NSAI alone, with or without goserelin [see Clinical Studies (14)] . The median duration of exposure to KISQALI was 33 months. Serious adverse reactions occurred in 14% of patients who received KISQALI. Serious adverse reactions in > 0.5% of patients who received KISQALI included COVID-19 (1.1%), pneumonia (0.8%), and pulmonary embolism (0.6%). Fatal adverse reactions occurred in 0.6% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1% of patients receiving KISQALI included COVID-19 or COVID-19 pneumonia (0.2%) and pulmonary embolism (0.1%). Permanent discontinuation of KISQALI due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of KISQALI in ≥ 2% of patients were alanine aminotransferase or aspartate aminotransferase increased (8%). Dosage interruptions of both KISQALI plus NSAI due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia or neutrophil count decreased (43%), alanine aminotransferase or aspartate aminotransferase increased (11%), COVID-19 (10%), and hypomagnesemia (5%). Dose reductions of KISQALI due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia or neutrophil count decreased (14%) and liver function abnormal (2.3%). The most common (≥ 20% on KISQALI plus NSAI and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutropenia, infections, nausea, headache, fatigue, leukopenia, and abnormal liver function tests. Table 10 summarizes the adverse reactions in NATALEE. Table 10: Adverse Reactions (≥ 10% and ≥ 2% Higher Than NSAI Alone Arm) in NATALEE Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 1 Infections: urinary tract infections; respiratory tract infections. 2 Only includes a Grade 3 adverse reaction. Adverse reaction KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Infections 1 37 2.0 27 0.9 Nervous system disorders Headache 2 23 0.4 17 0.2 Gastrointestinal disorders Nausea 2 23 0.2 8 0.1 Diarrhea 2 15 0.6 6 0.1 Constipation 2 13 0.2 5 0 Abdominal pain 2 11 0.5 7 0.4 General disorders and administration-site conditions Fatigue 2 22 0.8 13 0.2 Asthenia 2 17 0.6 12 0.1 Pyrexia 2 11 0.2 6 0.1 Skin and subcutaneous tissue disorders Alopecia 15 0 4.6 0 Respiratory, thoracic, and mediastinal disorders Cough 2 13 0.1 8 0.1 Clinically relevant adverse reactions reported in < 10% of patients who received KISQALI plus NSAI included rash (9%), dizziness (9%), vomiting (8%), peripheral edema (7%), pruritis (7%), dyspnea (7%), stomatitis (6%), oropharyngeal pain (6%), hypocalcemia (5%), hypokalemia (4.8%), decreased appetite (4.8%). Table 11 summarizes the laboratory abnormalities in NATALEE. Table 11: Select Laboratory Abnormalities (≥ 10%) in Patients in NATALEE Who Received KISQALI Plus NSAI Laboratory abnormality KISQALI + NSAI (n = 2526) NSAI (n = 2441) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 97 19 88 6 Leukocytes decreased 95 27 45 0.6 Neutrophils decreased 94 45 35 1.7 Hemoglobin decreased 47 0.6 26 0.3 Platelets decreased 28 0.4 13 0.3 Chemistry Alanine aminotransferase increased 45 8 35 1 Aspartate aminotransferase increased 44 5 33 1 Creatinine increased 33 0.3 11 0 Adverse reactions listed are based on the data of KISQALI in combination with NSAI [anastrozole or letrozole (FEMARA)]. For the complete list of known adverse reactions with KISQALI or FEMARA, see the Full Prescribing Information of KISQALI or FEMARA. MONALEESA-2: KISQALI in Combination with Letrozole Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy The safety of KISQALI was evaluated in MONALEESA-2, a clinical study of 668 postmenopausal women receiving KISQALI plus letrozole or placebo plus letrozole [see Clinical Studies (14)] . The median duration of exposure to KISQALI plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months. Serious adverse reactions occurred in 21% of patients who received KISQALI plus letrozole. Serious adverse reactions in ≥1% of patients receiving KISQALI plus letrozole included abdominal pain (1.5%),