$PRE_HEADER$ Developed under the direction and sponsorship of Novartis Pharmaceuticals Corporation.       FIRST AND ONLY CDK4/6 inhibitor indicated as initial therapy with fulvestrant in postmenopausal women1   KISQALI® (ribociclib) + fulvestrant achieved over 20 months mPFS; 20.5 months (95% CI: 18.5-23.5) in first- and second-line patients treated 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).1   Explore the evidence     • First-line patients, early adjuvant relapsers, and second-line patients were prespecified subgroups2* • 51% of women received first-line mBC treatment (no prior ET for advanced disease, n=367)2 • Randomized 2:1 to receive KISQALI + fulvestrant or placebo + fulvestrant1 • Women received KISQALI 600 mg or placebo orally once daily (3 weeks on, 1 week off) with fulvestrant 500 mg, administered intramuscularly on Days 1, 15, 29, and once monthly thereafter1 Superior efficacy across first- and second-line patients with KISQALI + fulvestrant in the largest trial to evaluate a CDK4/6 inhibitor with fulvestrant as initial therapy1,3     PFS PER INVESTIGATOR ASSESSMENT (ITT)1         ITT=intent to treat; PFS=progression-free survival. Rapid separation of the PFS curves evident at 8 weeks1 • Results reported at 8 weeks were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error KISQALI delivered sustained strength in first- and second-line patients2 • First line (n=367): mPFS not reached with KISQALI + fulvestrant vs 18.3 months with fulvestrant alone (HR=0.577 [95% CI: 0.415-0.802]) • Early adjuvant relapsers and second line (n=345): 14.6 months with KISQALI + fulvestrant vs 9.1 months with fulvestrant alone (HR=0.565 [95% CI: 0.428-0.744])   — Second-line patients were defined as those who had experienced prior progression on ET in the metastatic setting. Early adjuvant relapsers were defined as those who had experienced progression during or within 12 months of completion of adjuvant ET   See more data     End points included PFS (primary); OS, ORR, QOL, and safety (secondary).2,4 *Early adjuvant relapsers (those who had experienced progression during or within 12 months of completion of adjuvant ET) and second-line patients (those who had experienced prior progression on ET in the metastatic setting) were a prespecified subgroup (n=345).2 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 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. 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. 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. 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. 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 trials, 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. 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. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with KISQALI 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%). CDK=cyclin-dependent kinase; ET=endocrine therapy; HER2-=human epidermal growth factor receptor 2-negative; HR=hazard ratio; HR+=hormone receptor-positive; mPFS=median progression-free survival; ORR=overall response rate; OS=overall survival; QOL=quality of life. References: 1. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 20‍18. 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. Ju‍ne 3‍, 201‍8. J Clin Oncol. 2018. doi:10.12‍00‍/JCO.20‍1‍8.7‍8.99‍09. 3. 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. 4. Data on file. Novartis Pharmaceuticals Corp. Please see full Prescribing Information. This is a sponsored message from DMD on behalf of Novartis Pharmaceuticals Corporation. DMD provides sponsored health care-related messages from trusted third parties. This material is intended specifically and exclusively for US health care professionals. You are receiving this e-mail because you have subscribed and agreed to receive information from the DMD e-mail list. If you prefer not to receive further information from this sender, please click here and confirm your request. DMD 10‍255 W. Hig‍gins Ro‍ad, Suite 2‍80 Ros‍emont, I‍L 600‍18 DMD Privacy Policy       Novartis Pharmaceuticals Corporation © 20‌18 Novartis      9‌/‌18 KIS-1‌19‌49‌4‌2