Kisqali ribociclib 200 mg Tablet, Film Coated — NDC 0078-0867-42 (Billing 00078-0867-42)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).

In vitro , ribociclib decreased pRb phosphorylation, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. In vivo , treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g., letrozole) therapies resulted in increased tumor growth inhibition compared to each drug alone.

Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KISQALI have not been fully characterized in patients. Cardiac Electrophysiology A concentration-QT analysis of the data in patients with breast cancer treated with KISQALI at doses ranging from 50 to 1200 mg (0.083 to 2 times of the approved recommended high dose) suggested that ribociclib causes concentration-dependent increases in QTcF interval [see Warnings and Precautions (5.3, 5.4)] .

In patients with early breast cancer, the estimated mean QTcF interval change from baseline for the KISQALI 400 mg in combination with non-steroidal aromatase inhibitor (NSAI) was 10.0 ms (90% CI: 8.0, 11.9) at the mean steady-state C max [see Warnings and Precautions (5.3, 5.4)] . In patients with advanced or metastatic breast cancer the estimated mean QTcF interval change from baseline for the KISQALI 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the mean steady-state C max [see Warnings and Precautions (5.3, 5.4)] .

12.3Pharmacokinetics Ribociclib exhibited over-proportional increases in exposure (C max and AUC) across the dose range of 50 mg to 1200 mg (0.083 to 2 times of the approved recommended high dose) following both single dose and repeated doses of KISQALI. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a mean accumulation ratio of 2.5 (range, 0.97 to 6.4), and mean (coefficient of variation (CV%)) steady-state ribociclib C max was 1820 (62%) ng/mL and AUC was 23800 (66%) ng*h/mL.

Absorption The T max following KISQALI administration was between 1 and 4 hours. The mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8%. Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of KISQALI tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no clinically meaningful differences in ribociclib C max or AUC inf .

Distribution Ribociclib protein binding in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). The mean in vivo blood-to-plasma ratio was 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L.

Metabolism Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation,… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and are downstream of signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).

In vitro , ribociclib decreased pRb phosphorylation, resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models. In vivo , treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g., letrozole) therapies resulted in increased tumor growth inhibition compared to each drug alone.

Additionally, the combination of ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.

12.3Pharmacokinetics Ribociclib exhibited over-proportional increases in exposure (C max and AUC) across the dose range of 50 mg to 1200 mg (0.083 to 2 times of the approved recommended high dose) following both single dose and repeated doses of KISQALI. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a mean accumulation ratio of 2.5 (range, 0.97 to 6.4), and mean (coefficient of variation (CV%)) steady-state ribociclib C max was 1820 (62%) ng/mL and AUC was 23800 (66%) ng*h/mL.

Absorption The T max following KISQALI administration was between 1 and 4 hours. The mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8%. Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of KISQALI tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no clinically meaningful differences in ribociclib C max or AUC inf .

Distribution Ribociclib protein binding in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). The mean in vivo blood-to-plasma ratio was 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L.

Metabolism Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Ribociclib was the major circulating drug-derived entity in plasma (44%).

The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure. Clinical activity of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites. Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively.

Metabolite LEQ803 represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Elimination The mean plasma effective half-life (CV%) was 32.0 hours (63%) and the mean apparent oral clearance (CL/F) was

25.5L/hr (66%) at steady-state following 600 mg dose of KISQALI in patients with advanced cancer. The steady state mean CL/F was

38.4L/hr following the 400 mg dose of KISQALI in patients with early breast cancer. The mean apparent plasma terminal half-life of ribociclib ranged from 29.7 to 54.7 hours and mean CL/F of ribociclib ranged from 39.9 to

77.5L/hr at 600 mg across studies in healthy adults. Following a single oral dose of radio-labeled ribociclib in healthy adults, 92% of the total administered radioactive dose was recovered within 22 days; 69% in feces and 23% in urine. Specific Populations Patients with Hepatic Impairment Compared to adults with normal hepatic function, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of ribociclib; while in adults with moderate (Child-Pugh class B) hepatic impairment, the mean ratio was 1.44 for C max and 1.28 for AUC inf ; and in adults with severe (Child-Pugh class C) hepatic impairment, the mean ratio was 1.32 for C max and 1.29 for AUC inf .

Patients with Renal Impairment In adults with severe renal impairment and end stage renal disease, ribociclib AUC inf increased 2.4-fold and 3.8-fold, and C max increased 2.1-fold and 2.7-fold relative to the exposure in adults with normal renal function. Mild or moderate renal impairment had no effect on the exposure of ribociclib. A sub-group analysis of data from studies following oral administration of KISQALI in patients with advanced cancer or early breast cancer who… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KISQALI have not been fully characterized in patients. Cardiac Electrophysiology A concentration-QT analysis of the data in patients with breast cancer treated with KISQALI at doses ranging from 50 to 1200 mg (0.083 to 2 times of the approved recommended high dose) suggested that ribociclib causes concentration-dependent increases in QTcF interval [see Warnings and Precautions (5.3, 5.4)] .

In patients with early breast cancer, the estimated mean QTcF interval change from baseline for the KISQALI 400 mg in combination with non-steroidal aromatase inhibitor (NSAI) was 10.0 ms (90% CI: 8.0, 11.9) at the mean steady-state C max [see Warnings and Precautions (5.3, 5.4)] . In patients with advanced or metastatic breast cancer the estimated mean QTcF interval change from baseline for the KISQALI 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the mean steady-state C max [see Warnings and Precautions (5.3, 5.4)] .

14 CLINICAL STUDIES

14.1Early Breast Cancer NATALEE: KISQALI in Combination with a Non-steroidal Aromatase Inhibitor (NSAI) with or without Goserelin Adults with HR-positive, HER2-negative Stage II and III Early Breast Cancer at High Risk of Recurrence NATALEE (NCT03701334) was a randomized (1:1), open-label, multicenter study in adults (N = 5101) with HR-positive, HER2-negative early breast cancer that was: Anatomic Stage Group IIB-III, or Anatomic Stage Group IIA that is either: Node positive or Node negative, with: Histologic Grade 3, or Histologic Grade 2, with any of the following criteria: Ki67 ≥ 20% High risk by gene signature testing Applying TNM criteria, NATALEE included patients with any lymph node involvement, or if no nodal involvement either tumor size > 5 cm, or tumor size 2 to 5 cm with either Grade 2 (and high genomic risk or Ki67 ≥ 20%) or Grade 3.

Participants were randomized to receive KISQALI 400 mg plus a non-steroidal aromatase inhibitor (NSAI, letrozole or anastrozole) or NSAI only, and goserelin as indicated. Randomization was stratified by Anatomic Stage, prior treatment (neoadjuvant versus adjuvant chemotherapy), menopausal status (premenopausal and males versus postmenopausal) and region (North America/Western Europe/Oceania versus rest of the world). The main efficacy outcome measure was invasive disease-free survival (iDFS). iDFS was defined as the time from randomization to the first occurrence of: local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive breast cancer, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).

Overall survival (OS) was an additional outcome measure. KISQALI was given orally at a dose of 400 mg once daily for 21 consecutive days followed by 7 days off treatment in combination with letrozole 2.5 mg or anastrozole 1 mg orally once daily for 28 days; goserelin 3.6 mg was administered on Day 1 of each 28-day cycle. KISQALI was administered for up to 36 months in the absence of recurrence or unacceptable toxicity.

NSAI was administered for at least 5 years. The median age was 52 years (range, 24 to 90); > 99% women (n = 19 men); 73% White, 13% Asian, 1.7% Black or African American, < 0.1% Native Hawaiian or other Pacific Islander, < 0.1% American Indian or Alaskan Native; 8.5% Hispanic or Latino; 99% ECOG 0-1; 88% node positive disease; 88% received prior (neo)adjuvant chemotherapy. A statistically significant improvement in iDFS was observed in the intent-to-treat (ITT) population at an interim analysis.

The efficacy results at the time of the final iDFS analysis are summarized in Table 18 and Figure 1. At the time of the iDFS final analysis, OS was immature, and a total of 172 (3.5%) of patients had died across both study arms. Table 18: Efficacy Results – NATALEE (Investigator Assessment, Intent-to-Treat Population) Abbreviations: CI, confidence interval; iDFS, invasive disease-free survival; NSAI, non-steroidal aromatase inhibitor. a iDFS was statistically significant at an interim analysis based on a one-sided stratified log-rank p-value of 0.0014.

KISQALI + NSAI +/- Goserelin NSAI +/- Goserelin Invasive Disease-Free Survival (iDFS) a N = 2549 N = 2552 Events (n, %) 226 (8.9) 283 (11.1) Hazard ratio (95% CI) 0.749 (0.628, 0.892) iDFS at 36 months (%, 95% CI) 90.7 (89.3, 91.8) 87.6 (86.1, 88.9) Figure 1: Kaplan-Meier Plot of iDFS – NATALEE (Investigator Assessment, Intent-to-Treat Population)

14.2Advanced or Metastatic Breast Cancer MONALEESA-2: KISQALI in Combination with Letrozole Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy MONALEESA-2 (NCT01958021) was a randomized (1:1), double-blind, placebo-controlled, multicenter clinical study of KISQALI plus letrozole vs. placebo plus letrozole conducted in postmenopausal women (N = 668) with HR-positive, HER2-negative, advance… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study with oral administration of ribociclib daily in cycles of 3 weeks on/1 week off, ribociclib was not carcinogenic at doses up to 50 mg/kg in male rats and 600 mg/kg in female rats. Systemic exposure in male and female rats were 1.3 and 1.8 times, respectively, the human exposure at the highest recommended dose of 600 mg/day based on AUC. Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.

In a fertility and early embryonic development study, female rats received oral doses of ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC). A fertility study in male rats has not been performed with ribociclib.

In repeat-dose toxicity studies with oral administration of ribociclib daily for 3 weeks on/1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥ 75 mg/kg in rats and ≥ 1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively.

These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.

13.2Animal Toxicology and/or Pharmacology In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical C max ).