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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.
Pharmacodynamics: 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 QT Interval Prolongation and Increased QT Prolongation with Concomitant Use of Tamoxifen under Precautions].
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 Cmax [see QT Interval Prolongation and Increased QT Prolongation with Concomitant Use of Tamoxifen under Precautions].
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 Cmax [see QT Interval Prolongation and Increased QT Prolongation with Concomitant Use of Tamoxifen under Precautions].
Clinical Studies: Early 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 (excluding microscopic nodal 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 1 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. (See Table 1 and Figure 1.)
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Click on icon to see table/diagram/imageAdvanced 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, advanced breast cancer who received no prior therapy for advanced disease.
Participants were randomized to receive either KISQALI plus letrozole or placebo plus letrozole, stratified according to the presence of liver and/or lung metastases. Letrozole 2.5 mg was given orally once daily for 28 days, with either KISQALI 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
The median age was 62 years (range, 23 to 91) and 45% of patients were older than 65. The majority of patients were White (82%), and all patients had an ECOG performance status of 0 or 1. A total of 47% of patients had received chemotherapy and 51% had received antihormonal therapy in the neoadjuvant or adjuvant setting. Thirty-four percent (34%) of patients had de novo metastatic disease, 21% had bone only disease, and 59% had visceral disease.
The efficacy results are summarized in Table 2, Figure 2 and Figure 3. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. Consistent results were observed across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. (See Table 2 and Figures 2 and 3.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageMONALEESA-7: KISQALI in Combination with a Non-Steroidal Aromatase Inhibitor with or without Goserelin: Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: MONALEESA-7 (NCT02278120) was a randomized (1:1), double-blind, placebo-controlled study of KISQALI plus either a NSAI or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women (N=672) with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease.
Participants were randomized to receive KISQALI plus NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin, stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partner (tamoxifen and goserelin vs. NSAI and goserelin). NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg were given orally once daily on a continuous daily schedule, goserelin was administered as a subcutaneous injection on Day 1 of each 28-day cycle, with either KISQALI 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
The median age was 44 years (range, 25 to 58). Patients were primarily White (58%), Asian (29%), or Black (3%). Nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant vs. 18% in the neoadjuvant setting and 40% had received endocrine therapy in the adjuvant vs. 0.7% in the neoadjuvant setting prior to study entry. Forty percent (40%) of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, and endocrine combination partner.
The efficacy results from a pre-specified subgroup analysis of 495 patients who had received KISQALI or placebo with NSAI plus goserelin are summarized in Table 3, Figure 4, and Figure 5. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. (See Table 3 and Figures 4 and 5.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageMONALEESA-3: KISQALI in Combination with Fulvestrant: Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy: MONALEESA-3 (NCT06129786) was a randomized (2:1) double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of postmenopausal women (N=726) with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
Participants were randomized to receive KISQALI 600 mg and fulvestrant or placebo and fulvestrant, stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either KISQALI 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
The median age was 63 years (range, 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily White (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. Patients enrolled in this study were treated in the first- or second-line setting, and 19% had de novo metastatic disease. Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting, and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease, and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
The efficacy results from MONALEESA-3 are summarized in Table 4, Figure 6, and Figure 7. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. (See Table 4 and Figures 6 and 7.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePharmacokinetics: Ribociclib exhibited over-proportional increases in exposure (Cmax 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 Cmax was 1820 (62%) ng/mL and AUC was 23800 (66%) ng*h/mL.
Absorption: The Tmax 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 Cmax or AUCinf.
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 25.5 L/hr (66%) at steady-state following 600 mg dose of KISQALI in patients with advanced cancer. The steady state mean CL/F was 38.4 L/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 77.5 L/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 Cmax and 1.28 for AUCinf; and in adults with severe (Child-Pugh class C) hepatic impairment, the mean ratio was 1.32 for Cmax and 1.29 for AUCinf.
Patients with Renal Impairment: In adults with severe renal impairment and ESRD, ribociclib AUCinf increased 2.4-fold and 3.8-fold, and Cmax 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 have mild to moderate renal impairment, AUC and Cmax were comparable to those in patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure.
Effect of Age, Weight, Gender, and Race: No clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib were identified.
Drug Interaction Studies: Clinical Studies and Model-Informed Approaches: Drugs That Affect Ribociclib Plasma Concentrations: CYP3A Inhibitors: Following a single 400 mg dose of KISQALI with ritonavir (a strong CYP3A inhibitor), ritonavir (100 mg twice a day for 14 days) increased ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, compared to ribociclib alone. Cmax and AUC for LEQ803 (a prominent metabolite of ribociclib, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase ribociclib steady-state Cmax and AUC by 1.1-fold and 1.2-fold, respectively, following KISQALI 400 mg once daily, and 1.1-fold and 1.1-fold, respectively, following KISQALI 600 mg once daily.
CYP3A Inducers: Following a single 600 mg dose of KISQALI with rifampicin (a strong CYP3A4 inducer) at 600 mg daily for 14 days, ribociclib Cmax decreased by 81% and AUCinf decreased by 89%, while LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27% compared to ribociclib alone. A moderate CYP3A inducer (efavirenz) is predicted to decrease ribociclib steady-state Cmax by 55% and AUC by 74%, following KISQALI 400 mg once daily, and by 52% and 71%, respectively, following KISQALI 600 mg once daily.
Drugs That are Affected by KISQALI: CYP3A4 and CYP1A2 Substrates: In a cocktail study with midazolam (sensitive CYP3A4 substrate) multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam Cmax by 2.1-fold and increased AUCinf by 3.8-fold compared to midazolam alone. Administration of KISQALI 600 mg once daily is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg ribociclib on caffeine (sensitive CYP1A2 substrate) was minimal, with Cmax decreased by 10% and AUCinf increased by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at KISQALI 600 mg once daily dose.
Gastric pH-Elevating Agents: Coadministration of ribociclib with drugs that elevate the gastric pH is not predicted to alter ribociclib absorption.
Letrozole: Data from a clinical trial in patients with breast cancer indicated no drug interaction between ribociclib and letrozole following coadministration of the drugs.
Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and anastrozole following coadministration of the drugs.
Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between ribociclib and exemestane following coadministration of the drugs.
Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following coadministration of the drugs.
Tamoxifen: KISQALI is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen Cmax and AUC increased approximately 2-fold following coadministration of KISQALI 600 mg.
In vitro Studies: Effect of Ribociclib on CYP Enzymes: In vitro, ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 at clinically relevant concentrations.
Effect of Ribociclib on Transporters: In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations.
Effect of Transporters on Ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT1 in vitro.
Toxicology: Nonclinical Toxicology: Carcinogenesis, 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.
Animal 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 Cmax).
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