Pharmacology: Mechanism of action: Ribociclib is a selective inhibitor of CDK 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in 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, leading to arrest in the G1 phase of the cell cycle, and reduced cell proliferation in breast cancer cell lines.
In vivo, treatment with single-agent ribociclib led to tumor regressions which correlated with inhibition of pRb phosphorylation at well-tolerated doses.
In vivo studies using patient-derived estrogen-positive breast cancer xenograft models combination of ribociclib and antiestrogens (i.e. letrozole) resulted in superior inhibition of tumor growth compared to each drug alone. Tumor regrowth was delayed for 33 days after stopping dosing. Additionally, the
in vivo antitumor activity of ribociclib in combination with fulvestrant was assessed in immune-deficient mice bearing the ZR751 ER+ human breast cancer xenografts. The combination of ribociclib and fulvestrant resulted in complete tumor growth inhibition.
Pharmacodynamics: Ribociclib inhibits the CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes with concentration resulting in 50% inhibition (IC
50) values of 0.01 (4.3 ng/mL) and 0.039 micromolar (16.9 ng/mL) in biochemical assays, respectively.
In cell-based assays, ribociclib inhibits CDK4/6-dependent pRb phosphorylation with an average IC
50 of 0.06 micromolar (26 ng/mL). Ribociclib halts G1 to S phase cell cycle progression measured by flow cytometry with an average IC
50 of 0.11 micromolar (47.8 ng/mL). Ribociclib also inhibits cellular proliferation measured by bromodeoxyuridine (BrdU) uptake with an IC
50 of 0.8 micromolar (34.8 ng/mL). The similar IC
50 values obtained from the target modulation, cell cycle and proliferation assays confirm that the blockade of pRb phosphorylation by ribociclib directly leads to G1 to S phase arrest and subsequent inhibition of cellular proliferation. When tested in a panel of breast cancer cell lines with known ER status, ribociclib was demonstrated to be more efficacious in ER+ breast cancer cell lines than in the ER-ones. In the preclinical models tested so far, intact pRb was required for ribociclib activity.
Cardiac electrophysiology: Serial, triplicate ECGs were collected following a single dose and at steady state to evaluate the effect of ribociclib on the QTc interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1,200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. The estimated QTcF interval mean change from baseline for ribociclib 600 mg dose in combination with NSAI or fulvestrant was 22.00 ms (90% CI: 20.56, 23.44) and 23.7 ms (90% CI: 22.31, 25.08), respectively, at the geometric mean C
max at steady state compared to 34.7â—¦ms (90% CI: 31.64, 37.78) in combination with tamoxifen. (see PRECAUTIONS).
Clinical studies: Study CLEE011A2301 (MONALEESA-2): Ribociclib (Kryxana) was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III clinical study in the treatment of postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease in combination with letrozole versus letrozole alone.
A total of 668 patients were randomized in a 1:1 ratio to receive either ribociclib (Kryxana) 600 mg and letrozole (n=334) or placebo and letrozole (n=334), stratified according to the presence of liver and/or lung metastases Yes [n=292 (44%)] vs No [n=376 (56%)]. Demographics and baseline disease characteristics were balanced and comparable between study arms. Ribociclib was given orally at a dose of 600 mg daily for 21 consecutive days followed by 7 days off treatment in combination with letrozole 2.5 mg once daily for 28 days. Patients were not allowed to cross over from placebo to ribociclib during the study or after disease progression.
Patients enrolled in this study had a median age of 62 years (range 23 to 91). 44.2% patients were of age 65 years and older including 69 patients (10.3%) of age 75 years and older. The patients included were Caucasian (82.2%), Asian (7.6%), and Black (2.5%). All patients had an ECOG performance status of 0 or 1. A total of 46.6% of patients had received chemotherapy in the neoadjuvant or adjuvant setting and 51.3% had received antihormonal therapy in the neo/adjuvant setting prior to study entry. 34.1% of patients had de novo metastatic disease. 22.0% of patients had bone only disease and 58.8% of patients had visceral disease.
Primary analysis: The primary endpoint for the study was met at the planned interim analysis conducted after observing 80% of targeted progression-free survival (PFS) events using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in the full population (all randomized patients) and confirmed by a blinded independent central radiological assessment.
The efficacy results demonstrated a statistically significant improvement in PFS in patients receiving ribociclib plus letrozole compared to patients receiving placebo plus letrozole in the full analysis set (FAS) (HR: 0.556; 95% CI: 0.429, 0.720; one-sided stratified log-rank test p-value=0.00000329), with an estimated 44% reduction in risk of progression for patients treated with the combination of ribociclib plus letrozole. The median PFS was not reached in the ribociclib plus letrozole arm (95% CI: 19.3, NE) at the time of the primary analysis. The median PFS was 14.7 months (95% CI: 13.0, 16.5) for the placebo plus letrozole arm. Results were consistent across the sub-groups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease.
Progression free survival is summarized in Table 1 and the Kaplan-Meier curve for PFS is provided in Figure 1. The results for PFS based on the blinded independent central radiological assessment were consistent with the primary efficacy results based on the investigator's assessment (HR: 0.592; 95% CI: 0.412, 0.852). The one-sided stratified log-rank test p-value was 0.002.
The global health status/Quality of life (QoL) showed no relevant difference between the ribociclib plus letrozole arm and the placebo plus letrozole control arm.
A more mature update of efficacy data is provided in Table 2 and Figure 2. Median PFS was 25.3 months (95% CI: 23.0, 30.3) for ribociclib plus letrozole treated patients and 16.0 months (95% CI: 13.4, 18.2) for patients receiving placebo plus letrozole. 54.7% of patients receiving ribociclib plus letrozole were estimated to be disease progression free at 24 months compared with 35.9% in the placebo plus letrozole arm.
Hazard ratios based on a pre-specified sub-group analysis are in favor of the ribociclib plus letrozole arm, demonstrating that patients benefit independent of age, race, prior adjuvant/neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastasis disease. (See Tables 1 and 2, and Figures 1, 2, 3, and 4.)
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Other secondary endpoints included overall response rate (ORR), time to deterioration of ECOG performance status, safety and tolerability, and change in patient-reported outcomes (PROs) for health-related quality of life. In the FAS, the overall response rate according to the local radiologist assessment was 40.7% of patients (95% CI: 35.4%, 46.0%) in the ribociclib plus letrozole arm and 27.5% (95% CI: 22.8%, 32.3%) in the placebo plus letrozole arm (p=0.000155). The clinical benefit rate (CBR) was 79.6% of patients (95% CI: 75.3%, 84.0%) in the ribociclib plus letrozole arm and 72.8% (95% CI: 68.0%, 77.5%) in the placebo plus letrozole arm (p=0.018). In patients with measurable disease, the overall response rate according to the local radiologist assessment was 52.7% of patients (95% CI: 46.6%, 58.9%) in the ribociclib plus letrozole and 37.1% (95% CI: 31.1%, 43.2%) in the placebo plus letrozole arm (p=0.00028).
The clinical benefit rate was 80.1% (95% CI: 75.2%, 85.0%) in the ribociclib plus letrozole arm and 71.8% (95% CI: 66.2%, 77.5%) in the placebo plus letrozole arm (p=0.018) (see Table 3).
A series of pre-specified sub-group PFS analyses was performed based on prognostic factors and baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in favor of the ribociclib plus letrozole arm was observed in all individual patient sub-groups of age, race, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease. This was evident for patients with liver and/or lung disease (HR: 0.561 [95% CI: 0.424, 0.743], median progression-free survival [mPFS] 24.8 months vs 13.4 months for the ribociclib and placebo arms, respectively the same) benefit was observed for those patients without liver and/or lung disease (HR: 0.597 [95% CI: 0.426, 0.837]; mPFS 27.6 months vs 18.2 months).
Updated results for overall response and clinical benefit rates are displayed in Table 4. (See Tables 3 and 4.)
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Final OS analysis: At the time of the final overall survival (OS) analysis (10-Jun-2021 cut-off), the study met its key secondary endpoint demonstrating a statistically significant and clinically meaningful improvement in OS with a 23.5% relative reduction in risk of death (HR: 0.765, 95% CI: 0.628, 0.932; p-value=0.004).
OS benefit increased over time, with a 6-year survival rate of 44.2% (38.5, 49.8) for ribociclib vs. 32.0% (26.8, 37.3) for placebo. The median OS was 63.9 months (95% CI: 52.4, 71.0) for the ribociclib arm and 51.4 months (95% CI: 47.2, 59.7) for the placebo arm, with a 12.5-months improvement in median OS for the ribociclib arm. The exploratory OS results from subgroup analyses demonstrated that the OS benefit was generally consistent across the patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease (see Figure 6). This was evident for patients with liver and/or lung disease (HR: 0.806 [95% CI: 0.621, 1.045]; a similar benefit was observed for those patients without liver and/or lung disease (HR: 0.711 [95% CI: 0.526, 0.962].
The OS results from this final analysis are summarized in Table 5 and the Kaplan-Meier curve is provided in Figure 5. (See Table 5, and Figures 5, and 6.)
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Additionally, the median time to first subsequent chemotherapy was prolonged by 11.7 months in the ribociclib arm compared to the placebo arm (50.6 months, 95% CI: 38.9, 60.0 months vs 38.9 months, 95% CI: 31.4, 45.4). The probability of chemotherapy usage was reduced by 25.8% in the ribociclib arm compared to the placebo arm (HR: 0.742; 95% CI: 0.606, 0.909).
Study CLEE011E2301 (MONALEESA-7): Ribociclib was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III clinical study comparing ribociclib or placebo in combination with tamoxifen and goserelin or a non-steroidal aromatase inhibitor (NSAI) and goserelin for the treatment of pre-and perimenopausal women with hormone receptor (HR) positive, HER2-negative, advanced breast cancer.
A total of 672 patients were randomized to receive either ribociclib 600 mg plus tamoxifen or NSAI plus goserelin (n=335) or placebo plus tamoxifen or NSAI plus goserelin (n=337), stratified according to the presence of liver and/or lung metastases (Yes [n=344 (51.2%)] vs No [n=328 (48.8%)]), prior chemotherapy for advanced disease (Yes [n=120 (17.9%)] vs No [n=552 (82.1%)]) and endocrine combination partner (NSAI and goserelin) [n=493 (73.4%)] versus tamoxifen and goserelin [n=179 (26.6%)]. Demographics and baseline disease characteristics were balanced and comparable between study arms.
Tamoxifen 20 mg or NSAI (letrozole 2.5 mg or anastrazole 1 mg) were given orally once daily on a continuous schedule, goserelin 3.6 mg was administered as sub-cutaneous injection on day 1 of each 28 day cycle, with either ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. Patients were not allowed to cross over from placebo to ribociclib during the study or after disease progression. Patients were not allowed to switch between endocrine combination partners.
Patients enrolled in the study had a median age of 44 years (range 25 to 58) and 27.7% of patients were younger than 40 years of age. The majority of patients were Caucasian (57.7%), Asian (29.5%), or Black (2.8%) and nearly all patients (99.0%) had an ECOG performance status of 0 or 1. Of the 672 patients, 32.6% of patients had received chemotherapy in the adjuvant vs 18.0% in neo-adjuvant setting and 39.6% had received endocrine therapy in the adjuvant vs 0.7% in the neoadjuvant setting. Prior to study entry 40.2% of patients had
de novo metastatic disease, 23.7% had bone only disease, and 56.7% had visceral disease.
Primary analysis: The primary endpoint for the study was met after observing 318 progression-free survival (PFS) events using RECIST v1.1, based on the investigator assessment in the full analysis set (all randomized patients) and confirmed by a blinded independent central radiological assessment of a randomly selected subset of approximately 40% of randomized patients (BIRC). The median follow-up time at the time of the primary PFS analysis was 19.2 months.
In the overall study population, the median PFS (95% CI) was 23.8 months (19.2, NE) in the ribociclib plus tamoxifen or NSAI arm and 13.0 months (11.0, 16.4) in the placebo plus tamoxifen or NSAI arm [HR: 0.553 (95% CI: 0.441, 0.694); one-sided stratified long-rank test p-value: 9.83x10
-8]. Efficacy results are presented in the Kaplan-Meier curve for PFS in Figure 7. The results based on the BIRC were supportive of the primary efficacy results based on the investigator's assessment (HR: 0.427; 95% CI: 0.288, 0.633).
Overall response rate (ORR) per investigator assessment based on RECISTv1.1 was higher in the ribociclib arm (40.9%; 95% CI: 35.6, 46.2) compared to the placebo arm (29.7%; 95% CI: 24.8, 34.6; p=0.00098) (see Table 7).
The main pre-specified QoL measure was Time-To-Deterioration (TTD) in global health status. Definitive 10% deterioration was defined as a worsening in the EORTC QLQ-C30 global health scale score by at least 10% compared to baseline, with no later improvement above this threshold observed during the treatment period, or death due to any cause. Addition of ribociclib to tamoxifen or NSAI resulted in delaying time-to-deterioration in the EORTC QLQ-C30 global health scale score compared with placebo plus tamoxifen or NSAI (median not estimable versus 21.2 months; HR: 0.699 [95% CI: 0.533, 0.916]; p=0.004. (See Figure 7.)
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In the pre-specified sub-group analysis of 495 patients who had received Ribociclib or placebo in combination with NSAI plus goserelin, the median PFS (95% CI) was 27.5 months (19.1, NE) in the ribociclib plus NSAI sub-group and 13.8 months (12.6, 17.4) in the placebo plus NSAI sub-group [HR: 0.569 (95% CI: 0.436, 0.743)]. Efficacy results are summarized in Table 6 and the Kaplan-Meier curves for PFS are provided in Figure 8.
Results, in the ribociclib plus NSAI subgroup were consistent across subgroups of age, race, prior adjuvant/neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone only metastatic disease (see Figure 9).
In the NSAI sub-group, the median time to response (TTR) was not reached in either the ribociclib arm or the placebo arm and the probability of response by 6 months was 34.7% (95% CI: 29.0, 41.1) in the ribociclib arm and 23.7% (95% CI: 18.8, 29.6) in the placebo arm, indicating that a larger proportion of patients derived an earlier benefit in the ribociclib arm.
In the NSAI sub-group, the median duration of response (DOR) was not reached (95% CI: 18.3 months, NE) in the ribociclib arm and was 17.5 months (95% CI: 12.0, NE) in the placebo arm. Among patients with confirmed complete response or partial response, the probability of subsequent progression was 23.5% (95% CI: 15.6, 34.5) in the ribociclib arm and 36.4% (95% CI: 25.6, 49.8) in the placebo arm at 12 months. (See Tables 6 and 7, and Figures 8 and 9.)
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Final OS Analysis: At the time of the second OS analysis (30-Nov-2018 cut-off), the study met its key secondary endpoint, demonstrating a statistically significant improvement in OS.
The demonstrated OS benefit was consistent across exploratory subgroups and the safety profile of both treatment arms remained consistent with the results from the primary analysis.
A more mature update of overall survival data (30-Nov-2018 cut-off) is provided in Table 8 as well as in Figures 10 and 11. (See Table 8 and Figures 10 and 11.)
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Additionally, time to progression on next-line therapy or death (PFS2) in patients in the ribociclib arm was longer compared to patients in the placebo arm (HR: 0.692 (95% CI: 0.548, 0.875)) in the overall study population. The median PFS2 was 32.3 months (95% CI: 27.6, 38.3) in the placebo arm and was not reached (95% CI: 39.4, NE) in the ribociclib arm. Similar results were observed in the NSAI sub-group (HR: 0.660 (95% CI: 0.503, 0.868); median PFS2: 32.3 months (95% CI: 26.9, 38.3) in the placebo arm vs not reached (95% CI: 39.4, NE) in the ribociclib arm).
Study CLEE011F2301 (MONALEESA-3): Ribociclib was evaluated in a randomized double-blind, placebo controlled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor (HR) positive , HER2-negative advanced breast cancer who have received no or only one line of prior endocrine treatment.
A total of 726 patients were randomized in a 2:1 ratio to receive either ribociclib 600 mg and fulvestrant (n=484) or placebo and fulvestrant (n=242) stratified according to the presence of liver and/or lung metastases [Yes (n=351 (48.3%)) versus No (n=375 (51.7%))], prior endocrine therapy [A (n=354 (48.8%)) vs B (n=372 (51.2%)]. First-line patients with advanced breast cancer (A) include de novo advanced breast cancer with no prior endocrine therapy, and patients who relapsed after 12 months of (neo) adjuvant endocrine therapy completion.
Second-line patients' subgroup (B) includes those patients whose disease relapsed during adjuvant therapy or less than 12 months after endocrine adjuvant therapy completion, and those who progressed to first line endocrine therapy. Demographics and baseline disease characteristics were balanced and comparable between study arms. Ribociclib 600 mg or placebo was given orally daily for 21 consecutive days followed by 7 days off treatment in combination with fulvestrant 500 mg administered intramuscularly on Cycle 1, Day 1, Cycle 1, Day 15, Cycle 2, Day 1 and every 28 days thereafter.
Patients enrolled in this study had a median age of 63 years (range 31 to 89). 46.7% of patients were aged 65 years and older, including 13.8% patients aged 75 years and older. The patients included were Caucasian (85.3%), Asian (8.7%) or Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of whom 19.1 % of patients had de novo metastatic disease). 42.7% of patients had received chemotherapy in the adjuvant vs 13.1% in the neo-adjuvant setting and 58.5% had received endocrine therapy in the adjuvant vs 1.4% in the neoadjuvant setting. Prior to study entry 21.2% of patients had bone only disease and 60.5% of patients had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
Primary analysis: The primary endpoint for the study was performed after observing 361 PFS events using RECIST v1.1, based on the investigator assessment in the full analysis set (all randomized patients) and confirmed by a random central audit of 40% imaging subset by a blinded independent review committee (BIRC). The median follow-up time at the time of primary PFS analysis was 20.4 months.
PFS analyses based on the BIRC were supportive of the primary efficacy results, the PFS hazard ratio was 0.492 (95% CI, 0.345 to 0.703).
The primary efficacy results demonstrated a statistically significant improvement in PFS in patients receiving ribociclib plus fulvestrant compared to patients receiving placebo plus fulvestrant in the full analysis set (HR: 0.593; 95% CI: 0.480, 0.732; one sided stratified log-rank test p-value 4.1x10-7), with an estimated 41% reduction in relative risk of progression or death in favor of the ribociclib plus fulvestrant arm. The median (95% CI) PFS was 20.5 months (18.5, 23.5) in the ribociclib plus fulvestrant and 12.8 months (10.9, 16.3) in the placebo plus fulvestrant arm. Kaplan-Meier curve for PFS are provided in Figures 12 and 13, respectively. (See Figures 12 and 13.)
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The clinical benefit rate in the ribociclib plus fulvestrant arm and in the placebo plus fulvestrant arm is summarized in Table 9. (See Table 9.)
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The global health status/ QoL were similar between the ribociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The main pre-specified QoL measure was TTD in global health status. A definitive 10% deterioration was defined as a worsening in score (EORTC QLQ-C30 global health scale score) by at least 10% compared to baseline, with no later improvement above this threshold observed during the treatment period, or death due to any cause. Addition of ribociclib to fulvestrant resulted in delaying TTD in the EORTC QLQ-C30 global health scale score compared with placebo plus fulvestrant, (median not estimable versus 19.4 months; HR: 0.795 [95% CI: 0.602,1.050]; p-value 0.051.
Final OS Analysis: Since the median PFS for first line patients had not been reached at the time of the primary analysis, a descriptive update of primary efficacy results (PFS) was performed at the time of the second OS interim analysis, and the updated PFS results are summarized in Table 10 and the Kaplan-Meier curve is provided in Figure 14. (See Table 10 and Figure 14.)
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Results were consistent across pre-specified sub-groups of age, prior adjuvant or neo-adjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone only metastatic disease. The subgroup analysis based on prior endocrine therapy is presented in Table 11. (See Table 11.)
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In the pre-specified second OS interim analysis, the study crossed pre-specified Lan-DeMets (O'Brien-Fleming) stopping boundary, demonstrating a statistically significant improvement in OS.
The OS results from this interim analysis with a 03-Jun-19 cut-off are provided in Table 12 and Figure 15. (See Table 12 and Figure 15.)
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OS results for subgroups analyses are presented in Figures 16 and 17. (See Figures 16, 17, and 18.)
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Additionally, time to progression on next-line therapy or death (PFS2) in patients in the ribociclib arm was longer compared to patients in the placebo arm (HR: 0.670 (95% CI: 0.542, 0.830)) in the overall study population. The median PFS2 was 39.8 months (95% CI: 32.5, NE) for the Ribociclib arm and 29.4 months (95% CI: 24.1, 33.1) in the placebo arm.
Clinical efficacy in patients with advanced hormone receptor (HR)-positive, HER 2-negative breast cancer (Study CLEE011X2107): CLEE011X2107 is a phase Ib, multicenter study of the combination of Ribociclib and/or alpelisib with letrozole in adult patients with advanced hormone receptor (HR) positive, HER 2-negative breast cancer. The combination of Ribociclib 600 mg/day (3-weeks-on and 1 week-off) and letrozole 2.5 mg/day was studied in the dose escalation (previously treated patients (n=19)) and expansion (first line patients (n=28)) of one arm of this study.
The data from first-line patients treated with Ribociclib 600 mg plus letrozole 2.5 mg demonstrated clinical activity as shown by the ORR and CBR: the ORR was 39.3%, and the CBR was 78.6%. The Kaplan Meier estimate of PFS at 15 months was 57.5% for the expansion phase. Among the 24 patients with measurable disease, the ORR was 45.8% and CBR 79.2%.
Study CLEE011A2404 (COMPLEEMENT-1): Ribociclib was evaluated in an open-label, single arm, multicenter phase IIIb clinical study comparing ribociclib in combination with letrozole in pre/post-menopausal women and men with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease. Premenopausal women, and men, also received goserelin or leuprolide.
The study enrolled 3246 patients, including 39 male patients who received ribociclib 600 mg orally once daily for 21 consecutive days followed by 7 days off; and letrozole 2.5 mg orally once daily for 28 days; and goserelin 3.6 mg as injectable subcutaneous implant or leuprolide 7.5 mg as intramuscular injection administered on Day 1 of each 28 day cycle. Patients were treated until disease progression or unacceptable toxicity occurred.
Male patients enrolled in this study had a median age of 62 years (range 33 to 80). Of these patients, 38.5% were 65 years and older, including 10.3% aged 75 years and older. The male patients enrolled were Caucasian (71.8%), Asian (7.7%), and Black (2.6%), with 17.9% unknown. Nearly all male patients (97.4%) had an ECOG performance status of 0 or 1. The majority of male patients (97%) had 4 or less metastatic sites, which were primarily bone and visceral (69.2% each).
Table 13 summarizes the efficacy results in male patients. (See Table 13.)
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Pharmacokinetics: The pharmacokinetics of ribociclib were investigated in patients with advanced cancer following oral daily doses of 50 mg to 1,200 mg. Healthy subjects received single oral doses of 400 or 600 mg or repeated daily oral doses (8 days) of 400 mg.
Absorption: Following oral administration of ribociclib to patients with advanced solid tumors or lymphomas peak plasma levels (C
max) of ribociclib were achieved between 1 and 4 hours (time to reach maximum concentration, T
max). The geometric mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8% in healthy subjects. Ribociclib exhibited slightly over-proportional increases in exposure (C
max and AUC) across the dose range tested (50 to 1,200 mg). Following repeated once-daily dosing, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
Food effect: Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablet formulation with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib (C
max GMR: 1.00; 90% CI: 0.898, 1.11; AUC
inf GMR: 1.06; 90% CI: 1.01, 1.12) (see INTERACTIONS).
Distribution: Binding of ribociclib to human plasma proteins
in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean
in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1,090 L based on the population pharmacokinetic analysis.
Biotransformation/metabolism: In vitro and
in vivo studies indicated that ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of [
14C]ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C- and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (43.5%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9.39%, 8.60%, and 7.78% of total radioactivity, and 21.6%, 19.8%, and 17.9% of ribociclib exposure, respectively. Clinical activity (pharmacological and safety) of ribociclib was primarily due to parent drug, with negligible contribution from circulating metabolites.
Ribociclib was extensively metabolized with the unchanged drug accounting for 17.3% and 12.1% of the dose in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤2.78% of the administered dose).
Elimination: The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean plasma terminal half-life (T
½) of ribociclib ranged from 29.7 to 54.7 hours and the geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
Ribociclib is eliminated mainly via the feces, with a small contribution from the renal route. In 6 healthy male subjects, following a single oral dose of [
14C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 21 days; feces were the major route of excretion (69.1%), with 22.6% of the dose recovered in the urine.
Linearity/non-linearity: Ribociclib exhibited slightly over-proportional increases in exposure (C
max and AUC) across the dose range of 50 mg to 1,200 mg following both single dose and repeated doses. This analysis is limited by the small sample sizes for most of the dose cohorts, with a majority of the data coming from the 600 mg dose cohort.
Special populations: Renal impairment: The effect of renal function on the pharmacokinetics of ribociclib was also assessed in a renal impairment study in non-cancer subjects that included 14 subjects with normal renal function (absolute Glomerular Filtration Rate (aGFR) ≥90 mL/min), 8 subjects with mild renal impairment (aGFR 60 to <90 mL/min), 6 subjects with moderate renal impairment (aGFR 30 to <60 mL/min), 7 subjects with severe renal impairment (aGFR 15 to <30 mL/min), and 3 subjects with end stage renal disease (ESRD) (aGFR <15 mL/min) at a single oral ribociclib dose of 400 mg/day.
In the subjects with normal, mild, moderate, severe renal impairment and ESRD, the geometric mean AUCinf (geometric %CV, n) was 4100 ng*hr/mL (53.2%, 14), 6650 ng*hr/mL (36.4%, 8), 7960 ng*hr/mL (45.8%, 6), 10900 ng*hr/mL (38.1%, 7), 13600 ng*hr/mL (20.9%, 3), respectively, and Cmax (geometric %CV, n) was 234 ng/mL (58.5%, 14), 421 ng/mL (31.6%, 8), 419 ng/mL (30.3%, 6), 538 ng/mL (43.3%, 7), 593 ng/mL (11.3%, 3), respectively.
AUCinf increased to 1.62-fold, 1.94-fold and 2.67-fold, and C
max increased to 1.80-fold, 1.79-fold and 2.30-fold in subjects with mild, moderate and severe renal impairment, relative to the exposure in subjects with normal renal function. A fold difference for subjects with ESRD was not calculated due to the small number of subjects (see DOSAGE & ADMINISTRATION).
No dose adjustment is necessary in patients with mild or moderate renal impairment. The effect of renal function on the pharmacokinetics of ribociclib was also assessed in cancer patients. Based on a population pharmacokinetic analysis that included 438 cancer patients with normal renal function (eGFR ≥90 mL/min/1.73 m
2), 488 patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73m
2) and 113 patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m
2), mild and moderate renal impairment had no effect on the exposure of ribociclib. In addition, in a sub-group analysis of PK data from studies in cancer patients following oral administration of ribociclib 600 mg as a single dose or repeat doses (MONALEESA-7, CLEE011X2101 and CLEE011X2107), AUC and C
max of ribociclib following a single dose or at steady state in patients with mild or moderate renal impairment were comparable to patients with normal renal function, suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure (see DOSAGE & ADMINISTRATION).
Hepatic impairment: No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A); a dose adjustment is required in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) and a starting dose of 400 mg is recommended. Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib. The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for C
max; 1.28 for AUC
inf) and severe (GMR: 1.32 for C
max; 1.29 for AUC
inf) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib, further supporting the findings from the dedicated hepatic impairment study (see DOSAGE & ADMINISTRATION).
Effect of age, weight, gender and race: The population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib that would require a dose adjustment.
Geriatric patients: Of the 334 patients who received ribociclib (Kryxana) in the phase III study (MONALEESA 2, ribociclib plus letrozole arm), 150 patients (44.9%) were ≥65 years of age and 35 patients (10.5%) were ≥75 years of age. Of 483 patients who received Ribociclib in the phase III study (MONALEESA 3, ribociclib plus fulvestrant arm), 226 patients (46.8%) were ≥65 years of age and 65 patients (13.5%) were ≥75 years of age. No overall differences in the safety or effectiveness of ribociclib were observed between these patients and younger patients (see DOSAGE & ADMINISTRATION).
Interactions: Strong CYP3A inhibitors: A drug interaction study in healthy subjects was conducted with ritonavir (strong CYP3A inhibitor). Compared to ribociclib alone, ritonavir (100 mg b.i.d for 14 days) increased ribociclib C
max and AUC
inf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg ribociclib dose. C
max and AUC
last for LEQ803 (a prominent metabolite of ribociclib, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. Simulations using PBPK suggested that a moderate CYP3A4 inhibitor (erythromycin) may increase C
max and AUC of ribociclib 400 mg single dose by 1.3-fold and 1.9-fold, respectively (see DOSAGE & ADMINISTRATION, PRECAUTIONS and INTERACTIONS).
Strong CYP3A inducers: A drug interaction study in healthy subjects was conducted with rifampicin (strong CYP3A4 inducer). Compared to ribociclib alone, rifampicin (600 mg daily for 14 days) decreased ribociclib C
max and AUC
inf by 81% and 89%, respectively, following a single 600 mg ribociclib dose. LEQ803 C
max increased 1.7-fold and AUC
inf decreased by 27%, respectively. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease ribociclib single dose C
max and AUC by 37% and 60%, respectively (see INTERACTIONS).
Cytochrome P450 enzymes (CYP3A4 and CYP1A2 substrates): A drug interaction study in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of ribociclib (400 mg once daily for 8 days) increased midazolam C
max and AUC
inf by 2.1-fold and 3.8-fold, respectively. Simulations using PBPK suggested that at a 600 mg ribociclib dose, midazolam C
max and AUC may increase 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of ribociclib on caffeine was minimal, with C
max decreasing by 10% and AUC
inf increasing slightly by 20%. Simulations using PBPK suggested only weak inhibitory effects on CYP1A2 substrates at a 600 mg ribociclib dose (see INTERACTIONS).
Ribociclib exhibited no capacity to inhibit CYP2E1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and showed no apparent time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6 at clinically relevant concentrations. No induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4 was observed
in vitro at clinically relevant concentrations (see INTERACTIONS).
Gastric pH-elevating agents: Ribociclib exhibits high solubility at or below pH 4.5 and in bio-relevant media (at pH 5.0 and 6.5). Co-administration of ribociclib with medicinal products that elevate the gastric pH was not evaluated in a clinical trial; however, altered ribociclib absorption was not observed in population pharmacokinetic analysis nor in simulations using PBPK models (see DOSAGE & ADMINISTRATION and INTERACTIONS).
Letrozole: Data from clinical trials in patients with breast cancer and a population PK analysis indicated no drug interaction between ribociclib and letrozole following co-administration 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 co-administration 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.
Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on ribociclib exposure following co-administration of the drugs.
Tamoxifen: Data from a clinical trial in patients with breast cancer indicated that tamoxifen exposure was increased approximately 2-fold following co-administration of ribociclib and tamoxifen.
Effect of ribociclib on transporters:
In vitro evaluations indicated that ribociclib has a low potential to inhibit the activities of the drug transporters P-gp, OATP1B1/B3, OCT1, MATE2K at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations (see INTERACTIONS).
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 OCT-1
in vitro (see INTERACTIONS).
Toxicology: Non-Clinical Safety Data: Ribociclib was evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity studies.
Safety pharmacology: Ribociclib did not have effects on CNS or respiratory functions.
In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure that would be expected to be achieved in patients following the recommended dose of 600 mg. As well, there is potential to induce incidences of PVCs at elevated exposures (approximately 5 fold the anticipated clinical C
max).
Repeated dose toxicity: Repeated dose toxicity studies (treatment schedule of 3 weeks on/1 week off) in rats up to 27 weeks duration and dogs up to 39 weeks duration, revealed the hepatobiliary system (proliferative changes, cholestasis, sand-like gallbladder calculi, and inspissated bile) as the primary target organ of toxicity of ribociclib. Target organs associated with the pharmacological action of ribociclib in repeat dose studies include bone marrow (hypocellularity), lymphoid system (lymphoid depletion), intestinal mucosa (atrophy), skin (atrophy), bone (decreased bone formation), kidney (concurrent degeneration and regeneration of tubular epithelial cells) and testes (atrophy). Besides the atrophic changes seen in the testes, which showed a trend towards reversibility, all other changes were fully reversible after a 4-week treatment free period. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules. Exposure to ribociclib in animals in the toxicity studies was generally less than or equal to that observed in patients receiving multiple doses of 600 mg/day (based on AUC).
Reproductive toxicity/Fertility: See USE IN PREGNANCY & LACTATION.
Genotoxicity: Genotoxicity studies in bacterial
in vitro systems and in mammalian
in vitro and
in vivo systems with and without metabolic activation did not reveal any evidence for a mutagenic potential of ribociclib.
Phototoxicity: Ribociclib was shown to absorb light in the UV-B and UV-A range. An
in vitro phototoxicity test did not identify a relevant phototoxicity potential for ribociclib. The risk that ribociclib causes photosensitization in patients is considered very low.
Carcinogenesis: Ribociclib was assessed for carcinogenicity in a 2-year rat study.
Oral administration of ribociclib for 2 years resulted in an increased incidence of endometrial epithelial tumors and glandular and squamous hyperplasia in the uterus/cervix of female rats at doses ≥300 mg/kg/day as well as an increased incidence in follicular tumors in the thyroid glands of male rats at a dose of 50 mg/kg/day. Mean exposure at steady state (AUC0-24h) in female and male rats in whom neoplastic changes were seen was 1.2 and 1.4-fold that achieved in patients at the recommended dose of 600 mg/day, respectively. Mean exposure at steady state (AUC0-24h) in female and male rats in whom neoplastic changes were seen was 2.2- and 2.5-fold that achieved in patients at a dose of 400 mg/day, respectively.
Additional non-neoplastic proliferative changes consisted of increased liver altered foci (basophilic and clear cell) and testicular interstitial (Leydig) cell hyperplasia in male rats at doses of ≥5 mg/kg/day and 50 mg/kg/day, respectively.
The effects on the uterus/cervix and on the testicular interstitial (Leydig) cell may be related to prolonged hypoprolactinemia secondary to CDK4 inhibition of lactotrophic cell function in the pituitary gland, altering the hypothalamus-pituitary-gonadal axis.
Potential mechanisms for the thyroid findings in males include a rodent-specific microsomal enzyme induction in the liver and/or a dysregulation of the hypothalamus-pituitary-testis-thyroid axis secondary to a persistent on-target hypoprolactinemia.
Any potential increase of estrogen/progesterone ratio in humans by this mechanism would be compensated by an inhibitory action of concomitant anti-estrogen therapy on estrogen synthesis as in humans ribociclib (Kryxana) is indicated in combination with estrogen-lowering agents.
Considering important differences between rodents and humans with regard to synthesis and role of prolactin, this mode of action is not expected to have consequences in humans.
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