Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EF02 
Mechanism of action

Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC50) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, respectively. These kinases are activated upon binding to D-cyclins and play a crucial role in signalling 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 tumour regressions which correlated with inhibition of pRb phosphorylation.

In vivo studies using patient-derived oestrogen receptor-positive breast cancer xenograft model combinations of ribociclib and antioestrogens (i.e. letrozole) resulted in superior tumour growth inhibition with sustained tumour regression and delayed tumour regrowth after stopping dosing compared to each substance alone. Additionally, in vivo antitumour activity of ribociclib in combination with fulvestrant was assessed in immune-deficient mice bearing the ZR751 ER+ human breast cancer xenografts and the combination with fulvestrant resulted in complete tumour growth inhibition.

When tested in a panel of breast cancer cell lines with known ER status, ribociclib 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.
Apharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that ribociclib causes concentration-dependent increases in the QTc interval. The estimated QTcF mean change from baseline for 600 mg Kisqali in combination with NSAI or fulvestrant was 22.0 msec (90% CI: 20.56, 23.44) and 23.7 msec (90% CI: 22.31, 25.08), respectively at the geometric mean Cmax at steady-state compared to 34.7 msec (90% CI: 31.64, 37.78) in combination with tamoxifen (see section 4.4).

Clinical efficacy and safety

Study CLEE011A2301 (MONALEESA-2)
Kisqali was evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III clinical study in the treatment of postmenopausal women with hormone receptor-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 randomised in a 1:1 ratio to receive either Kisqali 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%)]) versus No [n=376 (56%)]). Demographics and baseline disease characteristics were balanced and comparable between study arms. Kisqali 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 Kisqali during the study or after progression of disease.

KIS API JUL24 V9                                                             EU SmPC JUN 24 15
Patients enrolled in this study had a median age of 62 years (range 23 to 91). 44.2% patients were aged 65 years and older, including 69 patients older than 75 years. 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. In the Kisqali arm 46.6% of patients had received chemotherapy in the neoadjuvant or adjuvant setting and 51.3% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to study entry. 34.1% of patients were de novo. 22.0% of patients had bone-only disease and 58.8% of patients had visceral disease. Patients with prior (neo) adjuvant therapy with anastrozole or letrozole must have completed this therapy at least 12 months before study randomisation.

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 Response Evaluation Criteria in Solid Tumours (RECIST v1.1), based on the investigator assessment in the full population (all randomised patients), and confirmed by a blinded independent central radiological assessment.

The efficacy results demonstrated a statistically significant improvement in PFS in patients receiving Kisqali plus letrozole compared to patients receiving placebo plus letrozole in the full analysis set (hazard ratio of 0.556, 95% CI: 0.429, 0.720, one sided stratified log-rank test p-value 0.00000329) with clinically meaningful treatment effect.

The global health status/QoL data showed no relevant difference between the Kisqali plus letrozole arm and the placebo plus letrozole arm.

A more mature update of efficacy data (02 January 2017 cut-off) is provided in Tables 8 and 9.

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 progression-free at 24 months compared with 35.9% in the placebo plus letrozole arm.


Table 8      MONALEESA-2 - Efficacy results (PFS) based on investigator radiological assessment (02 January 2017 cut-off)

Updated analysis
Kisqali plus letrozole                 Placebo plus letrozole
N=334                                  N=334
Progression-free survival
Median PFS [months] (95% CI) 25.3 (23.0-30.3)                                16.0 (13.4-18.2) Hazard ratio (95% CI)                                       0.568 (0.457-0.704) p-valuea                                                           9.63×10-8 CI=confidence interval; N=number of patients a p-value is obtained from the one-sided stratified log-rank test.



KIS API JUL24 V9                                                            EU SmPC JUN 24 16
Figure 1                               MONALEESA-2 - Kaplan-Meier plot of PFS based on investigator assessment Event-free probability (%)            (02 January 2017 cut-off)



Censoring times
Ribociclib (N=334)
Placebo (N=334)


No of events- Ribociclib: 140, Placebo: 205
Hazard Ratio = 0.568; 95% CI [0.457, 0.704]
Kaplan-Meier median - Ribociclib: 25.3 months; Placebo: 16.0 months
Log rank p-value = 9.63*10^(-8)



Time (Months)
Number of patients still at risk
Time                          0        2       4      6          8    10    12    14       16    18       20    22    24   26   28   30   32   34 
Ribociclib 334                        294     277    257     240      227   207   196      188   176      164   132   97   46   17   11    1    0 
Placebo                       334     279     265    239     219      196   179   156      138   124      110   93    63   34   10   7     2    0 


A series of pre-specified subgroup 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 favour of the Kisqali plus letrozole arm was observed in all individual patient subgroups of age, race, prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease. This was evident for patients with liver and/or lung metastases (HR of 0.561 [95% CI: 0.424, 0.743], median progression-free survival [mPFS] 24.8 months for Kisqali plus letrozole versus 13.4 months for letrozole alone), or without liver and/or lung metastases (HR of 0.597 [95% CI: 0.426, 0.837], mPFS 27.6 months versus 18.2 months).

Updated results for overall response and clinical benefit rates are displayed in Table 9.



KIS API JUL24 V9                                                                                                      EU SmPC JUN 24 17
Table 9     MONALEESA-2 - Efficacy results (ORR, CBR) based on investigator assessment (02 January 2017 cut-off)

Analysis                    Kisqali plus              Placebo plus             p-valuec letrozole                 letrozole
(%, 95% CI)               (%, 95% CI)
Full analysis set           N=334                     N=334
Overall response ratea      42.5 (37.2, 47.8)         28.7 (23.9, 33.6)       9.18 × 10-5 Clinical benefit rateb      79.9 (75.6, 84.2)         73.1 (68.3, 77.8)       0.018 Patients with               n=257                     n=245 measurable disease
Overall response ratea      54.5 (48.4, 60.6)         38.8 (32.7, 44.9)       2.54 × 10-4 Clinical benefit rateb      80.2 (75.3, 85.0)         71.8 (66.2, 77.5)       0.018 a
ORR: Overall response rate = proportion of patients with complete response + partial response b
CBR: Clinical benefit rate = proportion of patients with complete response + partial response (+ stable disease or non-complete response/Non-progressive disease ≥24 weeks) c p-values are obtained from one-sided Cochran-Mantel-Haenszel chi-square test 
Final OS analysis
The results from this final OS analysis on the overall study population are provided in Table 10 and Figure 2.

Table 10    MONALEESA-2 - Efficacy results (OS) (10 June 2021 cut-off) 
Overall survival, overall              Kisqali plus letrozole              Placebo plus letrozole study population                               N=334                              N=334 Number of events – n [%]                     181 (54.2)                          219 (65.6) Median OS [months] (95%                    63.9 (52.4, 71.0)                  51.4 (47.2, 59.7) CI)
Hazard ratioa (95% CI)                                      0.765 (0.628, 0.932) p-valueb                                                           0.004 OS event-free rate, (%) (95%
CI)
24 months                                  86.6 (82.3, 89.9)                  85.0 (80.5, 88.4)
60 months                                  52.3 (46.5, 57.7)                  43.9 (38.3, 49.4) 72 months                                  44.2 (38.5, 49.8)                  32.0 (26.8, 37.3) CI=confidence interval a
Hazard ratio is obtained from stratified Cox PH model b p value is obtained from the one-sided log rank test (p<0.0219 to claim superior efficacy).
Stratification performed by lung and/or liver metastases status as per IRT 


KIS API JUL24 V9                                                           EU SmPC JUN 24 18
Figure 2                                MONALEESA-2 - Kaplan-Meier plot of OS in overall population (10 June 2021 Event-free probability (%)            cut-off)



Censoring times
Ribociclib (N = 334)
Placebo (N = 334)

No. of events
Ribociclib: 181, Placebo: 219
Hazard Ratio = 0.765
95% CI [0.628, 0.932]
Kaplan-Meier median
Ribociclib: 63.9 months
Placebo: 51.4 months
Log-rank p-value = 0.004


Time (Months)
Number of patients still at risk
Time
Ribociclib
Placebo


Log-rank test and Cox PH model are stratified by liver and/or lung metastasis as per IRT.
One sided P-value is obtained from stratified log rank test.

Study CLEE011E2301 (MONALEESA-7)
Kisqali was evaluated in a randomised, double-blind, placebo-controlled, multicentre phase III clinical study in the treatment of pre- and perimenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer in combination with a NSAI or tamoxifen plus goserelin versus placebo in combination with a NSAI or tamoxifen plus goserelin. Patients in MONALEESA-7 had not received prior endocrine treatment in the advanced breast cancer setting.

A total of 672 patients were randomised in a 1:1 ratio to receive either Kisqali 600 mg plus NSAI/tamoxifen plus goserelin (n=335) or placebo plus NSAI/tamoxifen plus goserelin (n=337), stratified according to: the presence of liver and/or lung metastases (Yes [n=344 (51.2%)] versus No [n=328 (48.8%)]), prior chemotherapy for advanced disease (Yes [n=120 (17.9%)] versus 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. Kisqali was given orally at a dose of 600 mg daily for 21 consecutive days followed by 7 days off treatment in combination with NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen (20 mg) orally once daily for 28 days, and goserelin (3.6 mg) subcutaneously every 28 days, until disease progression or unacceptable toxicity. Patients were not allowed to cross over from placebo to Kisqali during the study or after disease progression. Switching the endocrine combination partners was also not permitted.

Patients enrolled in this study had a median age of 44 years (range 25 to 58) and 27.7% of patients were younger than 40 years old. The majority of patients included were Caucasian (57.7%), Asian (29.5%) or Black (2.8%) and nearly all patients (99.0%) had a baseline ECOG performance status of 0 or 1. Prior to study entry, of these 672 patients, 14% of patients had received prior chemotherapy for metastatic disease, 32.6% of patients had received chemotherapy in the adjuvant and 18.0% in the neoadjuvant setting; 39.6% had received endocrine therapy in the adjuvant setting and 0.7% in the neoadjuvant setting. In study E2301 40.2% of patients had de novo metastatic disease, 23.7% had bone-only disease, and 56.7% had visceral disease.


KIS API JUL24 V9                                                                            EU SmPC JUN 24 19
The study met the primary endpoint at the primary analysis conducted after 318 progression-free survival (PFS) events based on the investigator assessment using RECIST v1.1 criteria in the full analysis set (all randomised patients). The primary efficacy results were supported by PFS results based on blinded independent central radiological assessment. The median follow-up time at the time of primary PFS analysis was 19.2 months.

In the overall study population, the efficacy results demonstrated a statistically significant improvement in PFS in patients receiving Kisqali plus NSAI/tamoxifen plus goserelin compared to patients receiving placebo plus NSAI/tamoxifen plus goserelin (hazard ratio of 0.553, 95% CI: 0.441, 0.694, one-sided stratified log-rank test p-value 9.83x10-8) with clinically meaningful treatment effect.
Median PFS was 23.8 months (95% CI: 19.2, NE) for Kisqali plus NSAI/tamoxifen plus goserelin treated patients and 13.0 months (95% CI: 11.0, 16.4) for patients receiving placebo plus NSAI/tamoxifen plus goserelin.

Distribution of PFS is summarised in the Kaplan-Meier curve for PFS in Figure 3.

Figure 3                              MONALEESA-7 - Kaplan-Meier plot of PFS in overall population based on investigator assessment
Event-free probability (%)



Censoring times
Ribociclib (N=335)
Placebo (N=337)
No of events
Ribociclib: 131, Placebo: 187
Hazard Ratio = 0.553
95% CI [0.441, 0.694]
Kaplan-Meier median
Ribociclib: 23.8 months
Placebo: 13.0 months
Log rank p-value = 9.83*10^(-8)

Time (Months)
Number of patients still at risk
Time (months)
Ribociclib
Placebo


The results for PFS based on the blinded independent central radiological assessment of a randomly selected subset of approximately 40% of randomised patients were supportive of the primary efficacy results based on the investigator’s assessment (hazard ratio of 0.427; 95% CI: 0.288, 0.633).

At the time of the primary PFS analysis overall survival data were not mature with 89 (13%) of deaths (HR 0. 916 [95% CI: 0.601, 1.396]).

Overall response rate (ORR) per investigator assessment based on RECIST v1.1 was higher in the Kisqali 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). The observed clinical benefit rate (CBR) was higher in Kisqali arm (79.1%; 95% CI: 74.8:83.5) compared to placebo arm (69.7%; 95% CI: 64.8:74.6, p=0.002).

In the pre-specified subgroup analysis of 495 patients who had received Kisqali or placebo in combination with NSAI plus goserelin, the median PFS was 27.5 months (95% CI: 19.1, NE) in the Kisqali plus NSAI subgroup and 13.8 months (95% CI: 12.6, 17.4) in the placebo plus NSAI subgroup [HR: 0.569; 95% CI: 0.436, 0.743]. Efficacy results are summarised in Table 11 and the Kaplan-Meier curves for PFS are provided in Figure 4.

KIS API JUL24 V9                                                                          EU SmPC JUN 24 20
Table 11                                MONALEESA-7 - Efficacy results (PFS) in patients who received NSAI 
Kisqali plus NSAI        Placebo plus NSAI plus goserelin           plus goserelin
N=248                     N=247
Progression free survivala
Median PFS [months] (95% CI)                 27.5 (19.1, NE)                 13.8 (12.6 – 17.4) Hazard ratio (95% CI)                                     0.569 (0.436, 0.743) CI=confidence interval; N=number of patients; NE = Not estimable.
a
PFS based on investigator radiological assessment

Figure 4                                MONALEESA-7 – Kaplan-Meier plot of PFS based on investigator assessment in patients who received NSAI
Event-free probability (%)



Censoring times
Ribociclib (N=248)
Placebo (N=247)

No of events
Ribociclib: 92, Placebo: 132
Hazard Ratio = 0.569
95% CI [0.436, 0.743]
Kaplan-Meier median
Ribociclib: 27.5 months
Placebo: 13.8 months


Time (Months)
Number of patients still at risk
Time (months)
Ribociclib
Placebo


Efficacy results for overall response rate (ORR) and clinical benefit rate (CBR) per investigator assessment based on RECIST v1.1 are provided in Table 12.

Table 12                                MONALEESA-7 - Efficacy results (ORR, CBR) based on investigator assessment in patients who received NSAI

Analysis                                                          Kisqali plus NSAI plus   Placebo plus NSAI plus goserelin                goserelin
(%, 95% CI)               (%, 95% CI)
Full analysis set                                                         N=248                     N=247 Overall response rate (ORR)a                                         39.1 (33.0, 45.2)         29.1 (23.5, 34.8) Clinical benefit rate (CBR)b                                         80.2 (75.3, 85.2)         67.2 (61.4, 73.1) Patients     with      measurable                                         n=192                     n=199 disease
Overall response ratea                      50.5 (43.4, 57.6)                 36.2 (29.5, 42.9) Clinical benefit rateb                      81.8 (76.3, 87.2)                 63.8 (57.1, 70.5) a
ORR: proportion of patients with complete response + partial response b
CBR: proportion of patients with complete response + partial response + (stable disease or non-complete response/Non-progressive disease ≥24 weeks)


KIS API JUL24 V9                                                                             EU SmPC JUN 24 21
Results in the Kisqali plus NSAI subgroup were consistent across subgroups of age, race, prior adjuvant/ neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease.

A more mature update of overall survival data (30 November 2018 cut-off) is provided in Table 13 and Figures 5 and 6.

In the second OS analysis the study met its key secondary endpoint demonstrating a statistically significant improvement in OS.

Table 13     MONALEESA-7 – Efficacy results (OS) (30 November 2018 cut-off) 

Updated analysis
Overall survival, overall          Kisqali 600 mg                       Placebo study population                   N=335                                N=337 Number of events – n [%]           83 (24.8)                            109 (32.3) Median OS [months] (95% CI) NE (NE, NE)                                 40.9 (37.8, NE) Hazard ratio (95% CI)                                       0.712 (0.535, 0.948) p-valuea                                                           0.00973 Overall survival, NSAI             Kisqali  600 mg                      Placebo subgroup                           n=248                                n=247 Number of events – n [%]           61 (24.6)                            80 (32.4) Median OS [months] (95% CI) NE (NE, NE)                                 40.7 (37.4, NE) Hazard ratio (95% CI)                                       0.699 (0.501, 0.976) CI=confidence interval, NE=not estimable, N=number of patients;
a p-value is obtained from the one-sided log-rank test stratified by lung and/or liver metastases, prior chemotherapy for advanced disease, and endocrine partner per IRT (interactive response technology).



KIS API JUL24 V9                                                            EU SmPC JUN 24 22
Figure 5                  MONALEESA-7- Kaplan Meier plot of final OS analysis (30 November 2018 cut- off)



Censoring Times
Event-free probability (%)



Ribociclib (N=335)
Placebo (N=337)

No of events
Ribociclib: 83, Placebo: 109

Hazard Ratio = 0.712
95% CI [0.535, 0.948]
Kaplan-Meier median
Ribociclib: NE
Placebo: 40.9 months
Log-rank p-value = 0.00973


Number of patients still at risk     Time (Months)
Time (months)
Ribociclib
Placebo


Log-rank test and Cox model are stratified by lung and/or liver metastasis, prior chemotherapy for advanced disease, and endocrine combination partner per IRT


Figure 6                  MONALEESA-7- Kaplan Meier plot of final OS analysis in patients who received NSAI (30 November 2018 cut-off)


Censoring Times
Event-free probability (%)



Ribociclib (N=248)
Placebo (N=247)

No of events
Ribociclib: 61, Placebo: 80

Hazard Ratio = 0.699
95% CI [0.501, 0.976]
Kaplan-Meier median
Ribociclib: NE
Placebo: 40.7 months



Time (Months)
Number of patients still at risk
Time (months)
Ribociclib
Placebo
Hazard ratio is based on unstratified Cox model.

Additionally, the probability of progression on next-line therapy or death (PFS2) in patients who received prior ribociclib in the study was lower compared to patients in the placebo arm with an HR of 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) for the ribociclib 
KIS API JUL24 V9                                                                EU SmPC JUN 24 23
arm. Similar results were observed for the NSAI subgroup, with an HR of 0.660 (95% CI: 0.503, 0.868) and a median PFS2 of 32.3 months (95% CI: 26.9, 38.3) in the placebo arm versus not reached (95% CI: 39.4, NE) in the ribociclib arm.

Study CLEE011F2301 (MONALEESA-3)
Kisqali was evaluated in a 2:1 randomised double-blind, placebo-controlled, multicentre phase III clinical study in 726 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who had received no or only one line of prior endocrine treatment, in combination with fulvestrant versus fulvestrant alone.

Patients enrolled in this study had a median age of 63 years (range 31 to 89). 46.7% of patients were of age 65 years and older, including 13.8% patients of age 75 years and older. The patients included were Caucasian (85.3%), Asian (8.7%) or Black (0.7%) and 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% had de novo metastatic disease). Prior to study entry 42.7% of patients had received chemotherapy in the adjuvant and 13.1% in the neoadjuvant setting, while 58.5% had received endocrine therapy in the adjuvant and 1.4% in the neoadjuvant setting and 21% had received prior endocrine therapy in the advanced breast cancer setting. In study F2301 21.2% had bone-only disease and 60.5% had visceral disease.

Primary analysis
The study met the primary endpoint at the primary analysis conducted after 361 progression-free survival (PFS) events based on the investigator assessment and using RECIST v1.1 criteria in the full analysis set (all randomised patients, 03 November 2017 cut-off). The median follow-up time at the time of primary PFS analysis was 20.4 months.

The primary efficacy results demonstrated a statistically significant improvement in PFS in patients receiving Kisqali plus fulvestrant compared to patients receiving placebo plus fulvestrant in the full analysis set (hazard ratio of 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 favour of the
Kisqali plus fulvestrant arm.

The primary efficacy results were supported by a random central audit of 40% imaging subset by a blinded independent central radiological assessment (hazard ratio of 0.492; 95% CI: 0.345, 0.703).

A descriptive update of PFS was performed at the time of the second OS interim analysis, and the updated PFS results on the overall population and the subgroups based on prior endocrine therapy are summarised in Table 14 and the Kaplan-Meier curve is provided in Figure 7.



KIS API JUL24 V9                                                           EU SmPC JUN 24 24
Table 14               MONALEESA-3 (F2301) - Updated PFS results based on investigator assessment (03 June 2019 cut-off)

Kisqali plus fulvestrant         Placebo plus fulvestrant
N=484                             N=242
Progression free survival overall study population
Number of events- n [%]                        283 (58.5)                        193 (79.8) Median PFS [months] (95% CI)                20.6 (18.6, 24.0)                 12.8 (10.9, 16.3) Hazard ratio (95% CI)                                     0.587 (0.488, 0.705) First-line setting subgroupa             Kisqali plus fulvestrant          Placebo plus fulvestrant n=237                             n=128
Number of events- n [%]                       112 (47.3)                         95 (74.2) Median PFS [months] (95% CI)               33.6 (27.1, 41.3)                 19.2 (14.9, 23.6) Hazard ratio (95% CI)                                     0.546 (0.415, 0.718) Second-line setting or early             Kisqali plus fulvestrant          Placebo plus fulvestrant relapse subgroupb                                n=237                             n=109 Number of events- n [%]                        167 (70.5)                         95 (87.2) Median PFS [months] (95% CI)                14.6 (12.5, 18.6)                  9.1 (5.8, 11.0) Hazard ratio (95% CI)                                     0.571 (0.443, 0.737) CI=confidence interval a patients with de novo advanced breast cancer with no prior endocrine therapy, and patients who relapsed after 12 months of (neo)adjuvant endocrine therapy completion.
b patients whose disease relapsed during adjuvant therapy or within 12 months of (neo)adjuvant endocrine therapy completion, and patients who had progression after one line of endocrine therapy for advanced disease.



Figure 7               MONALEESA-3 (F2301) – Kaplan-Meier plot of PFS based on investigator assessment (FAS) (03 June 2019 cut-off)

10

Censoring Times
8                                                                                                                   Ribociclib+Fulvestrant (N = 484) Placebo+Fulvestrant (N = 242)
E v e nt 6
- fr e e p 4 r               No. of events o               Ribociclib+Fulvestrant: 283, Placebo+Fulvestyrant: 193 b a               Hazard Ratio = 0.587 bi 2            95% CI [0.488, 0.705]

Kaplan-Meier median
Ribociclib+Fluvestrant: 20.6 Months
Placebo+Fulvestrant: 12.8 Months
0

0  2  4
KIS API JUL24 V96                        8     10      12     14     16    18    20      22      24    26    28    30    32    34 EU   36
SmPC38  40
JUN 42
24                  44   46
Time (months)
25
Ribociclib 484     403    364    346     323    305    282    258    239   225   205     198     181   174   159   156   149   127      92    65     29     11    4    0 Placebo 242        195    168    156     144    134    116    106     98    88    82        68    62    59   51     47   45     41     21     13      6     2     1    0 Efficacy results for overall response rate (ORR) and clinical benefit rate (CBR) per investigator assessment based on RECIST v1.1 are provided in Table 15.

Table 15     MONALEESA-3 - Efficacy results (ORR, CBR) based on investigator assessment (03 November 2017 cut-off)

Analysis                             Kisqali plus fulvestrant       Placebo plus fulvestrant (%, 95% CI)                    (%, 95% CI)
Full analysis set                    N=484                          N=242 a
Overall response rate (ORR)          32.4 (28.3, 36.6)              21.5 (16.3, 26.7) Clinical benefit rate (CBR)b         70.2 (66.2, 74.3)              62.8 (56.7, 68.9) Patients    with      measurable n=379                              n=181 disease
Overall response ratea               40.9 (35.9, 45.8)              28.7 (22.1, 35.3) Clinical benefit rateb               69.4 (64.8, 74.0).             59.7 (52.5, 66.8) a
ORR: proportion of patients with complete response + partial response b
CBR: proportion of patients with complete response + partial response + (stable disease or non-complete response/Non-progressive disease ≥24 weeks)

Hazard ratios based on pre-specified subgroup analysis of the patients treated with Kisqali plus fulvestrant showed consistent benefit across different subgroups including age, prior treatment (early or advanced), prior adjuvant/neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement and bone-only metastatic disease.

OS Analysis
In the second OS analysis the study met its secondary endpoint, demonstrating a statistically significant improvement in OS.

The results from this final OS analysis on the overall study population and the subgroups analysis are provided in Table 16 and Figure 8.

Table 16     MONALEESA-3 (F2301) Efficacy results (OS) (03 June 2019 cut-off) 
Kisqali plus fulvestrant            Placebo plus fulvestrant

Overall study population                     N=484                               N=242 Number of events - n [%]                    167 (34.5)                          108 (44.6) Median OS [months] (95%
CI)                                       NE, (NE, NE)                          40 (37, NE) HR (95% CI)a                                             0.724 (0.568, 0.924) p valueb                                                       0.00455 First line setting subgroup                   n=237                               n=128 Number of events - n [%]                     63 (26.6)                           47 (36.7) HR (95% CI)c                                             0.700 (0.479, 1.021) Second-line setting or early n=237                               n=109 relapse subgroup
Number of events - n [%]                    102 (43.0)                           60 (55.0) HR (95% CI)c                                             0.730 (0.530, 1.004) NE = Not estimable


KIS API JUL24 V9                                                           EU SmPC JUN 24 26
a
Hazard ratio is obtained from the Cox PH model stratified by lung and/or liver metastasis, previous endocrine therapy.
b
One-sided P-value is obtained from log-rank test stratified by lung and/or liver metastasis, previous endocrine therapy per IRT. P-value is one-sided and is compared against a threshold of 0.01129 as determined by the Lan-DeMets (O’Brien-Fleming) alpha-spending function for an overall significance level of 0.025.
c
Hazard ratio is obtained from the unstratified Cox PH model.

Figure 8                MONALEESA-3 (F2301) -Kaplan-Meier plot of OS (full analysis set [FAS]) (03 June 2019 cut-off)

10



8
Ev en                         Censoring Times t-                        Ribociclib+Fulvestrant (N = 484) fre                        Placebo+Fulvestrant (N = 242) e6 pr ob          No. of events abi         Ribociclib+Fulvestrant: 167, Placebo+Fulvestyrant: 108 lity
(% 4        Hazard Ratio = 0.724
)         95% CI [0.568, 0.924]
Kaplan-Meier median
2        Ribociclib+Fluvestrant: NE
Placebo+Fulvestrant: 40.0 Months

Log-rant p-value = 0.00455

0
0      2      4      6      8     10    12     14     16     18    20    22    24    26    28    30   32   34    36    38    40   42   44   46   48 
Time (months)

Ribociclib 484     470    454 444        436   428 414      402    397    389   374   365   348   334   326   309 300   287   237   159   92   41   14   2    0 Placebo 242        233    227     223    218   213    207   199    194    187   184   174   169   159   155   147 141   134   107   64    37   14   3    0    0 


Log-rank test and Cox model are stratified by lung and/or liver metastasis, prior chemotherapy for advanced disease, and endocrine combination partner per IRT

Time to progression on next-line therapy or death (PFS2) in patients in the Kisqali 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 Kisqali arm and 29.4 months (95% CI: 24.1, 33.1) in the placebo arm.

Elderly patients
Of all patients who received Kisqali in studies MONALEESA-2 and MONALEESA-3, representative proportions of patients were ≥65 years and ≥75 years of age (see section 5.1). No overall differences in safety or effectiveness of Kisqali were observed between these patients and younger patients (see section 4.2).

Patients with renal impairment
In the three pivotal studies (MONALEESA-2, MONALEESA-3 and MONALEESA-7), 510 (53.8%) patients with normal renal function, 341 (36%) patients with mild renal impairment and 97 (10.2%) patients with moderate renal impairment were treated with ribociclib. No patient with severe renal impairment was enrolled. PFS results were consistent in patients with mild and moderate renal impairment who received ribociclib at the starting dose of 600 mg as compared to those with normal renal function. The safety profile was generally consistent across renal cohorts (see section 4.8).



KIS API JUL24 V9                                                                                                             EU SmPC JUN 24 27

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of ribociclib were investigated in patients with advanced cancer following oral daily doses of 50 mg to 1200 mg. Healthy subjects received single oral doses ranging from 400 mg to 600 mg or repeated daily doses (8 days) at 400 mg.

Absorption

The geometric mean absolute bioavailability of ribociclib after a single oral dose of 600 mg was 65.8% in healthy subjects.

The time to reach Cmax (Tmax) following ribociclib oral administration was between 1 and 4 hours.
Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose range tested (50 to 1200 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: 0.97 to 6.40).

Food effect
Compared to the fasted state, oral administration of a single 600 mg dose of ribociclib film-coated tablets with a high-fat, high-calorie meal had no effect on the rate and extent of absorption of ribociclib.

Distribution

Binding of ribociclib to human plasma proteins in vitro was approximately 70% and was independent of concentration (10 to 10000 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 1090 L based on population pharmacokinetic analysis.

Biotransformation

In vitro and in vivo studies indicated ribociclib is eliminated primarily via 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. The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide). Clinical activity (pharmacological and safety) of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites.

Ribociclib was extensively metabolised, with unchanged drug accounting for 17.3% and 12.1% of the dose in faeces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in faeces and urine, respectively. Numerous other metabolites were detected in both faeces 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 apparent plasma terminal half-life (T1/2) 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 and its metabolites are eliminated mainly via faeces, with a small contribution of the renal 
KIS API JUL24 V9                                                           EU SmPC JUN 24 28
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 22 days; faeces was the major route of excretion (69.1%), with 22.6% of the dose recovered in urine.

Linearity/non-linearity

Ribociclib exhibited slightly over-proportional increases in exposure (Cmax and AUC) across the dose range of 50 mg to 1200 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 assessed in a renal impairment study that included 14 healthy 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 ribociclib dose of 400 mg.

AUCinf increased 1.6-fold, 1.9-fold and 2.7-fold and Cmax increased 1.8- fold, 1.8-fold and 2.3-fold in subjects with mild, moderate and severe renal impairment relative to the exposure in subjects with normal renal function. Since the efficacy and safety studies of ribociclib included a large proportion of patients with mild renal impairment (see section 5.1), data from the subjects with moderate or severe renal impairment in the renal impairment study were also compared with pooled data for the subjects with normal renal function and mild renal impairment. Compared to the pooled data for the subjects with normal renal function and mild renal impairment, AUCinf increased 1.6-fold and 2.2-fold and Cmax increased 1.5-fold and 1.9-fold in subjects with moderate and severe renal impairment, respectively. A fold difference for subjects with ESRD was not calculated due to the small number of subjects, but results indicate a similar or somewhat larger increase in ribociclib exposure compared to subjects with severe renal impairment.

The effect of renal function on the pharmacokinetics of ribociclib was also assessed in cancer patients included in efficacy and safety studies where patients were given the 600 mg start dose (see section 5.1). In a sub-group analysis of pharmacokinetic data from studies in cancer patients following oral administration of 600 mg ribociclib as a single dose or repeat doses, AUCinf and Cmax of ribociclib in patients with mild (n=57) or moderate (n=14) renal impairment were comparable to the AUCinf and Cmax in patients with normal renal function (n=86), suggesting no clinically meaningful effect of mild or moderate renal impairment on ribociclib exposure.

Hepatic impairment
Based on a pharmacokinetic study in non-cancer subjects with hepatic impairment, mild hepatic impairment had no effect on the exposure of ribociclib (see section 4.2). The mean exposure for ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment (see section 4.2).

Based on a population pharmacokinetic analysis that included 160 breast cancer 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. Ribociclib has not been studied in breast cancer patients with moderate or severe hepatic impairment.


KIS API JUL24 V9                                                           EU SmPC JUN 24 29
Effect of age, weight, gender and race
Population pharmacokinetic analysis showed that there are no clinically relevant effects of age, body weight or gender on the systemic exposure of ribociclib that would require a dose adjustment. Data on differences in pharmacokinetics due to race are too limited to draw conclusions.

In vitro interaction data

Effect of ribociclib on cytochrome P450 enzymes
In vitro, ribociclib is 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. Ribociclib has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6.

In vitro data indicate that ribociclib has no potential to induce UGT enzymes or the CYP enzymes CYP2C9, CYP2C19 and CYP3A4 via PXR. Therefore, Kisqali is unlikely to affect substrates of these enzymes. In vitro data are not sufficient to exclude a potential of ribociclib to induce CYP2B6 via CAR.

Effect of transporters on ribociclib
Ribociclib is a substrate for P-gp in vitro, but based on mass balance data inhibition of P-gp or BCRP is unlikely to affect ribociclib exposure at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1, OATP1B3 or OCT-1 in vitro.

Effect of ribociclib on transporters
In vitro evaluations indicated that ribociclib has a potential to inhibit the activities of drug transporters P-gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP. Ribociclib did not inhibit OAT1, OAT3 or MRP2 at clinically relevant concentrations in vitro.