Kiskali film-coated tablets 200 mg blister No. 63

Instructions Kiskali film-coated tablets 200 mg blister No. 63

Composition

active substance: ribociclib;

1 tablet contains ribociclib succinate, equivalent to ribociclib 200 mg;

Excipients: microcrystalline cellulose, crospovidone (type A), low-substituted hydroxypropylcellulose, magnesium stearate, colloidal anhydrous silica, black iron oxide (E 172), red iron oxide (E 172), soy lecithin, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide (E 171), xanthan gum.

Dosage form

Film-coated tablets.

Main physicochemical properties:

round, curved tablets with beveled edges, light grayish-purple in color, without a score, embossed with “RIC” on one side and “NVR” on the other.

Pharmacotherapeutic group

Antineoplastic agents. Protein kinase inhibitors.

ATX code L01X E42.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Ribociclib is a selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6, and results in 50% inhibition (IC50) in biochemical assays at concentrations of 0.01 (4.3 ng/mL) and 0.039 μM (16.9 ng/mL), respectively. These kinases are activated upon binding to D-cyclins and play a critical role in signaling pathways that regulate cell cycle progression and cell proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression by phosphorylating the retinoblastoma protein (pRb).

In vitro, ribociclib reduced pRb phosphorylation, resulting in G1 cell cycle arrest and reduced cell proliferation in breast cancer cell lines. In vivo, ribociclib monotherapy resulted in tumor regression, consistent with inhibition of pRb phosphorylation.

In in vivo studies using a patient-derived estrogen receptor (ER+) breast cancer xenograft model, the combination of ribociclib and antiestrogens (e.g., letrozole) resulted in greater tumor growth inhibition with sustained tumor regression and delayed tumor regrowth after treatment discontinuation compared to either agent alone. In addition, the antitumor activity of ribociclib in combination with fulvestrant was evaluated in vivo in immunodeficient mice bearing ER+ human breast cancer ZR751 xenografts; this combination resulted in complete tumor growth inhibition.

Analysis of a panel of breast cancer cell lines with known ER status demonstrated greater efficacy of ribociclib in ER+ breast cancer cell lines than in ER- breast cancer cell lines. In the preclinical models tested, intact pRb was required for ribociclib to be active.

Electrophysiology of the heart.

To assess the effect of ribociclib on the QTc interval in patients with advanced cancer, ECGs were performed three times after a single dose at steady state. A total of 997 patients treated with ribociclib at doses ranging from 50 to 1200 mg were included in the pharmacokinetic and pharmacodynamic analyses. The analysis showed that ribociclib caused a concentration-dependent increase in the QTc interval. The estimated mean change from baseline in QTcF when Kisqali 600 mg was used in combination with a non-steroidal aromatase inhibitor (NSAID) or fulvestrant was 22.0 ms (90% CI: 20.56, 23.44) and 23.7 ms (90% CI: 22.31, 25.08), respectively, at geometric mean Cmax at steady state compared to 34.7 ms (90% CI: 31.64, 37.78) when used in combination with tamoxifen (see section 4.4).

Clinical efficacy and safety.

Study CLEE011A2301 (MONALEESA-2).

Kisqali was evaluated in a randomized, double-blind, placebo-controlled, multicenter, phase III clinical trial in postmenopausal women with hormone receptor-positive, HER2 (human epidermal growth factor receptor type 2)-negative advanced breast cancer who had not previously received therapy for advanced disease, in combination with letrozole compared with letrozole alone.

The median age of patients enrolled in this study was 62 years (range 23 to 91). 44.2% of patients were over 65 years of age, including 69 patients over 75 years of age. The patients were of Caucasian (82.2%), Asian (7.6%), and African American (2.5%) race. All patients had an ECOG performance status of 0 or 1. In the Kisqali arm, 43.7% of patients had received neoadjuvant or adjuvant chemotherapy, and 52.4% had received neoadjuvant or adjuvant hormonal therapy prior to enrollment. 34.1% of patients were de novo (newly diagnosed). 20.7% of patients had bone metastases only, and 59.0% had visceral metastases. Patients who had previously received (neo)adjuvant anastrozole or letrozole therapy were required to have completed this therapy for at least 12 months prior to randomization.

The primary endpoint of the study was met at a planned interim analysis conducted after observing 80% of the planned progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) based on investigator assessment in the entire population (all randomized patients), and confirmed by independent central radiology review of masked data.

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

Global health status/quality of life data showed no difference between the Kisqali and letrozole group and the placebo and letrozole group.

A more recent update of the effectiveness data (data cut-off date January 2, 2017) is provided in Tables 1 and 2.

The median PFS was 25.3 months (95% CI: 23.0, 30.3) for patients receiving ribociclib and letrozole and 16.0 months (95% CI: 13.4, 18.2) for patients receiving placebo and letrozole. 54.7% of patients receiving ribociclib and letrozole were free of disease progression at 24 months compared with 35.9% in the placebo and letrozole group.

There was no statistically significant difference in overall survival (OS) between the Kisqali plus letrozole group and the placebo plus letrozole group (HR 0.746 [95% CI: 0.517, 1.078]). OS data remain incomplete.

Table 1

MONALEESA-2 – Efficacy assessment results (PFS) based on investigator radiological assessment (data cut-off date 2 January 2017)

MONALEESA-2 – Kaplan–Meier plot for PFS based on investigator assessment (data cut-off date 2 January 2017)

Time (months)

A series of PFS analyses were performed in pre-specified subgroups based on prognostic factors and baseline characteristics to examine the internal consistency of the treatment effect. The reduction in the risk of disease progression or death in favor of the Kisqali plus letrozole group was observed in all individual patient subgroups by age, race, prior adjuvant or neoadjuvant chemotherapy or hormonal therapy, liver and/or lung involvement, and bone metastases only. The effect was evident in patients with liver and/or lung metastases (HR 0.561 [95% CI: 0.424, 0.743], median progression-free survival [mPFS] 24.8 months with Kisqali and letrozole compared to 13.4 months with letrozole alone) or without liver and/or lung metastases (HR 0.597 [95% CI: 0.426, 0.837], median progression-free survival [mPFS] 27.6 months compared to 18.2 months).

Updated results for overall response and clinical efficacy rates are shown in Table 2.

Table 2

MONALEESA-2 – efficacy evaluation results (QZVa, QKEb) based on investigator assessment (data collection end date January 2, 2017)

Study CLEE011E2301 (MONALEESA-7).

Kisqali was evaluated in a randomized, double-blind, placebo-controlled, multicenter, phase III clinical trial in pre- and perimenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer in combination with a NSAID or tamoxifen and goserelin compared to placebo in combination with a NSAID or tamoxifen and goserelin. Patients in MONALEESA-7 had not received prior endocrine therapy for advanced breast cancer.

A total of 672 patients were randomised 1:1 to receive Kisqali 600 mg and a NSAID/tamoxifen and goserelin (n = 335) or placebo and a NSAID/tamoxifen and goserelin (n = 337) and stratified by the presence of liver and/or lung metastases (yes [n = 344 (51.2%)] or no [n = 328 (48.8%)]), prior chemotherapy for advanced disease (yes [n = 120 (17.9%)] or no [n = 552 (82.1%)]), and additional endocrine combination therapy (NSAID and goserelin [n = 493 (73.4%)] or tamoxifen and goserelin [n = 179 (26.6%)]). Demographic and baseline disease characteristics were balanced and comparable across study arms. Kisqali was administered orally at a dose of 600 mg daily for 21 consecutive days followed by a 7-day treatment rest period in combination with a NSAID (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. Changes in the additional agent in the endocrine combination therapy were also not permitted.

The primary endpoint of the study was met at the primary analysis, which was conducted after observing 318 progression-free survival (PFS) events based on investigator assessment using RECIST version 1.1 criteria in the entire population (all randomized patients). The primary efficacy outcome was confirmed by PFS results based on an independent central radiology review of masked data. The median follow-up time at the time of the primary PFS analysis was 19.2 months.

In the overall study population, the efficacy results demonstrated a statistically significant improvement in PFS in patients treated with Kisqali and NSAID/tamoxifen and goserelin compared with patients treated with placebo and NSAID/tamoxifen and goserelin (hazard ratio 0.553; 95% CI: 0.441, 0.694; one-sided stratified log-rank p-value 9.83 × 10-8) with a clinically meaningful treatment effect.

The median PFS was 23.8 months (95% CI: 19.2; not estimable (NE)) for patients receiving Kisqali and NSAID/tamoxifen and goserelin and 13.0 months (95% CI: 11.0, 16.4) for patients receiving placebo and NSAID/tamoxifen and goserelin.

The distribution of PFS is summarized in the Kaplan–Meier curve for PFS in Figure 2.

MONALEESA-7 – Kaplan–Meier plot for PFS in the overall population based on investigator assessment

Time (months)

Fig. 2.

PFS results based on independent central radiological assessment of masked data from a randomly selected subgroup of approximately 40% of randomised patients confirmed the primary efficacy results based on investigator assessment (hazard ratio 0.427; 95% CI: 0.288, 0.633).

At the time of the primary PFS analysis, overall survival data were incomplete, with 89 (13%) deaths (HR 0.916 [95% CI: 0.601, 1.396]).

The overall response rate (ORR) as assessed by the investigator using RECIST version 1.1 was higher in the Kisqali group (40.9%; 95% CI: 35.6, 46.2) compared to the placebo group (29.7%; 95% CI: 24.8, 34.6; p = 0.00098). The clinical efficacy rate (CER) was higher in the Kisqali group (79.1%; 95% CI: 74.8, 83.5) compared to the placebo group (69.7%; 95% CI: 64.8, 74.6; p = 0.002).

In a pre-specified subgroup analysis of 495 patients treated with Kisqali or placebo in combination with an NSAID and goserelin, the median PFS was 27.5 months (95% CI: 19.1, ND) in the Kisqali and NSAID subgroup and 13.8 months (95% CI: 12.6, 17.4) in the placebo and NSAID subgroup [HR: 0.569; 95% CI: 0.436, 0.743]. The efficacy results are presented in Table 3, and the Kaplan-Meier curves for PFS are presented in Figure 3.

MONALEESA-7 – Kaplan–Meier plot for PFS based on investigator assessment in patients treated with NSAID

Time (months)

Fig. 3.

The results of the efficacy evaluation in terms of overall response rate (ORR) and clinical efficacy rate (CFR) as assessed by the investigator based on RECIST version 1.1 criteria are presented in Table 4.

Results in the Kisqali and NSAID subgroup were consistent across subgroups for age, race, prior adjuvant/neoadjuvant chemotherapy or hormonal therapy, liver and/or lung involvement, and bone-only metastasis.

A more recent update of overall survival data (data cut-off date November 30, 2018) is provided in Table 5 and Figures 4 and 5.

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

Table 5

MONALEESA-7 – results of the performance evaluation (PE)

MONALEESA-7 – Kaplan-Meier plot for final analysis of OS (data collection end date November 30, 2018)

Time (months)

Number of patients still at risk

Time (months)

Ribociclib

Placebo

Fig. 4.

The log-rank test and Cox model were stratified by the presence of lung and/or liver metastases, prior chemotherapy for advanced disease, and additional drug in the combination endocrine therapy using interactive response technology (IRT).

MONALEESA-7 – Kaplan–Meier plot for final analysis of OS in patients treated with NSIA (data cut-off date November 30, 2018)

Time (months)

Number of patients still at risk

Time (months)

Ribociclib

Placebo

Fig. 5.

Additionally, the probability of progression on next-line therapy or death (PFS2) in patients who had previously received ribociclib in the study was lower compared to patients in the placebo group with a 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 group and not reached (95% CI: 39.4, NR) in the ribociclib group. Similar results were observed in the NSIA subgroup, with HR of 0.660 (95% CI: 0.503; 0.868) and median PFS2 of 32.3 months (95% CI: 26.9; 38.3) in the placebo group compared to not reached (95% CI: 39.4; NR) in the ribociclib group.

Study CLEE011F2301 (MONALEESA-3).

Kisqali was evaluated in a randomized, double-blind, placebo-controlled, multicenter, phase III clinical trial in postmenopausal men and women with hormone receptor-positive, HER2-negative advanced breast cancer who had not received or had received only one prior endocrine therapy in combination with fulvestrant compared with fulvestrant alone.

A total of 726 patients were randomised in a 2:1 ratio to receive Kisqali 600 mg plus fulvestrant (n = 484) or placebo plus fulvestrant (n = 242) and stratified by the presence of liver and/or lung metastases (yes [n = 351 (48.3%)] or no [n = 375 (51.7%)]) and prior endocrine therapy (A [n = 354 (48.8%)] vs. B [n = 372 (51.2%)]). Demographic and baseline disease characteristics were balanced and comparable across study arms. Kisqali 600 mg daily or placebo was administered orally for 21 consecutive days followed by a 7-day treatment break in combination with fulvestrant 500 mg intramuscularly once daily on days 1 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle. Patients were not allowed to cross over from placebo to Kisqali during the study or upon disease progression.

The median age of patients enrolled in this study was 63 years (range 31 to 89). 46.7% of patients were 65 years of age or older, including 13.8% of patients 75 years of age or older. Patients enrolled in the study were of Caucasian (85.3%), Asian (8.7%), and Black (0.7%) race, and almost all patients (99.7%) had a baseline ECOG performance status of 0 or 1. This study included first- and second-line patients (of whom 19.1% had de novo metastatic disease). At study entry, 42.7% of patients had received adjuvant chemotherapy and 13.1% had received neoadjuvant chemotherapy, while 58.5% of patients had received adjuvant endocrine therapy and 1.4% had received neoadjuvant endocrine therapy, and 21% had received prior endocrine therapy for advanced breast cancer. In study F2301, 21.2% of patients had metastases to bone only, and 60.5% of patients had metastases to visceral organs.

The primary endpoint of the study was met at the primary analysis, which was conducted after evaluating 361 progression-free survival (PFS) events based on investigator assessment using RECIST version 1.1 criteria in the entire population (all randomized patients). The primary efficacy outcome was confirmed by PFS results based on blinded independent central radiology review. The median follow-up time at the time of the primary PFS analysis was 20.4 months.

The primary efficacy outcome demonstrated a statistically significant improvement in PFS in patients treated with Kisqali plus fulvestrant compared with patients treated with placebo plus fulvestrant in the overall population (hazard ratio 0.593; 95% CI: 0.480, 0.732; one-sided stratified log-rank p-value 4.1 × 10-7) with an estimated relative risk reduction of 41% in favour of the Kisqali plus fulvestrant treatment group.

The median PFS was 20.5 months (95% CI: 18.5, 23.5) for patients receiving Kisqali and fulvestrant and 12.8 months (95% CI: 10.9, 16.3) for patients receiving placebo and fulvestrant.

The distribution of PFS is summarized in Table 6 and the Kaplan–Meier curve for PFS in Figure 6.

MONALEESA-3 – Kaplan–Meier plot for PFS based on investigator assessment

Fig. 6.

PFS results based on independent central radiological assessment of masked data from a randomly selected subgroup of approximately 40% of randomised patients confirmed the primary efficacy results based on investigator assessment (hazard ratio 0.492; 95% CI: 0.345, 0.703).

At the time of the primary PFS analysis, overall survival data were incomplete and there were 120 (16.5%) deaths (HR 0.670 [95% CI: 0.465, 0.964]).

The results of the efficacy evaluation in terms of overall response rate (ORR) and clinical efficacy rate (CFR) as assessed by the investigator based on RECIST version 1.1 criteria are presented in Table 7.

In the subgroup of patients who had not received prior treatment for metastatic/advanced cancer, the hazard ratio was 0.577 (95% CI: 0.415, 0.802), with median PFS not reached in the Kisqali group and 18.3 months in the placebo group (95% CI: 14.8, 23.1).

In the subgroup of patients who had received no more than one prior therapy for metastatic/advanced cancer, the hazard ratio was 0.565 (95% CI: 0.428, 0.744), median PFS was 14.6 months (95% CI: 12.5, 18.5) and 9.1 months (95% CI: 6.1, 11.1) in the Kisqali and placebo groups, respectively. Within this subgroup, the hazard ratio for second-line patients who had received prior endocrine therapy for advanced breast cancer was 0.539 (95% CI: 0.333, 0.873), with median PFS of 18.8 months (95% CI: 12.5, ND) and 11.4 months (95% CI: 3.7, 16.3) in the Kisqali and placebo groups, respectively.

Hazard ratios based on analyses of pre-specified subgroups of patients treated with Kisqali and fulvestrant demonstrated consistent efficacy across subgroups, including age, race, prior treatment (early or advanced), prior adjuvant/neoadjuvant chemotherapy or hormonal therapy, liver and/or lung involvement, and bone metastases only.

Elderly patients.

Of all patients treated with Kisqali in MONALEESA-2 and MONALEESA-3, this age group included patients ≥ 65 years of age and ≥ 75 years of age. No overall differences in the safety or efficacy of Kisqali were observed between these patients and younger patients (see section 4.2).

Children.

The European Medicines Agency has deferred the obligation to submit the results of studies with Kisqali in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

Pharmacokinetics.

Pharmacokinetics of ribocycles