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Indications:1,2
- KISQALI® (ribociclib) is indicated for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy
- In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist
KISQALI is not recommended to be used in combination with tamoxifen.
Please refer to the Summary of Product Characteristics for the full safety profile and guidance regarding managing adverse events.
The adverse event profile of KISQALI is generally consistent across studies in pre- and postmenopausal patients with HR+/HER2– aBC1–11
The most common AEs were neutropenia, infections, nausea, fatigue, diarrhoea, leukopenia, vomiting, headache, constipation, alopecia, cough, rash, back pain, anaemia and abnormal liver function tests.1,2
Corresponding frequency category for each AR based on the CIOMS III: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data).1,2
| ADVERSE REACTION | FREQUENCY |
| Infections and infestations | |
| Infections* | Very common |
| Blood and lymphatic system disorders | |
| Neutropenia, leukopenia, anaemia, lymphopenia | Very common |
| Thrombocytopenia, febrile neutropenia | Common |
| Metabolism and nutrition disorders | |
| Decreased appetite | Very common |
| Hypocalcaemia, hypokalaemia, hypophosphataemia | Common |
| Nervous system disorders | |
| Headache, dizziness | Very common |
| Vertigo | Common |
| Eye disorders | |
| Lacrimation increased, dry eye | Common |
| Cardiac disorders | |
| Syncope | Common |
| Respiratory, thoracic and mediastinal disorders | |
| Dyspnoea, cough | Very common |
| Interstitial lung disease (ILD)/pneumonitis† | Common |
| ADVERSE REACTION | FREQUENCY |
| Gastrointestinal disorders | |
| Nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain,‡ dyspepsia | Very common |
| Dysgeusia | Common |
| Hepatobiliary disorders | |
| Hepatotoxicity§ | Common |
| Skin and subcutaneous tissue disorders | |
| Alopecia, rash,ǁ pruritus | Very common |
| Erythema, dry skin, vitiligo | Common |
| Toxic epidermal necrolysis (TEN)† | Not known |
| Musculoskeletal and connective tissue disorders | |
| Back pain | Very common |
| General disorders and administration site conditions | |
| Fatigue, peripheral oedema, asthenia, pyrexia | Very common |
| Dry mouth, oropharyngeal pain | Common |
| Investigations | |
| Abnormal liver function tests¶ | Very common |
| Blood creatinine increased, electrocardiogram QT prolonged | Common |
Adapted from KISQALI Summary of Product Characteristics.1,2
Permanent discontinuation was reported in 8.7% of patients receiving KISQALI + ET** in Phase III clinical trials.1,2
For further safety information, please refer to the Summary of Product Characteristics.1,2
Pooled safety data of adverse events of special interest (AESI), across MONALEESA-2, -3 and -7 studies10
| Pooled safety†† | ||
|---|---|---|
| Exposure-adjusted any-grade AESI irrespective of causality | n (incidence rate per 100 patient-treatment years)‡‡ | |
| KISQALI + ET** (n=1065) | Placebo + ET (n=818) | |
| Any AESI | 992 (561.4) | 543 (131.0) |
| Neutropenia | 788 (196.6) | 43 (5.1) |
| Leukopenia | 330 (34.9) | 36 (4.2) |
| Anaemia | 200 (18.2) | 51 (5.9) |
| Increased ALT | 161 (13.8) | 48 (5.7) |
| Increased AST | 150 (12.7) | 51 (6.0) |
| Prolonged QT interval | 69 (5.6) | 13 (1.5) |
Adapted from Tripathy D, et al. ESMO 2019.10
There were no new safety signals reported for KISQALI across follow-up OS analyses of the MONALEESA trials.3,4,8,11
Please see the respective Summary of Product Characteristics for further information on dose modifications and adjustments.
Contraindications
Hypersensitivity to the active substance or to peanut, soya, or any of the excipients in the KISQALI SmPC1,2
Special warnings and precautions for use:1,2
Critical visceral disease
The efficacy and safety of KISQALI have not been studied in patients with critical visceral disease.
Neutropenia
Based on the severity of the neutropenia, treatment with KISQALI may have to be interrupted, reduced or discontinued.
Hepatobiliary toxicity
Liver function tests should be performed before initiating treatment with KISQALI. After initiating treatment, liver function should be monitored.
Based on the severity of the transaminase elevations, treatment with KISQALI may have to be interrupted, reduced or discontinued. Recommendations for patients who have elevated AST/ALT grade ≥3 at baseline have not been established.
QT interval prolongation
ECG should be assessed before initiating treatment. Treatment with KISQALI should be initiated only in patients with QTcF values <450 msec. ECG should be repeated at approximately Day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated.
Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorus and magnesium) should be performed before initiating treatment, at the beginning of the first 6 cycles and then as clinically indicated. Any abnormality should be corrected before initiating treatment with KISQALI and during treatment with KISQALI.
The use of KISQALI should be avoided in patients who already have or who are at significant risk of developing QTc prolongation. This includes patients:
- with long QT syndrome;
- with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias;
- with electrolyte abnormalities
The use of KISQALI with medicinal products known to prolong QTc interval and/or strong CYP3A4 inhibitors should be avoided as this may lead to clinically meaningful prolongation of the QTcF interval. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the dose should be reduced to 400 mg once daily. Based on the observed QT prolongation during treatment, treatment with KISQALI may have to be interrupted, reduced or discontinued.
Severe cutaneous reactions
Toxic epidermal necrolysis has been reported with KISQALI treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g., progressive widespread skin rash often with blisters or mucosal lesions) appear, KISQALI should be discontinued immediately.
Interstitial lung disease/pneumonitis
Based on the severity of the ILD/pneumonitis, which may be fatal, KISQALI may require dose interruption, reduction or discontinuation.
Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough and dyspnoea, and dose modifications should be managed.
Blood creatine increase
KISQALI may cause blood creatinine increase as an inhibitor of the renal transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), which are involved in the active secretion of creatinine from the proximal tubules. In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.
CYP3A4 substrates
KISQALI is a strong CYP3A4 inhibitor at the 600 mg dose and a moderate CYP3A4 inhibitor at the 400 mg dose. Thus, KISQALI may interact with medicinal products which are metabolised via CYP3A4, which may lead to increased serum concentrations of CYP3A4 substrates. Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index, and the SmPC of the other product should be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors.
Renal impairment
The recommended starting dose of 200 mg for patients with severe renal impairment is estimated to result in approximately 45% lower exposure compared with the standard starting dose in patients with normal renal function. The e cacy at this starting dose has not been studied. Caution should be used in patients with severe renal impairment, with close monitoring for signs of toxicity.
Women of childbearing potential
Women of childbearing potential should be advised to use an e ective method of contraception while taking KISQALI and for at least 21 days after the last dose.
Soya lecithin
KISQALI contains soya lecithin. Patients who are hypersensitive to peanut or soya should not take KISQALI.
KISQALI + AI was generally well tolerated, with neutropenia and leukopenia the most common grade 3/4 AEs§§12
| KISQALI + AI (N=334) |
PLACEBO + AI (N=330) |
|
|---|---|---|
| Dose reductions due to AEs, % (n) | 54.5 (182) | 4.2 (14) |
| Discontinuations due to AEs, % (n) | 8.1 (27) | 2.4 (8) |
| Any grade AEs observed in ≥20% of patients in the KISQALI arm, % | Neutropenia, 76.9; Nausea, 53.3; Fatigue, 41.3; Diarrhoea, 38.3; Alopecia, 34.4; Vomiting, 33.5; Arthralgia, 33.2; Leukopenia, 32.9; Constipation, 27.8; Headache, 26.9; Hot flushes, 24.6; Back pain, 24.3; Cough, 23.1; Rash, 22.2; Anaemia, 21.3; Decreased appetite, 20.7; Abnormal LFTs, 20.1 |
Neutropenia, 5.8; Nausea, 30.6; Fatigue, 32.4; Diarrhoea, 24.5; Alopecia, 16.1; Vomiting, 16.7; Arthralgia, 32.7; Leukopenia, 4.5; Constipation, 21.5; Headache, 20.9; Hot flushes, 25.5; Back pain, 20.3; Cough, 21.2; Rash, 8.8; Anaemia, 5.8; Decreased appetite, 15.8; Abnormal LFTs, 6.4 |
| Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, % |
Neutropenia, 62.0; Leukopenia, 21.3; Abnormal LFTs, 10.2 |
Neutropenia, 1.2; Leukopenia, 0.9; Abnormal LFTs, 2.4 |
Source: Hortobagyi GN, et al. 2018.12
In the MONALEESA-2 protocol-specified final analysis of overall survival, no new safety signals were observed at a median follow-up of 6.6 years.3
MONALEESA-2: N=668, double-blind, placebo-controlled, 1:1 randomisation, multicentre, Phase III trial in postmenopausal women with HR+/HER2− aBC. As 1L in advanced disease and no prior endocrine therapy for aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + AI (letrozole 2.5 mg continuous).9
- The primary endpoint was locally assessed progression-free survival9
- The key secondary endpoint was overall survival9
- Other secondary endpoints included the overall response rate (complete or partial response), the clinical benefit rate (overall response plus stable disease lasting 24 weeks or more), safety, and quality-of-life assessments.9
The most frequent AEs in postmenopausal HR+/HER2− aBC patients in MONALEESA-3 were neutropenia, nausea and fatigue‖‖6
| KISQALI + FULVESTRANT (N=483) |
PLACEBO + FULVESTRANT (N=241) |
|
|---|---|---|
| Dose reductions due to AEs, % (n) | 33.1 (160) | 3.3 (8) |
| Discontinuations due to AEs, % (n) | 8.5 (41) | 4.1 (10) |
| Any grade AEs observed in ≥20% of patients in the KISQALI arm, % | Neutropenia, 69.6; Nausea, 45.3; Fatigue, 31.5; Diarrhoea, 29.0; Leukopenia, 28.4; Vomiting, 26.7; Constipation, 24.8; Arthralgia, 24.0; Cough, 21.7; Headache, 21.5 |
Neutropenia, 2.1; Nausea, 28.2; Fatigue, 33.2; Diarrhoea, 20.3; Leukopenia, 1.7; Vomiting, 12.9; Constipation, 11.6; Arthralgia, 26.6; Cough, 15.4; Headache, 20.3 |
| Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, % | Neutropenia, 53.4; Leukopenia, 14.1 | Neutropenia, 0; Leukopenia, 0 |
Source: Slamon DJ, et al. 2018.6
In a MONALEESA-3 exploratory analysis, there were no new safety signals detected at a median follow-up of ~4.5 years in HR+/HER2− postmenopausal women with aBC treated with KISQALI + fulvestrant.11
MONALEESA-3: N=726, double-blind, placebo-controlled, 2:1 randomisation, Phase III trial. As 1L and 2L in advanced disease plus those with early relapse in postmenopausal women with HR+/HER2− aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + 500 mg fulvestrant (administered intramuscularly on Day 1 of each 28-day cycle, with an additional dose on Day 15 of cycle 1).6
- The primary endpoint was locally assessed progression-free survival6
- Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate, and safety and tolerability6
Analyses were performed in the following subgroups:6
- Patients receiving 1L therapy
- Patients receiving 2L therapy plus those with early relapse (within 12 months after completion of adjuvant or neoadjuvant endocrine therapy)
Safety in MONALEESA-7
In MONALEESA-7, the majority of adverse events in pre- and perimenopausal HR+/HER2− aBC patients were generally manageable with dose modifications; few treatment discontinuations occurred due to adverse events.5
| KISQALI + AI + LHRH AGONIST (N=335) |
PLACEBO + AI + LHRH AGONIST (N=337) |
|
|---|---|---|
| Dose reductions due to AEs, % | 31 (104) | 5 (17) |
| Discontinuations due to AEs, % | 4 (alanine aminotransferase increase, 7; aspartate aminotransferase increase, 4; drug-induced liver injury, 3; prolonged QTcF, 1) | 3 (alanine aminotransferase increase, 0; aspartate aminotransferase increase, 1; drug-induced liver injury, 1; prolonged QTcF, 2) |
| Any grade AEs observed in ≥20% of patients in the KISQALI arm, % | Neutropenia, 76; Hot flush, 34; Nausea, 32; Leukopenia, 31; Arthralgia, 30; Fatigue, 23; Headache, 23; Anaemia, 21; Diarrhoea, 20 | Neutropenia, 8; Hot flush, 34; Nausea, 19; Leukopenia, 5; Arthralgia, 27; Fatigue, 25; Headache, 24; Anaemia, 10; Diarrhoea, 18. |
| Most common grade 3 or 4 AEs (≥5%) in the KISQALI arm, % | Neutropenia, 61; Leukopenia, 14¶¶ | Neutropenia, 4; Leukopenia, 1 |
Table adapted from Tripathy D, et al. 2018.5
MONALEESA-7: N=672, double-blind, placebo-controlled, 1:1 randomisation, Phase III trial in pre- and perimenopausal women with HR+/HER2− aBC. As 1L in advanced disease and in patients who received 1 or fewer lines of chemotherapy for aBC. KISQALI 600 mg or placebo orally once daily (3 weeks on/1 week off) + AI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen** 20 mg orally once daily continuously (KISQALI is not recommended to be used in combination with tamoxifen)** + LHRH agonist (goserelin 3.6 mg subcutaneously on Day 1 of every cycle).4
- The primary endpoint was investigator-assessed progression-free survival4
- The key secondary endpoint was overall survival, defined as the time from randomisation to death from any cause4
- Other secondary endpoints included: proportion of patients who achieved an objective response, clinical benefit, time to response, duration of response, time to definitive deterioration of ECOG performance status from baseline, time to 10% deterioration of EORTC QLQ-C30 and safety5
The MONALEESA safety findings were supported by evidence from the CompLEEment-1 study***13,14
| KISQALI + AI (N=3246) |
|
|---|---|
| Dose reductions due to AEs, n (%) (Neutropenia, ALT increased, AST increased, QTcF prolongation) | 21.4 |
|
Discontinuations due to AE s, n (%) |
16.3 |
| Any grade AEs observed in ≥20% of patients | Neutropenia, 74.5; Nausea, 35.9; Leukopenia, 27.3; Fatigue, 23.4; Diarrhoea, 21.3; Arthralgia, 20.9; Vomiting, 20.0 |
| Grade 3 or 4 haematologic abnormalities and biochemical abnormalities (>5.0%), % |
Neutropenia, 57.2; leukopenia, 10.6; increased ALT 7.7%; increased AST 5.7 |
Table adapted from De Laurentiis M, et al. 2021.13
CompLEEment-1: N=3246, Phase IIIb, open-label study in men and women (any menopausal status) with HR+/HER2− aBC, KISQALI is not licensed for use in men. In 1L setting for advanced disease. 1L of prior CT therapy permitted for aBC. Patients received KISQALI 600 mg once daily (3 weeks on/1 week off) + AI 2.5 mg once daily. Men††† and premenopausal women received concomitant goserelin (3.6 mg subcutaneous implant every 28 days).
- Primary endpoints were safety and tolerability13
- Secondary endpoints included time to progression, ORR, CBR and patient-reported outcomes13
KISQALI + ET** is the only CDK4/6i that achieved statistically significant OS results vs placebo across three Phase III trials in HR+/HER2– aBC patients‡‡‡3–7,14
KISQALI + ET** has maintained QoL relative to placebo + ET in HR+/HER2– aBC patients regardless of menopausal status§§§15
KISQALI + AI has the highest clinical ESMO-MCBS rating of any CDK4/6i + AI used in 1L postmenopausal patients with HR+/HER2– aBCǁǁǁ16
*Infections: urinary tract infections, respiratory tract infections, gastroenteritis, sepsis (<1%).1,2
†Adverse reaction reported during post-marketing experience.1,2
‡Abdominal pain: abdominal pain, abdominal pain upper.1,2
§Hepatotoxicity: hepatic cytolysis, hepatocellular injury, drug-induced liver injury (<1%), hepatotoxicity, hepatic failure, autoimmune hepatitis (single case).1,2
ǁRash: rash, rash maculopapular, rash pruritic.1,2
¶Abnormal liver function tests: ALT increased, AST increased, blood bilirubin increased.12
**KISQALI is not recommended for use with tamoxifen.1,2
††This pooled study includes the full population of MONALEESA-2, the first-line endocrine therapy subset of MONALEESA-3 and the AI subset of MONALEESA-7.10
‡‡The exposure-adjusted incidence rate is the number of patients with an event divided by the corresponding sum of the exposure duration for all patients. Duration of exposure in patient-treatment years is counted to the first qualifying event (or duration of exposure to study treatment for patients without an event).10
§§Results from a second interim analysis at a median duration of follow-up of 26.4 months.12
ǁǁResults from the first interim analysis. Median time from random assignment to data cut-off was 20.4 months.6
¶¶In the MONALEESA-7 full safety set, grade 3/4 increased ALT was reported in 5% of patients.5
***Mean duration of follow-up was 25.4 months.14
†††KISQALI is not licensed for use in men.1,2
‡‡‡MONALEESA-2 primary endpoint: PFS. In the primary analysis ITT population, mPFS was 25.3 months in the KISQALI + AI arm vs 16.0 months in the placebo + AI arm, HR 0.57 (95% CI: 0.46–0.70), p<0.0001. Key secondary endpoint: OS. In the protocol-specified final analysis of overall survival, at a median follow-up of 80 months, median OS was 63.9 months with KISQALI + AI vs 51.4 months with placebo + AI; HR 0.76 (95% CI: 0.63–0.93), two-sided p=0.008.3 MONALEESA 7 primary endpoint: PFS. At a median follow-up of 19.2 months, mPFS was 23.8 months (95% CI: 19.2–NR) in the KISQALI group versus 13.0 months (95% CI: 11.0–16.4) in the placebo group (HR 0.55, 95% CI: 0.44–0.69; p<0.001). Key secondary endpoint: OS. In the ITT population KISQALI + ET** (not estimated) demonstrated significant OS vs placebo + ET (40.9 months) (HR: 0.71, 95% CI: 0.54–0.95; p=0.00973). Extended follow-up exploratory analysis: An exploratory OS analysis was conducted at a median follow-up of 53.5 months, whereupon OS was 58.7 months with KISQALI + ET** vs 48 months with placebo + ET**; HR 0.76 (95% CI: 0.61–0.96).4,5,8 MONALEESA-3 primary endpoint: PFS. In the primary analysis of the overall study population, PFS was 20.5 months in the KISQALI + fulvestrant arm vs 12.8 months in the placebo + fulvestrant arm, HR 0.59 (95% CI: 0.48–0.73), p<0.001. Key secondary endpoint: OS. The second prespecified interim analysis reported a significant OS benefit for KISQALI + fulvestrant vs placebo + fulvestrant (p=0.00455), with a median OS of NR vs 40.0 months (95% CI: 37.0–not estimated). Therefore, exploratory analysis was conducted at a median follow-up of 56.3 months, whereupon median OS was 53.7 months (95% CI: 46.9–NR) with KISQALI + fulvestrant vs 41.5 months (95% CI: 37.4–49) with placebo + fulvestrant; HR 0.73 (95% CI: 0.59–0.90).6,7,11
§§§KISQALI + ET** delays TTD by 6.5 months (KISQALI + ET 39.6 months mTTD vs placebo + ET 33.1 months mTTD as measured by EORTC [HR], 0.79 [95% CI, 0.66–0.94]). Women in the pooled analysis who were pre- or perimenopausal were also treated with an LHRH agonist.15
ǁǁǁKISQALI holds a rating of 4/5 as a treatment for first-line postmenopausal patients in combination with AI, abemaciclib and palbociclcib have a rating of 3/5.16
1L, first-line; 2L, second-line; aBC, advanced breast cancer; AE, adverse event; AESI, adverse event of special interest; AI, aromatase inhibitor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBR, clinical benefit rate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; CIOMS, Council for International Organizations of Medical Sciences; CT, chemotherapy; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Core 30 Quality of Life questionnaire; ESMO-MCBS, European Society for Medical Oncology magnitude of clinical benefit scale; ET, endocrine therapy; HER2−, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone receptor-positive; ILD, interstitial lung disease; LFT, liver function test; LHRH, luteinising hormone-releasing hormone; mTTD, median time-to-deterioration; NSAI, non-steroidal aromatase inhibitor; ORR, overall response rate; OS, overall survival; QoL, quality of life; QTcF, corrected QT interval by Fredericia’s formula; TTD, time-to-deterioration.
References
- KISQALI® (ribociclib) Great Britain Summary of Product Characteristics.
- KISQALI® (ribociclib) Northern Ireland Summary of Product Characteristics.
- Hortobagyi GN, et al. N Engl J Med 2022;386(10):942–950 and supplementary data.
- Im S-A, et al. N Engl J Med 2019;381(4):307–316 and supplementary data.
- Tripathy D, et al. Lancet Oncol 2018;19(7):904–915.
- Slamon DJ, et al. J Clin Oncol 2018;36(24):2465–2472.
- Slamon DJ, et al. N Engl J Med 2020;382(6):514–524.
- Lu Y-S, et al. Clin Cancer Res 2022;2(5):851–859.
- Hortobagyi GN, et al. N Engl J Med 2016;375(18):1738–1748.
- Tripathy D, et al. European Society for Medical Oncology. 2–4 May 2019, Berlin, Germany, Poster 166P.
- Slamon DJ, et al. Ann Oncol 2021;32(8):1015–1024.
- Hortobagyi GN, et al. Ann Oncol 2018;29:1541–1547.
- De Laurentiis M, et al. Breast Cancer Res Treat 2021;189(3):689–699.
- Hortobagyi GN, et al. Oral presentation. ESMO Congress 2021, 16–21 September 2021, virtual.
- Fasching PA, et al. Oral presentation. European Society for Medical Oncology Breast Cancer Congress; 5–8 May 2021, virtual.
- European Society for Medical Oncology. ESMO-MCBS Score cards for HR+/HER2– breast cancer. Available at: https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-for-solid-tumours/es... [Accessed February 2024].