KISQALI (Page 3 of 8)
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to KISQALI in 1065 patients in MONALEESA-2, MONALEESA-7, and MONALEESA-3. Among these patients who received KISQALI, 76% were exposed for 6 months or longer and 62% were exposed for greater than one year. In this pooled safety population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%), creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%), vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash (24%), back pain (24%), and glucose serum decreased (20%).
MONALEESA-2: KISQALI in Combination with Letrozole
Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy
The safety of KISQALI was evaluated in MONALEESA-2, a clinical study of 668 postmenopausal women receiving KISQALI plus letrozole or placebo plus letrozole [see Clinical Studies (14)]. The median duration of exposure to KISQALI plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months.
Serious adverse reactions occurred in 21% of patients who received KISQALI plus letrozole. Serious adverse reactions in ≥1 % of patients receiving KISQALI plus letrozole included abdominal pain (1.5%), vomiting (1.5%), constipation (1.2%), nausea (1.2%), anemia (1.2%), febrile neutropenia (1.2%), dyspnea (1.2%), and alanine aminotransferase increased (1.2%).
Permanent discontinuation of both KISQALI and letrozole due to an adverse reaction occurred in 7% of patients. Permanent discontinuation of KISQALI alone occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and letrozole in ≥ 2% of patients were alanine aminotransferase increased (5%), aspartate aminotransferase increased (3%), and vomiting (2%).
Dosage interruptions of both KISQALI and letrozole due to an adverse reaction occurred in 71% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (39%), neutrophils decreased (12%), vomiting (6%), nausea (5%), alanine aminotransferase increased (5%), and leukocytes decreased (5%).
Dose reductions of KISQALI due to an adverse reaction occurred in 45% of patients receiving KISQALI plus letrozole. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia (24%), neutrophils decreased (8%), and alanine aminotransferase increased (3%).
Antiemetics and antidiarrheal medications were used to manage symptoms as clinically indicated.
The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutrophils decreased, leukocytes decreased, hemoglobin decreased, nausea, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhea, alopecia, vomiting, platelets decreased, constipation, headache, and back pain.
Table 8 summarizes the adverse reactions in MONALEESA-2.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.1 Only includes a Grade 3 adverse reaction. | ||||
Adverse reaction | KISQALI + Letrozole(n = 334) | Placebo + Letrozole(n = 330) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Gastrointestinal disorders | ||||
Nausea1 | 52 | 2.4 | 29 | 0.6 |
Diarrhea1 | 35 | 1.2 | 22 | 0.9 |
Vomiting1 | 29 | 3.6 | 16 | 0.9 |
Constipation1 | 25 | 1.2 | 19 | 0 |
Stomatitis1 | 12 | 0.3 | 7 | 0 |
Abdominal pain1 | 11 | 1.2 | 8 | 0 |
General disorders and administration-site conditions | ||||
Fatigue | 37 | 2.4 | 30 | 0.9 |
Pyrexia1 | 13 | 0.3 | 6 | 0 |
Edema peripheral1 | 12 | 0 | 10 | 0 |
Skin and subcutaneous tissue disorders | ||||
Alopecia1 | 33 | 0 | 16 | 0 |
Rash1 | 17 | 0.6 | 8 | 0 |
Pruritus1 | 14 | 0.6 | 6 | 0 |
Nervous system disorders | ||||
Headache1 | 22 | 0.3 | 19 | 0.3 |
Insomnia1 | 12 | 0.3 | 9 | 0 |
Musculoskeletal and connective tissue disorders | ||||
Back pain1 | 20 | 2.1 | 18 | 0.3 |
Metabolism and nutrition disorders | ||||
Decreased appetite1 | 19 | 1.5 | 15 | 0.3 |
Respiratory, thoracic and mediastinal disorders | ||||
Dyspnea1 | 12 | 1.2 | 9 | 0.6 |
Infections and infestations | ||||
Urinary tract infections1 | 11 | 0.6 | 8 | 0 |
Clinically relevant adverse reactions in < 10% of patients in MONALEESA-2 receiving KISQALI plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%). Table 9 summarizes the laboratory abnormalities in MONALEESA-2.
Laboratory abnormality | KISQALI + Letrozole(n = 334) | Placebo + Letrozole(n = 330) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Hematology | ||||
Leukocytes decreased | 93 | 34 | 29 | 1.5 |
Neutrophils decreased | 93 | 60 | 24 | 1.2 |
Hemoglobin decreased | 57 | 1.8 | 26 | 1.2 |
Lymphocytes decreased | 51 | 14 | 22 | 3.9 |
Platelets decreased | 29 | 0.9 | 6 | 0.3 |
Chemistry | ||||
Alanine aminotransferase increased | 46 | 10 | 36 | 1.2 |
Aspartate aminotransferase increased | 44 | 7 | 32 | 1.5 |
Creatinine increased | 20 | 0.6 | 6 | 0 |
Phosphorous decreased | 13 | 5 | 4 | 0.6 |
Potassium decreased | 11 | 1.2 | 7 | 1.2 |
MONALEESA-7: KISQALI in Combination with an Aromatase Inhibitor
Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy
The safety of KISQALI was evaluated in MONALEESA-7, a clinical study of 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KISQALI plus a NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin [see Clinical Studies (14)]. The median duration of exposure on the KISQALI plus a NSAI arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving KISQALI plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
Serious adverse reactions occurred in 17% of patients who received KISQALI plus NSAI plus goserelin. Serious adverse reactions in ≥ 1% of patients receiving KISQALI plus NSAI plus goserelin included drug-induced liver injury (1.6%), abdominal pain (1.2%), dyspnea (1.2%), febrile neutropenia (1.2%), and back pain (1.2%).
Permanent discontinuation of both KISQALI and NSAI due to an adverse reaction occurred in 3% of patients. Permanent discontinuation of KISQALI alone occurred in 3% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and NSAI in ≥ 2% of patients were alanine aminotransferase increased (2%), and aspartate aminotransferase increased (2%).
Dosage interruptions of KISQALI plus NSAI plus goserelin due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (41%), neutrophils decreased (26%), and leukocytes decreased (6%).
Dose reductions of KISQALI due to an adverse reaction occurred in 33% of patients receiving KISQALI plus NSAI plus goserelin. Adverse reactions which required dose reductions in ≥ 2 % of patients included neutropenia (17%), neutrophils decreased (5%), and alanine aminotransferase increased (2%).
The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, infections, arthralgia, alanine aminotransferase increased, nausea, platelets decreased, and alopecia.
Table 10 summarizes the adverse reactions in MONALEESA-7.
Abbreviation: NSAI, non-steroidal aromatase inhibitor.Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.1 Infections: urinary tract infections; respiratory tract infections, gastroenteritis, sepsis (< 1%).2 Only includes a Grade 3 adverse reactions. | ||||
Adverse reaction | KISQALI + NSAI + Goserelin(n = 248) | Placebo + NSAI + Goserelin(n = 247) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Infections and infestations | ||||
Infections1;2 | 36 | 1.6 | 24 | 0.4 |
Musculoskeletal and connective tissue disorders | ||||
Arthralgia2 | 34 | 0.8 | 29 | 1.2 |
Gastrointestinal disorders | ||||
Nausea2 | 32 | 0 | 20 | 0 |
Constipation2 | 16 | 0 | 12 | 0 |
Stomatitis2 | 10 | 0 | 8 | 0.4 |
Skin and subcutaneous tissue disorders | ||||
Alopecia2 | 21 | 0 | 13 | 0 |
Rash2 | 17 | 0.4 | 9 | 0 |
Pruritus2 | 11 | 0 | 4 | 0 |
General disorders and administration-Site Conditions | ||||
Pyrexia2 | 17 | 0.8 | 7 | 0 |
Pain in extremity2 | 10 | 0 | 8 | 1.2 |
Respiratory, thoracic and mediastinal disorders | ||||
Cough2 | 15 | 0 | 10 | 0 |
Clinically relevant adverse reactions in < 10% of patients in MONALEESA-7 receiving KISQALI plus NSAI included thrombocytopenia (9%), dry skin (9%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%).
Laboratory abnormality | KISQALI + NSAI + Goserelin(n = 248) | Placebo + NSAI + Goserelin(n = 247) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Hematology | ||||
Leukocytes decreased | 93 | 36 | 30 | 0.8 |
Neutrophils decreased | 92 | 63 | 27 | 2.4 |
Hemoglobin decreased | 84 | 2.4 | 51 | 0.4 |
Lymphocytes decreased | 55 | 14 | 18 | 2.8 |
Platelets decreased | 26 | 0.4 | 9 | 0.4 |
Chemistry | ||||
Gamma-glutamyl transferase increased | 42 | 7 | 42 | 9 |
Aspartate aminotransferase increased | 37 | 4.8 | 35 | 1.6 |
Alanine aminotransferase increased | 33 | 6 | 31 | 1.6 |
Phosphorous decreased | 14 | 1.6 | 11 | 0.8 |
Potassium decreased | 11 | 1.2 | 14 | 1.2 |
Glucose serum decreased | 10 | 0.4 | 10 | 0.4 |
Creatinine increased | 8 | 0 | 2 | 0 |
MONALEESA-3: KISQALI in Combination with Fulvestrant
Postmenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy
The safety of KISQALI was evaluated in MONALEESA-3, a clinical study of 724 postmenopausal women receiving KISQALI plus fulvestrant or placebo plus fulvestrant [see Clinical Studies (14)].
The median duration of exposure to KISQALI plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months.
Serious adverse reactions occurred in 29% of patients who received KISQALI plus fulvestrant. Serious adverse reactions in ≥ 1% of patients receiving KISQALI plus fulvestrant included pneumonia (1.9%), nausea (1.4%), vomiting (1.4%), anemia (1.2%), dyspnea (1.2%), neutropenia (1.2%). One case (0.2%) of fatal adverse reaction (pneumonia) occurred in patients who received KISQALI plus fulvestrant.
Permanent discontinuation of both KISQALI and fulvestrant due to an adverse reaction occurred in 8% of patients. Permanent discontinuation of KISQALI alone occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of both KISQALI and fulvestrant in ≥ 2% of patients were alanine aminotransferase increased (5%), and aspartate aminotransferase increased (3%).
Dosage interruptions of KISQALI plus fulvestrant due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients included neutropenia (40%), neutrophils decreased (13%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), and leukocytes decreased (5%).
Dose reductions of KISQALI due to an adverse reaction occurred in 32% of patients receiving KISQALI plus fulvestrant. Adverse reactions which required dose reductions in ≥ 2% of patients included neutropenia (15%), and neutrophils decreased (3%).
The most common (≥ 20% on the KISQALI arm and ≥ 2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, lymphocytes decreased, creatinine increased, hemoglobin decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, infections, platelets decreased, diarrhea, vomiting, constipation, glucose serum decreased, cough, rash, and pruritus.
Table 12 summarizes the adverse reactions in MONALEESA-3.
Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.1 Infections: urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (1%).2 Only include Grade 3 adverse reactions.3 Includes the following fatal adverse reactions: pneumonia (n = 1). | ||||
Adverse reaction | KISQALI + Fulvestrant(n = 483) | Placebo + Fulvestrant(n = 241) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Gastrointestinal disorders | ||||
Nausea2 | 45 | 1.4 | 28 | 0.8 |
Diarrhea2 | 29 | 0.6 | 20 | 0.8 |
Vomiting2 | 27 | 1.4 | 13 | 0 |
Constipation2 | 25 | 0.8 | 12 | 0 |
Abdominal pain2 | 17 | 1.4 | 13 | 0.8 |
Infections and infestations | ||||
Infections1;2;3 | 42 | 4.6 | 30 | 1.7 |
Skin and subcutaneous tissue disorders | ||||
Rash2 | 23 | 0.8 | 8 | 0 |
Pruritus2 | 20 | 0.2 | 7 | 0 |
Alopecia2 | 19 | 0 | 5 | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
Cough2 | 22 | 0 | 15 | 0 |
Dyspnea | 15 | 1.4 | 12 | 1.7 |
Metabolism and nutrition disorders | ||||
Decreased appetite2 | 16 | 0.2 | 13 | 0 |
General disorders and administration-site conditions | ||||
Edema peripheral2 | 15 | 0 | 7 | 0 |
Pyrexia2 | 11 | 0.2 | 7 | 0 |
Nervous system disorders | ||||
Dizziness2 | 13 | 0.2 | 8 | 0 |
Clinically relevant adverse reactions in < 10% of patients in MONALEESA-3 receiving KISQALI plus fulvestrant included thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%).
Laboratory abnormality | KISQALI + Fulvestrant(n = 483) | Placebo + Fulvestrant(n = 241) | ||
All Grades(%) | Grade 3 or 4(%) | All Grades(%) | Grade 3 or 4(%) | |
Hematology | ||||
Leukocytes decreased | 95 | 26 | 26 | 0.4 |
Neutrophils decreased | 92 | 53 | 21 | 0.8 |
Lymphocytes decreased | 69 | 16 | 35 | 4.1 |
Hemoglobin decreased | 60 | 4.3 | 35 | 2.9 |
Platelets decreased | 33 | 1.9 | 11 | 0 |
Chemistry | ||||
Creatinine increased | 65 | 1 | 33 | 0.4 |
Gamma-glutamyl transferase increased | 52 | 8 | 49 | 10 |
Aspartate aminotransferase increased | 50 | 7 | 43 | 2.9 |
Alanine aminotransferase increased | 44 | 11 | 37 | 1.7 |
Glucose serum decreased | 23 | 0 | 18 | 0 |
Phosphorous decreased | 18 | 4.6 | 8 | 0.8 |
Albumin decreased | 12 | 0 | 8 | 0 |
COMPLEEMENT-1: KISQALI in Combination with Letrozole and Goserelin or Leuprolide
Men with HR-positive, HER2-negative Advanced Breast Cancer for Initial Endocrine-Based Therapy
The safety of KISQALI in combination with letrozole was evaluated in men (n = 39) in an open-label, multicenter clinical study for the treatment of adult patients with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease (COMPLEEMENT-1) [see Clinical Studies (14)].
The median duration of exposure to KISQALI was 20.8 months (range, 0.5 to 30.6 months).
Other adverse reactions occurring in men treated with KISQALI plus letrozole and goserelin or leuprolide were similar to those occurring in women treated with KISQALI plus endocrine therapy.
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