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.

Table 8: Adverse Reactions (≥ 10% and ≥ 2% Higher Than Placebo Arm) 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.

Table 9: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-2 Who Received KISQALI Plus Letrozole
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.

Table 10: Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher Than Placebo Arm in MONALEESA-7 (NSAI) (All Grades)
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%).

Table 11: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-7 Who Received KISQALI Plus NSAI Plus Goserelin
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.

Table 12: Adverse Reactions (≥ 10% and ≥ 2% Higher Than Placebo Arm) 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%).

Table 13: Select Laboratory Abnormalities (≥ 10%) in Patients in MONALEESA-3 Who Received KISQALI Plus Fulvestrant
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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