Itovebi

1 INDICATIONS AND USAGE ITOVEBI, in combination with palbociclib and fulvestrant, is indicated for the treatment of adults with endocrine-resistant, PIK3CA -mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy [see Clinical Studies (14.1) ] . ITOVEBI is a kinase inhibitor indicated in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA -mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. ( 1 , 14.1 )

2 DOSAGE AND ADMINISTRATION Select patients for the treatment of HR-positive, HER2-negative, locally advanced or metastatic breast cancer with ITOVEBI based on the presence of one or more PIK3CA mutations in plasma specimen. ( 2.1 ) Recommended dosage: 9 mg orally once daily with or without food. ( 2.3 ) See Full Prescribing Information for dosage modifications of ITOVEBI due to adverse reactions. ( 2.4 ) Reduce the starting dose in patients with moderate renal impairment. ( 2.5 ) 2.1 Patient Selection Select patients for the treatment of HR-positive, HER2-negative, locally advanced or metastatic breast cancer with ITOVEBI based on the presence of one or more PIK3CA mutations in plasma specimens [see Clinical Studies (14.1) ] . Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at: http://www.fda.gov/companiondiagnostics. 2.2 Recommended Evaluation Before Initiating ITOVEBI Evaluate fasting plasma glucose (FPG)/blood glucose (FBG) and hemoglobin A 1C (HbA 1C ) and optimize blood glucose prior to starting ITOVEBI and at regular intervals during treatment [see Warnings and Precautions (5.1) ]. 2.3 Recommended Dosage The recommended dosage of ITOVEBI is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity. Advise patients to take ITOVEBI at approximately the same time each day. Swallow ITOVEBI tablet(s) whole. Do not chew, crush, or split prior to swallowing. If a patient misses a dose, instruct the patient to take the missed dose as soon as possible within 9 hours. After more than 9 hours, instruct the patient to skip the dose and take the next dose at the scheduled time. If a patient vomits a dose, instruct patients not to take an additional dose on that day and resume the usual dosing schedule the next day. Administer ITOVEBI in combination with palbociclib and fulvestrant. The recommended dosage of palbociclib is 125 mg taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days. Refer to the Full Prescribing Information for palbociclib and fulvestrant for dosing information. For premenopausal and perimenopausal women, administer a luteinizing hormone-releasing hormone (LHRH) agonist in accordance with local clinical practice. For men, consider administering an LHRH agonist in accordance with local clinical practice. 2.4 Dosage Modifications for Adverse Reactions The recommended dose reduction levels of ITOVEBI for adverse reactions are listed in Table 1 . Permanently discontinue ITOVEBI if patients are unable to tolerate the second dose reduction. Table 1: Dose Reduction for Adverse Reactions Dose Level Dose and Schedule Recommended starting dose 9 mg daily First dose reduction 6 mg daily Second dose reduction 3 mg daily The recommended dosage modifications of ITOVEBI for adverse reactions are summarized in Table 2 . Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Hyperglycemia Before initiating treatment with ITOVEBI, test FPG or FBG, and HbA 1C levels, and optimize plasma/blood glucose levels in all patients. After initiating treatment with ITOVEBI, monitor FPG or FBG levels based on the recommended schedule, and as clinically indicated [see Warnings and Precautions (5.1) ]. [see Warnings and Precautions (5.1) ] Fasting glucose levels (FPG or FBG) > ULN to 160 mg/dL (> ULN – 8.9 mmol/L) No adjustment of ITOVEBI required. Consider dietary modifications and ensure adequate hydration. Initiate or intensify oral anti-hyperglycemic medications for patients with risk factors for hyperglycemia. Fasting glucose levels > 160 to 250 mg/dL (> 8.9 – 13.9 mmol/L) Withhold ITOVEBI until FPG or FBG ≤ 160 mg/dL (≤ 8.9 mmol/L). Initiate or intensify anti-hyperglycemic medications. Resume ITOVEBI at the same dose level. If FPG or FBG persists > 200 – 250 mg/dL (> 11.1 – 13.9 mmol/L) for 7 days under appropriate anti-hyperglycemic treatment, consider consultation with a healthcare professional experienced in the treatment of hyperglycemia. Fasting glucose levels > 250 to 500 mg/dL (> 13.9 – 27.8 mmol/L) Withhold ITOVEBI. Initiate or intensify anti-hyperglycemic medications. Administer appropriate hydration if required. If FPG or FBG decreases to ≤ 160 mg/dL (≤ 8.9 mmol/L) within 7 days, resume ITOVEBI at the same dose level. If FPG or FBG decreases to ≤ 160 mg/dL (≤ 8.9 mmol/L) in ≥ 8 days, resume ITOVEBI at one lower dose level. If FPG or FBG > 250 to 500 mg/dL (> 13.9 – 27.8 mmol/L) recurs within 30 days, withhold ITOVEBI until FPG or FBG decreases to ≤ 160 mg/dL (≤ 8.9 mmol/L). Resume ITOVEBI at one lower dose level. Fasting glucose levels > 500 mg/dL (> 27.8 mmol/L) Withhold ITOVEBI. Initiate or intensify anti-hyperglycemic medications. Assess for volume depletion and ketosis and administer appropriate hydration. If FPG or FBG decreases to ≤ 160 mg/dL (≤ 8.9 mmol/L), resume ITOVEBI at one lower dose level. If FPG or FBG > 500 mg/dL (> 27.8 mmol/L) recurs within 30 days, permanently discontinue ITOVEBI. Stomatitis [see Warnings and Precautions (5.2) ] Grade 1 Based on CTCAE version 5.0. No adjustment of ITOVEBI required. Initiate or intensify appropriate medical therapy (e.g., corticosteroid-containing mouthwash) as clinically indicated. Grade 2 Withhold ITOVEBI until recovery to Grade ≤ 1. Initiate or intensify appropriate medical therapy. Resume ITOVEBI at the same dose level. For recurrent Grade 2 stomatitis, withhold ITOVEBI until recovery to Grade ≤ 1, then resume ITOVEBI at one lower dose level. Grade 3 Withhold ITOVEBI until recovery to Grade ≤ 1. Initiate or intensify appropriate medical therapy. Resume ITOVEBI at one lower dose level. Grade 4 Permanently discontinue ITOVEBI. Diarrhea [see Warnings and Precautions (5.3) ] Grade 1 No adjustment of ITOVEBI required. Initiate appropriate medical therapy and monitor as clinically indicated. Grade 2 Withhold ITOVEBI until recovery to Grade ≤ 1, then resume ITOVEBI at the same dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. For recurrent Grade 2 diarrhea, withhold ITOVEBI until recovery to Grade ≤ 1, then resume ITOVEBI at one lower dose level. Grade 3 Withhold ITOVEBI until recovery to Grade ≤ 1, then resume ITOVEBI at one lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Grade 4 Permanently discontinue ITOVEBI. Hematologic Toxicities [see Adverse Reactions (6.1) ] Grade 1, 2, or 3 No adjustment of ITOVEBI required. Monitor complete blood count and for signs or symptoms of hematologic toxicities as clinically indicated. Grade 4 Withhold ITOVEBI until recovery to Grade ≤ 2. Resume ITOVEBI at the same dose level or reduce to one lower dose level as clinically indicated. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 1 No adjustment of ITOVEBI required. Grade 2 Consider withholding ITOVEBI, if clinically indicated, until recovery to Grade ≤ 1. Resume ITOVEBI at the same dose level. Grade 3 (first event) Withhold ITOVEBI until recovery to Grade ≤ 1. Resume ITOVEBI at the same dose level or one lower dose level based on clinical evaluation. Grade 3 (recurrent) Withhold ITOVEBI until recovery to Grade ≤ 1. Resume ITOVEBI at one lower dose level. Grade 4 Permanently discontinue ITOVEBI. 2.5 Dosage Modification for Moderate Renal Impairment The recommended starting dosage of ITOVEBI for patients with moderate renal impairment (eGFR 30 to < 60 mL/min based on CKD-EPI) is 6 mg orally once daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hyperglycemia : ITOVEBI can cause severe or fatal hyperglycemia including ketoacidosis. Before initiating treatment with ITOVEBI, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue ITOVEBI if severe hyperglycemia occurs. ( 2.4 , 5.1 ) Stomatitis : ITOVEBI can cause severe stomatitis. Consider treating with a corticosteroid-containing mouthwash if stomatitis occurs. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity. ( 2.4 , 5.2 ) Diarrhea : ITOVEBI can cause diarrhea, which may be severe, and result in dehydration and acute kidney injury. Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if severe diarrhea occurs. Interrupt, reduce dose, or discontinue ITOVEBI if severe diarrhea occurs. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity : ITOVEBI can cause fetal harm. Advise patients of potential risk to a fetus and to use effective non-hormonal contraception. ( 5.4 , 8.1 , 8.3 ) Refer to the Full Prescribing Information of palbociclib and fulvestrant for pregnancy and contraception information. 5.1 Hyperglycemia Severe or fatal hyperglycemia, including ketoacidosis, can occur in patients treated with ITOVEBI. Ketoacidosis with a fatal outcome has occurred in the postmarketing setting. Increased fasting glucose occurred in 85% of patients treated with ITOVEBI, including 22% of patients with Grade 2 (FPG > 160 to 250 mg/dL), 12% with Grade 3 (FPG > 250 to 500 mg/dL), and 0.6% with Grade 4 (FPG > 500 mg/dL) events. In INAVO120, 46% (74/162) of patients who received ITOVEBI were treated with oral anti-hyperglycemic medications and 7% (11/162) were treated with insulin to manage increased fasting glucose. In patients who experienced increased fasting glucose of > 160 mg/dL, 96% (52/54) had an improvement in fasting glucose of at least one grade level with a median time to improvement of 8 days (range: 2 to 43 days). Among patients with hyperglycemia, the median time to first onset was 7 days (range: 2 to 955 days). Hyperglycemia led to dose interruption in 28%, to dose reduction in 2.5%, and to discontinuation of ITOVEBI in 1.2% of patients. The safety of ITOVEBI in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment have not been studied. Before initiating treatment with ITOVEBI, test fasting glucose levels (FPG or FBG), HbA 1C levels, and optimize fasting glucose. After initiating treatment with ITOVEBI, or in patients who experience hyperglycemia after initiating treatment with ITOVEBI, monitor or self-monitor fasting glucose levels once every 3 days for the first week (Day 1 to 7), then once every week for the next 3 weeks (Day 8 to 28), then once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated. Monitor HbA 1C every 3 months and as clinically indicated. Manage hyperglycemia with anti-hyperglycemic medications as clinically indicated. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose levels. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of fasting glucose levels. Consider consultation with a healthcare professional experienced in the treatment of hyperglycemia, and initiation of fasting glucose monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia. Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes. Based on the severity of the hyperglycemia, ITOVEBI may require dose interruption, reduction, or discontinuation [see Dosage and Administration (2.4) ] . 5.2 Stomatitis Severe stomatitis can occur in patients treated with ITOVEBI. Stomatitis occurred in 51% of patients treated with ITOVEBI in combination with palbociclib and fulvestrant, including Grade 3 events in 6% of patients. The median time to first onset was 13 days (range: 1 to 610 days). Stomatitis led to dose interruption in 10%, to dose reduction in 3.7%, and to discontinuation of ITOVEBI in 0.6% of patients. In patients who received ITOVEBI in combination with palbociclib and fulvestrant, 38% used a mouthwash containing corticosteroid for management or prophylaxis of stomatitis. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity [see Dosage and Administration (2.4) ] . 5.3 Diarrhea Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with ITOVEBI. Diarrhea occurred in 48% of patients treated with ITOVEBI in combination with palbociclib and fulvestrant, including Grade 3 events in 3.7% of patients. The median time to first onset was 15 days (range: 2 to 602 days). Diarrhea led to dose interruptions in 7% of patients, and dose reductions in 1.2% of patients. Anti-diarrheal medicines were used in 28% (46/162) of patients who received ITOVEBI in combination with palbociclib and fulvestrant to manage symptoms. Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start anti-diarrheal treatment at the first sign of diarrhea while taking ITOVEBI. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity [see Dosage and Administration (2.4) ] . 5.4 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, ITOVEBI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ITOVEBI and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ITOVEBI and for 1 week after the last dose [see Use in Specific Populations (8.1 and 8.3) ] . ITOVEBI is used in combination with palbociclib and fulvestrant. Refer to the Full Prescribing Information of palbociclib and fulvestrant for pregnancy and contraception information.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hyperglycemia [see Warnings and Precautions (5.1) ] Stomatitis [see Warnings and Precautions (5.2) ] Diarrhea [see Warnings and Precautions (5.3) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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. Locally Advanced or Metastatic Breast Cancer INAVO120 The safety of ITOVEBI was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer [see Clinical Studies (14.1) ] . Patients received either ITOVEBI 9 mg (n=162) or placebo (n=162) with palbociclib and fulvestrant. The median duration of treatment with ITOVEBI was 9 months (range: 0 to 39 months) in the ITOVEBI with palbociclib and fulvestrant arm. Serious adverse reactions occurred in 24% of patients who received ITOVEBI with palbociclib and fulvestrant. Serious adverse reactions in ≥ 1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%). Fatal adverse reactions occurred in 3.7% of patients who received ITOVEBI with palbociclib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage. Permanent discontinuation of ITOVEBI due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of ITOVEBI included hyperglycemia (1.2%), and (0.6% each) stomatitis, gastric ulcer, intestinal perforation, anal abscess, increased ALT, decreased weight, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury. Dosage interruptions of ITOVEBI due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included hyperglycemia (28%), neutropenia (23%), COVID-19 infection (16%), stomatitis (10%), diarrhea (7%), thrombocytopenia (4.9%), anemia (4.3%), upper respiratory tract infection (4.3%), decreased white blood cell count (3.7%), pyrexia (3.1%), nausea (2.5%), and fatigue (2.5%). Dose reductions of ITOVEBI due to adverse reactions occurred in 14% of patients. Adverse reactions which required dose reduction of ITOVEBI in ≥ 2% of patients were stomatitis (3.7%) and hyperglycemia (2.5%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache. Adverse reactions and laboratory abnormalities in INAVO120 are summarized in Table 3 and Table 4 , respectively. Patient-reported symptoms are summarized in Table 5 . Table 3: Adverse Reactions (≥ 10% with ≥ 5% [All Grades] or ≥ 2% [Grade 3-4] Higher Incidence in the ITOVEBI Arm) in INAVO120 Adverse Reaction ITOVEBI + Palbociclib + Fulvestrant N=162 Placebo + Palbociclib + Fulvestrant N=162 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal Disorders Stomatitis Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis. 51 6 No Grade 4 adverse reactions were observed. 27 0 Diarrhea 48 3.7 16 0 Nausea 28 0.6 17 0 Vomiting 15 0.6 5 1.2 General Disorders and Administration Site Conditions Fatigue 38 1.9 25 1.2 Skin and Subcutaneous Tissue Disorders Rash Includes other related terms. 26 0 19 0 Alopecia 19 0 6 0 Dry skin Includes dry skin, skin fissures, xerosis, and xeroderma. 13 0 4.3 0 Metabolism and Nutrition Disorders Decreased appetite 24 0 9 0 Infections and Infestations COVID-19 infection 23 1.9 11 0.6 Urinary tract infection 15 1.2 9 0 Nervous System Disorders Headache 22 0 14 0 Investigations Decreased weight 17 3.7 0.6 0 Clinically relevant adverse reactions occurring in < 10% of patients who received ITOVEBI in combination with palbociclib and fulvestrant included abdominal pain, dry eye, dysgeusia, and dyspepsia. Table 4: Select Laboratory Abnormalities (≥ 10% with a ≥ 2% [All Grades or Grade 3-4] Higher Incidence in the ITOVEBI Arm) in INAVO120 Laboratory Abnormality ITOVEBI + Palbociclib + Fulvestrant The denominator used to calculate the rate varied from 122 to 160 based on the number of patients with a baseline value and at least one post-treatment value. Placebo + Palbociclib + Fulvestrant The denominator used to calculate the rate varied from 131 to 161 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) ALT = alanine aminotransferase Hematology Neutrophils (total, absolute) decreased 95 82 97 79 Hemoglobin decreased 88 8 No Grade 4 laboratory abnormalities were observed. 85 2.5 Platelets decreased 84 16 71 3.7 Lymphocytes (absolute) decreased 72 9 68 14 Chemistry Glucose (fasting) increased Grading according to CTCAE version 4.03. 85 12 43 0 Calcium decreased 42 3.1 32 3.7 Potassium decreased 38 6 21 0.6 Creatinine increased 38 1.9 30 1.2 ALT increased 34 3.1 29 1.2 Sodium decreased 28 2.5 19 2.5 Magnesium decreased 27 0.6 21 0 Lipase (fasting) increased 16 1.4 7 0 In INAVO120, patient-reported symptomatic toxicities (i.e., diarrhea, nausea, vomiting, fatigue, mouth sores, decreased appetite, and rash) were assessed via the Patient-Reported Outcomes – Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline, every two weeks through Cycle 3 Day 15, and then Day 1 of every other 28-day cycle until treatment discontinuation. Completion rates in both arms were > 90% at baseline and > 80% at subsequent time points where > 50% of randomized patients were on treatment. Table 5: Patient-Reported Symptoms Assessed by PRO-CTCAE in INAVO120 ITOVEBI+P+F = ITOVEBI with palbociclib and fulvestrant arm; Placebo+P+F = placebo with palbociclib and fulvestrant arm. Symptom (Attribute) The symptom attribute scoring is defined by amount/frequency/severity with a score of 0 = 'not at all'/'never'/'none'; 1 = 'a little bit'/'rarely'/'mild'; 2 = 'somewhat'/'occasionally'/'moderate'; 3 = 'quite a bit'/'frequently'/'severe'; 4 = 'very much'/'almost constantly'/'very severe'. Any Symptom Before Treatment (%) The percentage of patients whose symptom score before treatment was 1-4. Any Worsening on Treatment (%) The percentage of patients whose symptom score increased during treatment, with respect to their score before treatment. Worsening to Score 3 or 4 (%) The percentage of patients whose symptom score increased to 3 or 4 during treatment, with respect to their score before treatment. ITOVEBI + P + F (N=148) The number of patients who provided a score before treatment and at least one on-treatment score. Placebo + P + F (N=152) ITOVEBI + P + F (N=148) Placebo + P + F (N=152) ITOVEBI + P + F (N=148) Placebo + P + F (N=152) Diarrhea (frequency), % 23 15 78 49 32 8 Nausea (frequency), % 21 21 59 50 20 11 Vomiting (frequency), % 9 6 35 26 6 3.3 Fatigue (severity), % 72 69 72 58 32 22 Mouth sores (severity), % 11 14 74 52 30 9 Decreased appetite (severity), % 38 28 78 55 26 12 Symptom (Attribute) Baseline Presence Post-baseline Presence ITOVEBI + P + F (N=148) Placebo + P + F (N=152) ITOVEBI + P + F (N=148) Placebo + P + F (N=152) Rash (yes), % 5 5 50 38 Patient-reported overall side-effect impact was assessed using the Modified Bother Item (MBI). Patients provided a response to "I am bothered by side effects of treatment," and at baseline the proportion of patients with MBI responses of "not at all" were 70% in the ITOVEBI with palbociclib and fulvestrant arm and 76% in the placebo with palbociclib and fulvestrant arm. At Cycle 2 Day 15, the proportion of patients with MBI responses of "not at all" were 25% in the ITOVEBI with palbociclib and fulvestrant arm and 53% in the placebo with palbociclib and fulvestrant arm. Through 31 cycles of treatment, patients in the ITOVEBI with palbociclib and fulvestrant arm reported more side effect bother compared to the placebo with palbociclib and fulvestrant arm. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ITOVEBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Metabolism and Nutrition Disorders : Ketoacidosis

8.1 Pregnancy Risk Summary ITOVEBI is used in combination with palbociclib and fulvestrant. Refer to the Full Prescribing Information of palbociclib and fulvestrant for pregnancy information. Based on animal data and its mechanism of action, ITOVEBI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of ITOVEBI in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on AUC (see Data ) . Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis. Administration of doses ≥ 2 mg/kg/day resulted in decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations (including kyphosis of vertebral column, fused thoracic arch, microphthalmia) and variations (including dilated renal pelvis, short supernumerary rib, wavy rib). At a dose of 2 mg/kg/day, maternal exposures were 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC.