Itovebi Drug Information

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 . 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.

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 . 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% or ≥ 2% 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

General Disorders and

Administration Site Conditions Fatigue 38 1.9 25

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

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% 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

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

Potassium decreased 38 6 21 0.6 Creatinine increased 38 1.9 30 1.2

ALT increased 34 3.1 29

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

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.

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

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 . 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.

Pediatric Use The safety and efficacy of ITOVEBI in pediatric patients have not been established.