FDA label 2e70a60b-0ae4-4c25-976e-cfe174bdd39c

5 WARNINGS AND PRECAUTIONS Hyperglycemia : ITOVEBI can cause hyperglycemia. 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 hyperglycemia can occur in patients treated with ITOVEBI. 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 from the first event 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 interruption of ITOVEBI 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). Anti-diarrheal medicines were used in 28% (46/162) of patients who received ITOVEBI in combination with palbociclib and fulvestrant to manage symptoms. Dose interruptions were required in 7% of patients, and dose reductions occurred in 1.2% of patients. 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 10 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.

<table width="90%" ID="table3"><caption>Table 3: Adverse Reactions (&#x2265; 10% with &#x2265; 5% [All Grades] or &#x2265; 2% [Grade 3-4] Higher Incidence in the ITOVEBI Arm) in INAVO120</caption><col width="28%" align="left" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="18%" align="center" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2"> Adverse Reaction</th><th styleCode="Rrule" colspan="2">ITOVEBI + Palbociclib + Fulvestrant N=162</th><th styleCode="Rrule" colspan="2">Placebo + Palbociclib + Fulvestrant N=162</th></tr><tr><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3-4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3-4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Stomatitis<footnote>Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis.</footnote></td><td styleCode="Rrule">51</td><td styleCode="Rrule">6<footnote ID="foot2">No Grade 4 adverse reactions were observed.</footnote></td><td styleCode="Rrule">27</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">48</td><td styleCode="Rrule">3.7<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">28</td><td styleCode="Rrule">0.6<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0.6<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">5</td><td styleCode="Rrule">1.2<footnoteRef IDREF="foot2"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue</td><td styleCode="Rrule">38</td><td styleCode="Rrule">1.9<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">25</td><td styleCode="Rrule">1.2<footnoteRef IDREF="foot2"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote ID="foot3">Includes other related terms.</footnote></td><td styleCode="Rrule">26</td><td styleCode="Rrule">0</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alopecia</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0</td><td styleCode="Rrule">6</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry skin<footnote>Includes dry skin, skin fissures, xerosis, and xeroderma.</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4.3</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Infections and Infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> COVID-19 infection</td><td styleCode="Rrule">23</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection<footnoteRef IDREF="foot3"/></td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.2<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">9</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache<footnoteRef IDREF="foot3"/></td><td styleCode="Rrule">22</td><td styleCode="Rrule">0</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Investigations</content></td></tr><tr><td styleCode="Lrule Rrule"> Decreased weight </td><td styleCode="Rrule">17</td><td styleCode="Rrule">3.7<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="90%" ID="table4"><caption>Table 4: Select Laboratory Abnormalities (&#x2265; 10% with a &#x2265; 2% [All Grades or Grade 3-4] Higher Incidence in the ITOVEBI Arm) in INAVO120</caption><col width="28%" align="left" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><col width="18%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2">ITOVEBI + Palbociclib + Fulvestrant<footnote>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.</footnote></th><th styleCode="Rrule" colspan="2">Placebo + Palbociclib + Fulvestrant<footnote>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.</footnote></th></tr><tr><th styleCode="Rrule" align="center">All Grades (%)</th><th styleCode="Rrule">Grade 3-4 (%)</th><th styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3-4 (%)</th></tr></thead><tfoot><tr><td colspan="5" align="left">ALT = alanine aminotransferase</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophils (total, absolute) decreased</td><td styleCode="Rrule">95</td><td styleCode="Rrule">82</td><td styleCode="Rrule">97</td><td styleCode="Rrule">79</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hemoglobin decreased</td><td styleCode="Rrule">88</td><td styleCode="Rrule">8<footnote ID="foot4">No Grade 4 laboratory abnormalities were observed.</footnote></td><td styleCode="Rrule">85</td><td styleCode="Rrule">2.5<footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Platelets decreased</td><td styleCode="Rrule">84</td><td styleCode="Rrule">16</td><td styleCode="Rrule">71</td><td styleCode="Rrule">3.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocytes (absolute) decreased</td><td styleCode="Rrule">72</td><td styleCode="Rrule">9</td><td styleCode="Rrule">68</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Glucose (fasting) increased<footnote>Grading according to CTCAE version 4.03.</footnote></td><td styleCode="Rrule">85</td><td styleCode="Rrule">12</td><td styleCode="Rrule">43</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Calcium decreased</td><td styleCode="Rrule">42</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">32</td><td styleCode="Rrule">3.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Potassium decreased</td><td styleCode="Rrule">38</td><td styleCode="Rrule">6</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0.6<footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatinine increased</td><td styleCode="Rrule">38</td><td styleCode="Rrule">1.9<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">30</td><td styleCode="Rrule">1.2<footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT increased</td><td styleCode="Rrule">34</td><td styleCode="Rrule">3.1<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">29</td><td styleCode="Rrule">1.2<footnoteRef IDREF="foot4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sodium decreased</td><td styleCode="Rrule">28</td><td styleCode="Rrule">2.5<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">19</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Magnesium decreased</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0.6</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Lipase (fasting) increased</td><td styleCode="Rrule">16</td><td styleCode="Rrule">1.4<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">7</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="90%" ID="table5"><caption>Table 5: Patient-Reported Symptoms Assessed by PRO-CTCAE in INAVO120</caption><col width="16%" align="left" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="7%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><tfoot><tr><td colspan="9" align="left">ITOVEBI+P+F = ITOVEBI with palbociclib and fulvestrant arm; Placebo+P+F = placebo with palbociclib and fulvestrant arm.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="top"><content styleCode="bold">Symptom (Attribute)<footnote>The symptom attribute scoring is defined by amount/frequency/severity with a score of 0 = &apos;not at all&apos;/&apos;never&apos;/&apos;none&apos;; 1 = &apos;a little bit&apos;/&apos;rarely&apos;/&apos;mild&apos;; 2 = &apos;somewhat&apos;/&apos;occasionally&apos;/&apos;moderate&apos;; 3 = &apos;quite a bit&apos;/&apos;frequently&apos;/&apos;severe&apos;; 4 = &apos;very much&apos;/&apos;almost constantly&apos;/&apos;very severe&apos;.</footnote></content></td><td styleCode="Rrule" colspan="3"><content styleCode="bold">Any Symptom Before Treatment (%)<footnote>The percentage of patients whose symptom score before treatment was 1-4.</footnote></content></td><td styleCode="Rrule" colspan="2"><content styleCode="bold">Any Worsening on Treatment (%)<footnote>The percentage of patients whose symptom score increased during treatment, with respect to their score before treatment.</footnote></content></td><td styleCode="Rrule" colspan="3"><content styleCode="bold">Worsening to Score 3 or 4 (%)<footnote>The percentage of patients whose symptom score increased to 3 or 4 during treatment, with respect to their score before treatment.</footnote></content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule" align="center"><content styleCode="bold">ITOVEBI + P + F (N=148)<footnote ID="foot5">The number of patients who provided a score before treatment and at least one on-treatment score.</footnote></content></td><td styleCode="Rrule" colspan="2"><content styleCode="bold">Placebo + P + F (N=152)<footnoteRef IDREF="foot5"/></content></td><td styleCode="Rrule"><content styleCode="bold">ITOVEBI + P + F (N=148)<footnoteRef IDREF="foot5"/></content></td><td styleCode="Rrule"><content styleCode="bold">Placebo + P + F (N=152)<footnoteRef IDREF="foot5"/></content></td><td styleCode="Rrule" colspan="2"><content styleCode="bold">ITOVEBI + P + F (N=148)<footnoteRef IDREF="foot5"/></content></td><td styleCode="Rrule"><content styleCode="bold">Placebo + P + F (N=152)<footnoteRef IDREF="foot5"/></content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea (frequency), %</td><td styleCode="Rrule">23</td><td styleCode="Rrule" colspan="2">15</td><td styleCode="Rrule">78</td><td styleCode="Rrule">49</td><td styleCode="Rrule" colspan="2">32</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea (frequency), %</td><td styleCode="Rrule">21</td><td styleCode="Rrule" colspan="2">21</td><td styleCode="Rrule">59</td><td styleCode="Rrule">50</td><td styleCode="Rrule" colspan="2">20</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting (frequency), %</td><td styleCode="Rrule">9</td><td styleCode="Rrule" colspan="2">6</td><td styleCode="Rrule">35</td><td styleCode="Rrule">26</td><td styleCode="Rrule" colspan="2">6</td><td styleCode="Rrule">3.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue (severity), %</td><td styleCode="Rrule">72</td><td styleCode="Rrule" colspan="2">69</td><td styleCode="Rrule">72</td><td styleCode="Rrule">58</td><td styleCode="Rrule" colspan="2">32</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mouth sores (severity), %</td><td styleCode="Rrule">11</td><td styleCode="Rrule" colspan="2">14</td><td styleCode="Rrule">74</td><td styleCode="Rrule">52</td><td styleCode="Rrule" colspan="2">30</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite (severity), %</td><td styleCode="Rrule">38</td><td styleCode="Rrule" colspan="2">28</td><td styleCode="Rrule">78</td><td styleCode="Rrule">55</td><td styleCode="Rrule" colspan="2">26</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top" rowspan="2"><content styleCode="bold">Symptom (Attribute)</content></td><td styleCode="Rrule" colspan="4"><content styleCode="bold">Baseline Presence</content></td><td styleCode="Rrule" colspan="4"><content styleCode="bold">Post-baseline Presence</content></td></tr><tr styleCode="Botrule"><td styleCode="Rrule" align="center" colspan="2"><content styleCode="bold">ITOVEBI + P + F (N=148)</content></td><td styleCode="Rrule" align="center" colspan="2"><content styleCode="bold">Placebo + P + F (N=152)</content></td><td styleCode="Rrule" align="center" colspan="2"><content styleCode="bold">ITOVEBI + P + F (N=148)</content></td><td styleCode="Rrule" align="center" colspan="2"><content styleCode="bold">Placebo + P + F (N=152)</content></td></tr><tr><td styleCode="Lrule Rrule">Rash (yes), %</td><td styleCode="Rrule" colspan="2">5</td><td styleCode="Rrule" colspan="2">5</td><td styleCode="Rrule" colspan="2">50</td><td styleCode="Rrule" colspan="2">38</td></tr></tbody></table>