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Itovebi Regimen Safety Profile

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ADVERSE REACTIONS
LABORATORY ABNORMALITIES

Safety profile in the INAVO120 trial1

Most adverse reactions were mild to moderate (grade 1-2) in the Itovebi arm of INAVO1201

ADVERSE REACTIONS IN INAVO120 (≥10% WITH ≥5% ALL GRADES OR ≥2% GRADE 3-4 HIGHER INCIDENCE IN THE ITOVEBI ARM)1

  Itovebi + palbociclib
and fulvestrant (n=162)		 Placebo + palbociclib
and fulvestrant (n=162)
Adverse reaction All grades (%) Grade 3-4 (%) All grades (%) Grade 3-4 (%)
Gastrointestinal disorders
Stomatitis* 51 6† 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‡ 26 0 19 0
Alopecia 19 0 6 0
Dry skin§ 13 0 4.3 0
Metabolism and nutrition disorders
Decreased appetite 24 0 9 0
Infections and infestations
COVID-19 23 1.9 10 0.6
Uninary tract infection‡ 15 1.2† 9 0
Nervous system disorders
Headache‡ 22 0 14 0
Investigations
Weight decreased 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

*Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis.
†No grade 4 adverse reactions were observed.
‡Includes other related terms.
§Includes dry skin, skin fissures, xerosis, and xeroderma.

LABORATORY ABNORMALITIES IN INAVO120 (≥10% WITH ≥2% ALL GRADES OR GRADE 3-4 HIGHER INCIDENCE IN THE ITOVEBI ARM)1

  Itovebi + palbociclib
and fulvestrant*		 Placebo + palbociclib
and fulvestrant†
Select laboratory abnormalities All grades (%) Grade 3-4 (%) All grades (%) Grade 3-4 (%)
Hematology
Neutrophils (total, absolute) decreased 95 82 97 79
Hemoglobin decreased 88 8‡ 85 2.5‡
Platelets decreased 84 16 71 3.7
Lymphocytes (absolute) decreased 72 9 68 14
Chemistry
Glucose (fasting) increased§ 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
  • 96% (52/54) of patients who experienced an increased fasting glucose of >160 mg/dL had an improvement of at least 1 grade level; the median time to improvement from the first event was 8 days (range: 2 to 43 days)

ALT=alanine aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events.

*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.
†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.
‡No grade 4 laboratory abnormalities were observed.
§Grading according to CTCAE version 4.03.

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INAVO120 trial data

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Important Safety Information & Indication

Indication

Itovebi (inavolisib), 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.

Warnings and Precautions

Itovebi has warnings and precautions for hyperglycemia, stomatitis, diarrhea, and embryo-fetal toxicity.

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), HbA1C 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 HbA1C 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.

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.

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%.

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.

Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, Itovebi can cause fetal harm when administered to a pregnant woman. 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.

Most Common Adverse Reactions

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.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see the full Prescribing Information for additional Important Safety Information.

    • Itovebi Prescribing Information. Genentech, Inc. 2024.

      Itovebi Prescribing Information. Genentech, Inc. 2024.

    • Jeselsohn R, Chen L, Chaudhary N, et al. Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2- mBC): prevalence, biomarker characteristics, and outcomes. Poster presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

      Jeselsohn R, Chen L, Chaudhary N, et al. Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2- mBC): prevalence, biomarker characteristics, and outcomes. Poster presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.

    • Lambertini M, Blondeaux E, Bisagni G, et al. Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies. EClinicalMedicine. 2023;59:101931.

      Lambertini M, Blondeaux E, Bisagni G, et al. Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies. EClinicalMedicine. 2023;59:101931.

    • Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490(7418):61-70.

      Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature. 2012;490(7418):61-70.

    • Martínez-Sáez O, Chic N, Pascual T, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22(1):45.

      Martínez-Sáez O, Chic N, Pascual T, et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22(1):45.

    • Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. Int J Breast Cancer. 2020:2020:3759179.

      Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. Int J Breast Cancer. 2020:2020:3759179.

    • Chen JW, Murugesan K, Newberg JY, et al. Comparison of PIK3CA mutation prevalence in breast cancer across predicted ancestry populations. JCO Precis Oncol. 2022;6:e2200341.

      Chen JW, Murugesan K, Newberg JY, et al. Comparison of PIK3CA mutation prevalence in breast cancer across predicted ancestry populations. JCO Precis Oncol. 2022;6:e2200341.

    • Fillbrunn M, Signorovitch J, André F, et al. PIK3CA mutation status, progression and survival in advanced HR+/HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002.

      Fillbrunn M, Signorovitch J, André F, et al. PIK3CA mutation status, progression and survival in advanced HR+/HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002.

    • Brufsky AM, Dickler MN. Estrogen receptor-positive breast cancer: exploiting signaling pathways implicated in endocrine resistance. Oncologist. 2018;23(5):528-539.

      Brufsky AM, Dickler MN. Estrogen receptor-positive breast cancer: exploiting signaling pathways implicated in endocrine resistance. Oncologist. 2018;23(5):528-539.

    • Jhaveri KL, Im S-A, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: phase III INAVO120 primary analysis. Abstract presented at San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX.

      Jhaveri KL, Im S-A, Saura C, et al. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: phase III INAVO120 primary analysis. Abstract presented at San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX.

    • Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. Abstract 1003 presented at American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.

      Juric D, Kalinsky K, Turner N, et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. Abstract 1003 presented at American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2024; Chicago, IL.