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Measure, Monitor, and Manage PI3K Inhibitor–Associated Hyperglycemia

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EFFECT OF PI3K INHIBITION
HYPERGLYCEMIA MANAGEMENT
3 Ms: MEASURE, MONITOR, MANAGE

Elevated blood glucose is an expected, on-target effect of PI3K inhibition16,17

Insulin binds to the insulin receptor and activates the PI3K/AKT pathway, which leads to normal blood glucose levels, or homeostasis, due to17,18:

  • Increased glucose transport from blood vessels, predominantly into liver, muscle, and fat cells
  • Activated glucose usage for immediate energy or storage as glycogen in the liver
  • Inhibited glucose production in the liver
  • Increased protein and fat production

PI3K inhibition interferes with insulin–PI3K/AKT signaling, which leads to elevated blood glucose levels, or hyperglycemia, due to17,19:

  • Decreased glucose transport from blood vessels, predominantly into liver, muscle, and fat cells
  • Inhibited glucose usage for immediate energy or storage as glycogen in the liver
  • Activated glucose production because the liver is no longer effectively suppressed by insulin
  • Decreased protein and fat production

Adapted from Goncalves et al. 2022.17
Adapted from Huang et al. 2018.18
Adapted from Engelman et al. 2006.19

AKT=alpha serine/threonine-protein kinase; PI3K=phosphatidylinositol 3-kinase.

*Nurse Educators are representatives of Genentech and do not give medical advice. Patients should contact their healthcare provider for medical advice.

Download the Itovebi hyperglycemia management guide

Learn more about how you can proactively measure, monitor, and manage increased fasting glucose associated with PI3K inhibition by Itovebi.

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Hyperglycemia in INAVO1201

Hyperglycemia was shown to be manageable with intervention1

Severe hyperglycemia can occur with Itovebi.1

Increased fasting glucose incidence in the Itovebi arm of INAVO120 (n=162)*:

All grades: 85%

  • Grade 2 (FPG >160 to 250 mg/dL): 22%
  • Grade 3 (FPG >250 to 500 mg/dL): 12%
  • Grade 4 (FPG >500 mg/dL): 0.6%

Dose modification due to hyperglycemia in the Itovebi arm of INAVO120 (n=162):

  • Dose interruption: 28%
  • Dose reduction: 2.5%
  • Discontinuation: 1.2%

Median time to first onset of hyperglycemia: 7 days (range: 2 to 955 days)

Antihyperglycemics were used to manage increased fasting glucose in the Itovebi arm of INAVO1201:

  • 46% (74/162) of patients were treated with oral antihyperglycemic medications
  • 7% (11/162) of patients were treated with insulin

Hyperglycemia was shown to be reversible for most patients1,20

  • Among patients who experienced increased fasting glucose >160 mg/dL (grade 2 or higher)1
    • 96% (52/54) had an improvement of at least 1 grade level
    • Median time to improvement from first event: 8 days (range: 2 to 43 days)
  • In a long-term safety analysis of the INAVO120 study (exploratory analysis), patients in the Itovebi arm who experienced any grade of hyperglycemia (93/162) reported 90% of hyperglycemia events (211/235) as recovered/resolved20†

The safety of Itovebi in patients with type 1 diabetes mellitus, or type 2 diabetes mellitus requiring ongoing systemic therapy, has not been studied.1

CTCAE=Common Terminology Criteria for Adverse Events; FPG=fasting plasma glucose.
*In the placebo arm of INAVO120, 43% of patients experienced increased fasting glucose (all grades; 0% grade 3-4 incidence).1
†A descriptive analysis of cumulative hyperglycemia events (grading according to CTCAE version 5.0) in the entire safety evaluable population (N=162), based on investigator assessment.20

Remember the 3 Ms of hyperglycemia management

MEASURE fasting glucose and renal function at baseline1

Before initiating treatment with Itovebi:

  • Assess fasting glucose levels (FPG or FBG) and HbA1C levels, and optimize fasting glucose
  • Assess renal function. The recommended starting dose of Itovebi for patients with moderate renal impairment (eGFR 30 to <60 mL/min based on CKI-EPI) is 6 mg taken orally once daily

MONITOR proactively to help identify increased fasting blood glucose levels early1,16

After initiating treatment with Itovebi or in patients who experience hyperglycemia after initiating treatment with Itovebi:

Monitor or have patients self-monitor fasting glucose levels at regular intervals during treatment, and as clinically indicated1
Month 1
Week 1 Week 2 Week 3 Week 4
Every 3
days
(Day 1-7)		 Once every week
(Day 8-28)
Month 2 and Month 3
Week 1 Week 2 Week 3 Week 4
Once every
2 weeks
Month 4 and thereafter
Week 1 Week 2 Week 3 Week 4
Once every 4 weeks

Monitor HbA1c every 3 months and as clinically indicated

MANAGE hyperglycemia with Itovebi dose modification and antihyperglycemic medications as clinically indicated1,16,17

During treatment with antihyperglycemic medication:

  • Continue monitoring fasting glucose levels1
  • Patients with a history of well-controlled type 2 diabetes mellitus may require intensified antihyperglycemic treatment and close monitoring of fasting glucose levels1
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.1

CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; FBG=fasting blood glucose; FPG=fasting plasma glucose; HbA1C=hemoglobin A1C.

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Itovebi Patient Education

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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. 2025.

      Itovebi Prescribing Information. Genentech, Inc. 2025.

    • Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596.

      Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.4.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed April 17, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding the content, use, or application of these guidelines and disclaims any responsibility for their application or use in any way.

      Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.4.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed April 17, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding the content, use, or application of these guidelines and disclaims any responsibility for their application or use in any way.

    • 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.

    • Jhaveri KL, Im S-A, Saura C, et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer [published online ahead of print May 31, 2025]. N Engl J Med and Supplementary Material. doi:10.1056/NEJMoa2501796.

      Jhaveri KL, Im S-A, Saura C, et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer [published online ahead of print May 31, 2025]. N Engl J Med and Supplementary Material. doi:10.1056/NEJMoa2501796.

    • Turner N, Im S-A, Saura C, et al. INAVO120 phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2- negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Abstract 1003 presented at: American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025; Chicago, IL.

      Turner N, Im S-A, Saura C, et al. INAVO120 phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2- negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Abstract 1003 presented at: American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025; 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.

      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.

    • Protocol for: Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596.

      Protocol for: Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584-1596.

    • Goncalves MD, Farooki A. Management of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia. Integr Cancer Ther. 2022;21:15347354211073163.

      Goncalves MD, Farooki A. Management of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia. Integr Cancer Ther. 2022;21:15347354211073163.

    • Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496.

      Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496.

    • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606-619.

      Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606-619.

    • Saura C, Turner NC, Jhaveri KL, et al. First-line inavolisib/placebo + palbociclib + fulvestrant in PIK3CA-mutated, hormone receptor+, HER2–locally advanced/metastatic breast cancer with relapse during/within 12 months of adjuvant endocrine therapy completion: INAVO120 long-term safety. Abstract P2-09-22 presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.

      Saura C, Turner NC, Jhaveri KL, et al. First-line inavolisib/placebo + palbociclib + fulvestrant in PIK3CA-mutated, hormone receptor+, HER2–locally advanced/metastatic breast cancer with relapse during/within 12 months of adjuvant endocrine therapy completion: INAVO120 long-term safety. Abstract P2-09-22 presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX.