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Key Prognostic Factors in Itovebi-Eligible Patients

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ENDOCRINE RESISTANCE
PIK3CA MUTATION

Itovebi (inavolisib), in combination with palbociclib and fulvestrant, is indicated for the treatment of adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.

Endocrine resistance has been observed in ~60% of recurrent 1L HR+/HER2- mBC and has been associated with worse outcomes3,4

In a pooled analysis of 4 trials,
Shorter mOS was observed in endocrine-resistant vs endocrine-sensitive patients with HR+/HER2- mBC4*

Stratified log-rank P=0.03.4
Median follow-up among patients with a distant relapse as the first disease-free survival event and available data on adjuvant endocrine therapy completion (N=493) from diagnosis of a distant relapse was 3.8 years (IQR 1.6–7.5).4

This analysis included patient-level data from 4 adjuvant phase 3 randomized trials conducted in Italy between 1992 and 2012. 493 HR+/HER2- patients who had a distant relapse and met the endocrine resistance/sensitivity classification criteria were included. The impact of the endocrine resistance/sensitivity classification on mOS was assessed in both univariate and multivariate Cox proportional hazards models.4

Endocrine resistance definitions were adapted from the 5th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer. Primary endocrine resistance: Relapse while on the first 2 years of adjuvant endocrine therapy. Secondary resistance: Relapse while on adjuvant endocrine therapy after at least 2 years or relapse within 12 months of completing adjuvant endocrine therapy.4

Endocrine sensitivity was defined as relapse after at least 12 months from adjuvant endocrine therapy completion or a relapse in the context of no prior exposure to adjuvant endocrine therapy.4

ESO–ESMO=European School of Oncology and the European Society of Medical Oncology; IQR=interquartile range; mOS=median overall survival.

*Computed from the date distance relapse and death from any cause.4

PIK3CA is the most commonly mutated gene in HR+/HER2- BC (~40% prevalence†) and can lead to a poor prognosis5-9

In a meta-analysis of 11 trials,
PIK3CA mutation was associated with shorter mOS vs wild-type PIK3CA in HR+/HER2- mBC9

30.8-month median follow-up.9‡

  • In the unadjusted meta-regression model, mutated PIK3CA was associated with an 8.4-month shorter mOS (95% CI: -13.4 to -3.5)

Meta-analysis of 3219 patients from 33 study arms across 11 randomized clinical trials of patients with HR+/HER2- mBC. Of the 3219 patients, 1386 harbored mutated PIK3CA and 1833 were wild-type. The analysis of median OS included 1545 patients from 14 study arms: 708 with mutated PIK3CA, 837 with wild-type PIK3CA. Trials were identified via systematic literature review of articles published from January 1993 to April 2019. Trial arms with PI3K-targeted therapies were excluded. Meta-regression analysis was used to estimate the association between PIK3CA status and OS across included studies.9

1L=first-line; BC=breast cancer; CI=confidence interval; ESO–ESMO=European School of Oncology and the European Society of Medical Oncology; HER2-=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; IQR=interquartile range; mBC=metastatic breast cancer; mOS=median overall survival; PI3K=phosphatidylinositol 3-kinase.

†A range of 30% to 45% has been reported.5-9
‡2 of 14 study arms did not report follow-up.9

National Comprehensive Cancer Network® (NCCN®) recommends testing for PIK3CA mutations at mBC diagnosis to inform eligibility for targeted therapies.2

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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. 2025.

      Itovebi Prescribing Information. Genentech, Inc. 2025.

    • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed February 13, 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.1.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed February 13, 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.

    • 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.

    • 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.