Dosing and Administration¹

* The recommended dosage of Itovebi is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity [see Prescribing Information, Recommended Dosage (2.3)]. The recommended starting dosage of Itovebi for patients with moderate renal impairment (eGFR 30 to <60 mL/min based on CKD-EPI) is 6 mg orally once daily [see Prescribing Information, Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

• Before initiating Itovebi, evaluate renal function, evaluate fasting plasma glucose (FPG)/blood glucose (FBG) and hemoglobin A1c (HbA1c) and optimize blood glucose prior to starting Itovebi and at regular intervals during treatment [see Prescribing Information, Warnings and Precautions (5.1)].

INAVO120 Study Design^1-3

Enrollment period: December 2019 to September 2023.

1. PIK3CA mutation status was prospectively determined in a central laboratory using the FoundationOne^® Liquid CDx assay on plasma-derived ctDNA or in local laboratories using various validated PCR or NGS assays on tumor tissue or plasma.
2. Premenopausal women received ovarian suppression.
3. Defined per 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer in the early setting.²
4. OS testing only if PFS is positive; interim OS analysis at primary PFS analysis.

The Phase 3 INAVO120 study was a randomized, double-blind, placebo-controlled trial comparing inavolisib plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in 325 patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancers. The PIK3CA mutation was confirmed by central circulating tumor DNA (ctDNA) testing or local tissue or ctDNA testing. All patients had measurable disease and had progressed during or within 12 months of completing adjuvant endocrine therapy, consistent with the ESMO definition of endocrine resistance. No prior therapy for advanced breast cancer was allowed. Patients with a history of type 1 or type 2 diabetes requiring ongoing antihyperglycemic treatment were excluded. Key eligibility criteria included a fasting blood glucose less than 126 mg/dL or an A1c less than 6%. Patients were randomized 1:1 to receive either the inavolisib-based regimen or the placebo-based regimen until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and patient-reported outcomes. Stratification factors included the presence of visceral disease, region, and type of endocrine resistance. Enrollment occurred between December 2019 and September 2023.

Demographics and Baseline Characteristics

* The data are for patients in the full analysis population, which included all the patients who had undergone randomization. Palbociclib–fulvestrant was included in the inavolisib and placebo regimens. Percentages may not sum to 100 because of rounding.
† Race was reported by the patient.
‡ Performance-status scores range from 0 (no disability) to 5 (death).
§ Visceral disease is defined as lung, liver, brain, pleural, or peritoneal involvement.
¶ Patients with evaluable bone-only disease were not eligible; patients with disease that was limited to bone but had lytic lesions or both lytic lesions and blastic lesions and at least one measurable soft-tissue component (as defined according to RECIST, v1.127) were eligible.
** Tumors were considered to be positive if ≥1% of tumor cells expressed ER or PR, according to ASCO CAP guidelines.
†† Primary resistance: relapse during the first 2 years of adjuvant ET. Secondary resistance: relapse after the start of year 2 of adjuvant ET or relapse within 12 months after the completion of adjuvant ET.

The demographics and baseline characteristics of the study population were generally balanced across both arms. The patients enrolled were considered to be higher-risk, with more than half in each arm having more than three sites of metastatic disease. Visceral liver metastasis was the most prevalent site of metastatic disease.

Regarding endocrine resistance, approximately one-third of the patients had primary endocrine resistance (relapse during the first two years of adjuvant endocrine therapy), while two-thirds had secondary endocrine resistance (relapse after at least two years of adjuvant endocrine therapy or within 12 months of completion).

It is important to note the limited representation of Black or African-American patients in the trial, highlighting the need for more data in underrepresented or understudied populations in ongoing inavolisib trials.

For biomarker testing, 301 patients were enrolled via ctDNA testing (284 by central and 17 by local testing), while 24 patients were enrolled with local tissue testing.

Prior Therapy

This section describes the prior therapies received by patients in the INAVO120 study.

• Prior Chemotherapy: 82% of patients in the inavolisib arm and 83.5% in the control arm had received prior neo- or adjuvant chemotherapy.
• Prior Endocrine Therapy: As these were endocrine-resistant patients, they had prior exposure to adjuvant endocrine therapy, including aromatase inhibitors, tamoxifen, or a combination of both.
• Prior CDK4/6 Inhibitor Use: Prior CDK4/6 inhibitor use was permitted by the protocol. However, due to the study's start date in 2019 and the later approval of adjuvant CDK4/6 inhibitors, only a small number of patients had received them: three in the inavolisib arm and one in the control arm.

Efficacy and Safety From INAVO120^1-27

Primary Endpoint: Progression Free Survival (Investigator Assessed)

Data cutoff: September 29, 2023.

The primary endpoint of the INAVO120 trial was investigator-assessed progression-free survival (PFS). The primary analysis data was presented at SABCS 2023 and published in the New England Journal of Medicine in October 2024.

The Kaplan-Meier curves from this analysis showed a statistically significant improvement in PFS with the inavolisib, palbociclib, and fulvestrant combination.

• Median PFS: The median PFS was 15 months for the inavolisib arm compared to 7.3 months for the placebo arm.
• Hazard Ratio: The hazard ratio was 0.43 (95% CI).
• p-value: The p-value was less than 0.0001.
• Median Follow-up: The median follow-up at the primary analysis was 21.3 months.

Primary Endpoint: Progression Free Survival* (PFS) (Investigator Assessed) (Updated Analysis)

Data cutoff: November 15, 2024.
* Investigator assessed.

At ASCO 2025, an updated descriptive analysis of progression-free survival (PFS) was presented. The Kaplan-Meier curves showed a clear and early separation that was maintained throughout the follow-up period, demonstrating significant improvements in PFS.

• Median PFS: With a median follow-up of 34.2 months, the inavolisib-containing arm had a median PFS of 17.2 months, compared to 7.3 months for the placebo arm.
• Hazard Ratio: The hazard ratio (HR) was 0.42.

Secondary Endpoint: Overall Survival (OS) (Final Analysis)

Data cutoff: November 15, 2024.
* The prespecified boundary for statistical significance (p < 0.0469) was crossed. At the previous primary analysis of PFS (data cutoff September 29, 2023; median follow-up of 21.3 months), the data from the interim analysis of overall survival were not mature, with 30% deaths in the overall population.^1,3

At ASCO 2025, the final analysis of the secondary endpoint of overall survival (OS) was presented. The data showed a median OS of 34 months for the inavolisib-containing arm versus 27 months for the placebo arm, with a hazard ratio of 0.67. This result was statistically significant, with a p-value of 0.0190, as it crossed the pre-specified boundary. This translates to a 33% reduction in the risk of death with the inavolisib combination.

Time From Randomization to First Subsequent Chemotherapy After Treatment Discontinuation (Updated Analysis)

Data cutoff: November 15, 2024.

A descriptive, post-hoc analysis was conducted to evaluate the time from randomization to the first subsequent chemotherapy after treatment discontinuation.

• Median Time to Subsequent Chemotherapy: The addition of inavolisib in the first-line setting delayed the time to chemotherapy by almost two years. The median time to chemotherapy was 35.6 months for the inavolisib arm, compared to 12.6 months for the placebo arm. This represents an improvement of almost 23 months.
• Hazard Ratio: The hazard ratio was 0.43.
• Median Follow-up: The median follow-up for this analysis was 34.2 months.

It is important to note that this was a descriptive, post-hoc analysis, and no definitive conclusions can be made.

Key Post-Progression Therapies (Updated Analysis)

Following treatment discontinuation, fewer patients in the inavolisib group than in the placebo group received chemotherapy in the second line, antibody–drug conjugates in the third line or later, or a PI3K inhibitor in the second line or later
Data cutoff: November 15, 2024.
* Twenty-eight of 111 patients (25.2%) did not receive subsequent therapy in the inavolisib arm due to PD (12 patients), death/censored (7), AEs (2), loss to follow-up (1), non-compliance with study drug (1), physician decision (1), symptomatic deterioration (1), or withdrawal by subject (3). Eleven patients in the inavolisib group had not received subsequent treatment but were documented being alive as of the clinical cutoff date. Thirty-four of 144 patients (23.6%) did not receive subsequent therapy in the placebo group due to PD (24 patients), death/censored (4), withdrawal by subject (3), symptomatic deterioration (2), or AEs (1). Twelve patients in the placebo arm had not received subsequent treatment but were documented as being alive as of the clinical cutoff date.
† One-hundred-and-ten patients in this group received post-progression therapies but one patient was excluded as they were listed as “not applicable” in the database.

An updated analysis of post-progression therapies provides further insight into the clinical benefit of the inavolisib combination. The data shows that after progression on the study treatment, a higher percentage of patients in the placebo arm (72.5%) went on to receive chemotherapy as a second-line treatment, compared to the inavolisib arm (55.4%).

Looking further down the line, in the third-line setting, the utilization of antibody-drug conjugates (ADCs) was also analyzed. The data indicates that 16.7% of patients in the inavolisib arm received an ADC in the third line and beyond, in contrast to 35.7% in the placebo arm.

Additionally, when looking at PI3 kinase inhibitor use in subsequent lines of therapy, the control arm showed that 10.1% of patients used this in the second line and 5.4% of patients in the third line. These findings highlight sustained treatment options after progression.

Adverse Reactions (≥ 10% With ≥ 5% (All Grades) or ≥ 2% (Grade 3-4) Higher Incidence in the Inavolisib Arm - Table 3 From the USPI

* No Grade 4 adverse reactions were observed.

1. Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis.
2. Includes other related terms.
3. Includes dry skin, skin fissures, xerosis, and xeroderma.

Select Lab Abnormalities (≥ 10% With a ≥ 2% (All Grades or Grade 3-4) Higher Incidence in the Inavolisib Arm - Table 4 From the USPI

* In the INAVO120 study, per the INAVO120 study protocol, not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets certain criteria defined in the study protocol. It is the investigator's responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse event.
☨ No Grade 4 laboratory abnormalities were observed.

1. The denominator used to calculate the rate varied from 122 to 160 on the basis of the number of patients with a baseline value and at least one posttreatment value.
2. 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.
3. Grading according to CTCAE version 4.03.

• Increased Fasting Blood Glucose: 85% of patients in the inavolisib arm experienced elevated fasting blood glucose. The majority of these were Grade 1 and 2, with 12% being Grade 3. It is notable that 43% of patients in the placebo arm also experienced an increase in fasting blood glucose.

CTCAE Grading Criteria for Hyperglycemia in INAVO120

• Hyperglycemia was graded according to CTCAE v5.0 in INAVO 120 and as assessed by the investigator.^a
• Glucose (fasting) increased was graded according to CTCAE v4.03 in INAVO 120.^a

The INAVO120 study start date was January 29, 2020.⁶

1. Per the INAVO120 study protocol, not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets certain criteria defined in the study protocol. It is the investigator's responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse event.

This section explains the differences in CTCAE (Common Terminology Criteria for Adverse Events) grading criteria for hyperglycemia and increased fasting glucose, which are based on different versions.

It is important to note that in the INAVO120 trial, hyperglycemia was graded by the investigator according to CTCAE version 5, while increased fasting glucose was graded based on numeric lab ranges from CTCAE version 4.03.

CTCAE Version 5 (Hyperglycemia)

CTCAE version 5 grading is not based on numeric lab ranges, but rather on the need for medical intervention:

• Grade 1: Abnormal glucose above baseline with no medical intervention.
• Grade 2: Change in daily management for a diabetic, or initiation of an oral anti-hyperglycemic agent, or a workup for diabetes.
• Grade 3: Insulin therapy initiated or hospitalization indicated.
• Grade 4: Life-threatening consequences or urgent intervention indicated.
• Grade 5: Death.

CTCAE Version 4.03 (Increased Fasting Glucose)

CTCAE version 4.03 grading is based on numeric lab ranges for fasting glucose:

• Grade 1: Upper limit of normal (ULN) to 160 mg/dL.
• Grade 2: >160 mg/dL to 250 mg/dL.
• Grade 3: >250 mg/dL to 500 mg/dL.
• Grade 4: >500 mg/dL.
• Grade 5: Death.

Hyperglycemia and Fasting Glucose Rates in INAVO120

1. Per the INAVO120 study protocol4, not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets certain criteria defined in the study protocol. It is the investigator's responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse event.
2. Section 5.1 of the Itovebi^® US Prescribing Information has important Warnings & Precautions information about hyperglycemia.

Side-by-side comparison of the two different grading systems used in the INAVO120 trial: hyperglycemia based on CTCAE version 5 and increased fasting glucose based on CTCAE version 4.03.

Hyperglycemia (CTCAE v5):

• All grades: 58.6% (inavolisib arm) vs. 8.6% (placebo arm).
• Grade 3: 5.6% (inavolisib arm) vs. 0% (placebo arm).

Increased Fasting Glucose (CTCAE v4.03):

• All grades: 85% (inavolisib arm) vs. 43% (placebo arm).
• Grade 3/4: 12% (inavolisib arm) vs. 0% (placebo arm).

Key Selected Adverse Events

1. The majority of key selected AEs had resolved (“resolution” was per investigator decision) by the CCOD; some patients were enrolled close to the CCOD, and AE follow-up is ongoing for these patients.
2. Denominators are patients with at least one AE (hyperglycemia, Inavo+Palbo+Fulv: n=95, Pbo+Palbo+Fulv: n=14; diarrhea, Inavo+Palbo+Fulv: n=78, Pbo+Palbo+Fulv: n=26; rash, Inavo+Palbo+Fulv: n=41, Pbo+Palbo+Fulv: n=28; and stomatitis/mucosal inflammation, Inavo+Palbo+Fulv: n=83, Pbo+Palbo+Fulv: n=43).

Most Common Adverse Reactions and Lab Abnormalities:

• 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
• Headache

Incidence and Resolution of Key Adverse Events:

As expected with the addition of a targeted therapy, the inavolisib arm showed a higher incidence of all these adverse events, with the majority being Grade 1 or 2 toxicities. The resolution of these events was assessed by the investigator. The majority of adverse events in both treatment groups did resolve.

Time to Onset of Key Selected Adverse Events

1. Median time to onset of first occurrence of the AE (ie, if an AE was resolved and recurred in the same patient) is not included a second time in this dataset.

• Hyperglycemia: 7 days
• Diarrhea: 15 days
• Stomatitis: 13 days
• Rash: 29 days

Concomitant Medications for Key Selected Adverse Events

• Hyperglycemia: 40.7% of patients received one or more medications, with metformin being the most common.
• Diarrhea: 28.4% of patients received one or more medications, with loperamide being the most common.
• Rash: 16% of patients received one or more medications, with topical hydrocortisone cream being the most common.
• Stomatitis: 42.6% of patients received one or more medications, with a steroid mouthwash being the most common. 20% of patients were treated prophylactically with this medication.

Phase 1/1b (GO39374) Safety

• Hyperglycemia was graded according to CTCAE v5.0 in INAVO120 and as assessed by the investigator*^1,2
• Hyperglycemia was graded according to CTCAE v4.0 in the Phase 1/1b (GO39374) and as assessed by the investigator.*

The INAVO120 study start date was January 29, 2020.⁶ The Phase 1/1b (GO39374) study start date was December 13, 2016.⁸
* Per the INAVO120 study protocol, not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets certain criteria defined in the study protocol. It is the investigator's responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse event.

GO39374: A Phase 1/1b Study of Inavolisib ± ET ± Palbociclib in Patients With PIK3CAmut HR+ MBC

1. Arms A, B, C, D, E, and F: Participants will receive oral inavolisib once daily on Days 1–28 of each 28-day cycle.
2. Palbociclib is a Pfizer drug.
3. Arm G: Participants will receive oral inavolisib once daily on Days 1–21 of each 21-day cycle.
4. Patients in Arm F were obese and/or prediabetic (BMI ≥30 kg/m2 and/or HbA1c ≥5.7%).¹³

Phase 1/1b (GO39374) Arms E and F: Additional Information

Median cumulative fulvestrant dose intensity was 100% in both arms.

Study Design and Context

The GO39374 study was a Phase 1/1b trial of inavolisib with or without endocrine therapy and palbociclib in patients with PIK3CA hormone receptor-positive metastatic breast cancer. It's important to note that different studies have different CTCAE grading criteria. Hyperglycemia was graded according to CTCAE version 5 in the INAVO120 trial, while it was graded according to CTCAE version 4 in the Phase 1/1b G039374 study.

The trial included two notable arms:

• Arm E: Inavolisib plus fulvestrant and palbociclib, which led to the development of the Phase 3 INAVO120 clinical trial.
• Arm F: A high-risk patient population (BMI >30, pre-diabetic, or both) who also received prophylactic metformin (less than 2,000 mg daily). These patients started metformin on Cycle 1, Day 1, and did not begin inavolisib treatment until Cycle 1, Day 15.

A key disclaimer is that this study had a small sample size, and no formal hypothesis testing was conducted. Therefore, no conclusions can be made, and the study population is not the same as in INAVO120.

Phase 1/1b (GO39374) Arms E and F Safety: Inavo + Fulv + Palbo (± Metformin)

1. Adverse events were graded according to NCI CTCAE v4.0. a AEs occurring in ≥4 patients, except those AEs related to metformin.
2. Stomatitis grouped term includes glossodynia, mucositis, mucosal inflammation, mouth ulceration, and lip ulceration.
3. Thrombocytopenia grouped term = thrombocytopenia, decreased platelet count.

Hyperglycemia in High-Risk Patients

Patients in Arm F, who were obese and/or pre-diabetic, received metformin at a dose of ≤2000 mg daily. Inavolisib treatment for these patients did not begin until Cycle 1, Day 15.

In this high-risk patient group, all-grade hyperglycemia was present in 69% of patients, with a 44% incidence of Grade 3/4 hyperglycemia. This data utilized CTCAE version 4.

Note: The available clinical data for prophylactic metformin use are limited, and caution should be used when interpreting these results.

Phase 1/1b (GO39374): Hyperglycemia AEs Related to Any Study Treatment

Data are n patients (%), unless otherwise stated. Adverse events were graded according to NCI CTCAE v4.0.

• Treatment for Hyperglycemia: 43% of patients required treatment for hyperglycemia. Of these, 16% were managed with only one medication, and metformin was the most frequently utilized. Insulin was used in 6% of patients in the acute setting and for short-term use.
• Dose Reductions: Across all arms, dose reductions occurred in 9% of patients.
• Time to Onset: The median time to onset of hyperglycemia was 9 days. The median time to onset for the first anti-hyperglycemic agent was 15 days. For patients in Arm F, who received prophylactic metformin, this was the median time to the second medication.

Note: The available clinical data for prophylactic metformin use are limited, and caution should be used when interpreting these results.

Descriptive Ad Hoc Analysis of Hyperglycemia in Pre-Diabetic/Obese Patients Within the Phase 1/1b (GO39374) Trial

At ASCO 2025, a descriptive ad hoc analysis of hyperglycemia was presented for pre-diabetic and/or obese patients from the Phase 1/1b GO39374 trial. This analysis included all patients across arms A through F.

Definition of Risk Factors

Baseline risk factors for hyperglycemia were defined as:

• Pre-diabetes: Hemoglobin A1c of 5.7% to 6.5% or a fasting blood glucose of 100 to 126 mg/dL.
• Obesity: Body mass index (BMI) of 30 kg/m² or greater.

This analysis has several important limitations:

• It was not a pre-specified part of the study protocol.
• The Phase 1/1b study was conducted in a clinical trial setting with rigorous glucose monitoring and safety management guidelines, which may limit the applicability of the findings to standard clinical practice.
• The patient population was predominantly white and heavily pretreated for advanced/metastatic breast cancer.

Phase 1/1b (GO39374): Patient Demographics and Disease Characteristics

Prediabetic and/or obese patients were a majority of the Phase 1/1b study population; inavolisib dose intensity was high in this population.
* 191 patients enrolled; 190 treated with any study treatment.

The analysis included data from the overall Phase 1 patient population as well as a specific subgroup of pre-diabetic and/or obese patients.

• Overall Patient Population: A total of 191 patients were enrolled in the study.
• Pre-diabetic and/or Obese Subgroup: 110 patients met the criteria for this subgroup, making them the majority of the study population.
  • Prediabetes (HbA1c): 54 patients
  • Prediabetes (Fasting Glucose): 60 patients
  • Obesity (BMI): 49 patients

The median inavolisib cumulative dose intensity was 96% in the overall patient population and 92% in the pre-diabetic and/or obese patient population.

Phase 1/1b (GO39374): Incidence and Severity of Hyperglycemia

Hyperglycemia was assessed according to NCI-CTCAE v4.
Risk factors for prediabetic and/or obese patients: HbA1c ≥5.7% and <6.5%; fasting blood glucose ≥100 mg/dL and <126 mg/dL; or BMI ≥30 kg/m².

Hyperglycemia was assessed according to NCI-CTCAE v4.
Risk factors for prediabetic and/or obese patients: HbA1c ≥5.7% and <6.5%; fasting blood glucose ≥100 mg/dL and <126 mg/dL; or BMI ≥30 kg/m².

Hyperglycemia was a frequent adverse event, especially in the pre-diabetic and/or obese patients.

• Overall Patient Population: 68% experienced all-grade hyperglycemia, and 24% experienced Grade 3 or 4 hyperglycemia.
• Pre-diabetic and/or Obese Subgroup: 81% experienced all-grade hyperglycemia, and this increased to 35% for Grade 3 or 4 hyperglycemia.

The risk for hyperglycemia increased with the number of baseline risk factors, highlighting the importance of baseline assessment. In the pre-diabetic and/or obese subgroup, the incidence of hyperglycemia based on the number of risk factors was:

• One risk factor: All-grade: 76%; Grade 3/4: 30%
• Two risk factors: All-grade: 88%; Grade 3/4: 39%
• Three risk factors: All-grade: 90%; Grade 3/4: 50%

Phase 1/1b (GO39374): Dose Reduction or Discontinuation Due to Hyperglycemia

Hyperglycemia led to dose modifications in both patient groups.

• Overall Patient Population: 32% had a dose interruption, 9% had a dose reduction, and 1% had a dose discontinuation.
• Pre-diabetic and/or Obese Subgroup: 42% had a dose interruption, 14% had a dose reduction, and 1% had a dose discontinuation.

Note: As previously stated, this analysis was performed in a rigorous clinical trial setting with close monitoring, which may limit its applicability to standard clinical practice.

Phase 1/1b (GO39374): Management of Hyperglycemia

* Metformin use excluded Arm F (prophylactic metformin was administered as part of study treatment).
^† Medications administered sequentially or concomitantly.

Medication Use: 47% of patients in the overall population and 64% of patients in the pre-diabetic and/or obese subgroup required medication for hyperglycemia. The most commonly utilized oral agent was metformin, followed by SGLT2 inhibitors, DPP4 inhibitors, and pioglitazone. Insulin was the least utilized agent.
Metformin Details: The median start day for metformin was approximately 14 days into treatment, with a median starting dose of 1,000 mg. The most common daily doses were 1,000 mg (36% of patients) and 2,000 mg (31% of patients).

Adverse Events Management Information for Hyperglycemia

Pathophysiology of PI3K Inhibitor-Associated Hyperglycemia

Understanding the pathophysiology of PI3 kinase-associated hyperglycemia is essential for effective management. The PI3 kinase pathway plays a critical role in regulating glucose homeostasis. When this pathway is inhibited, particularly the P110-alpha isoform targeted by inavolisib, the following cascade occurs:

1. The intracellular response to insulin signaling is blocked.
2. This leads to decreased glucose transport and uptake by cells.
3. Glycogenolysis (the breakdown of glycogen to glucose) and gluconeogenesis (the production of new glucose by the liver) increase.
4. This results in a transitory state of insulin resistance and hyperglycemia, along with an increase in circulating insulin levels.

Knowing this pathophysiology helps in choosing effective management strategies, such as using metformin or SGLT2 inhibitors. Preclinical data also suggests that the resulting hyperinsulinemia can partially reactivate the PI3 kinase pathway. It is important to understand that PI3 kinase inhibition and hyperglycemia is an expected and on-target effect.

Warnings and Precautions for Hyperglycemia

• Severe or fatal hyperglycemia, including ketoacidosis, can occur in patients treated with Itovebi. Ketoacidosis with a fatal outcome has occurred in the postmarketing setting.
• The safety of Itovebi in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing anti- hyperglycemic treatment has 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 on lifestyle changes.
• Based on the severity of the hyperglycemia, Itovebi may require dose interruption, reduction, or discontinuation.

Additional Information on Ketoacidosis

• In the phase 3 trial, INAVO120 (WO41554, NCT04191499), no cases of ketoacidosis were reported. However, cases of life-threatening ketoacidosis have been reported in patients receiving Itovebi in the post- marketing setting.
• Ketoacidosis is a medical emergency characterized by hyperglycemia, electrolyte derangements, metabolic acidosis, and ketonemia. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement, and treatment of any underlying precipitating event. Without optimal treatment, ketoacidosis could result in morbidity and mortality.
• A Dear Healthcare Provider (DHCP) letter was issued by Genentech on March 10, 2025 to inform HCPs of this and important safety information for Itovebi.

Management of Hyperglycemia in the INAVO120 Study

1. High-risk factors for diabetes include prediabetes, overweight, obesity, BMI ≥30 kg/m2, HbA1c ≥5.7%, >45 years of age, family history of diabetes, certain ethnicities, inactive lifestyle, and history of gestational diabetes.
2. Fasting glucose should be checked by finger stick or lab value (if patient has a scheduled appointment) PRIOR to dosing. Oral antidiabetic medications should be titrated to the maximum allowed dosages to achieve control of blood glucose to ≤160 mg/dL or 8.9 mmol/L. For example, metformin may be administered to the maximum dose allowed per local prescribing information, given in divided doses, as tolerated. Refer to local prescribing information of individual oral antidiabetic agent for dosing guidelines.
3. If, in the investigator’s opinion, the benefit-risk assessment favors continued inavolisib dosing without interruption, inavolisib may be continued without interruption upon discussion with the Medical Monitor once patients are managed on antidiabetic agent(s) and fasting glucose ≤200 mg/dL (≤11.1 mmol/L). It is recommended that patients be instructed to utilize a glucometer to monitor fasting glucose and to call the clinic if fasting glucose >200 mg/dL (>11.1 mmol/L) prior to inavolisib dosing at home.
4. There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are started during periods of inavolisib exposure and doses are not adjusted appropriately during periods of treatment interruption, during which patients’ insulin sensitivity may increase rapidly. Short-term insulin is allowed to control blood glucose levels, but the goal should be to maintain blood glucose on oral agents once acute episode resolves.

1. There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are started during periods of inavolisib exposure and doses are not adjusted appropriately during periods of treatment interruption, during which patients’ insulin sensitivity may increase rapidly. Short-term insulin is allowed to control blood glucose levels, but the goal should be to maintain blood glucose on oral agents once acute episode resolves.
2. It is recommended that the patient is reassessed within 24 hours and preferably the same day for assessments of hydration status and renal function.
3. Fasting glucose should be checked by finger stick or lab value PRIOR to dosing. Oral anti-diabetic medications should be titrated to the maximum allowed dosages to achieve control of blood glucose to ≤160 mg/dL or 8.9 mmol/L. Refer to local prescribing information of individual oral antidiabetic agent for dosing guidelines.
4. A maximum of two dose reductions was allowed.

The above tables outline the management guidelines and treatment algorithms included in the INAVO120 clinical trial protocol. These guidelines correlate fasting blood glucose ranges with specific recommendations for inavolisib management, medical management, and monitoring.

Key Recommendation: It is recommended to evaluate fasting blood glucose and hemoglobin A1c, and optimize blood glucose levels prior to starting inavolisib and at regular intervals during treatment.

Disclaimer: Treatment decisions are ultimately at the discretion of the treating healthcare professional and local institutional guidelines. For specific dose modifications for adverse reactions, please refer to the USPI (U.S. Prescribing Information) Table 2.

Management of Patients at High Risk for Hyperglycemia in the INAVO120 Study

In the INAVO120 trial, patients were considered high-risk for hyperglycemia based on a number of factors:

• Age greater than 45 years.
• Hemoglobin A1c greater than or equal to 5.7%.
• Pre-diabetic status.
• A family history of diabetes.
• Body mass index (BMI) greater than or equal to 30.
• A history of gestational diabetes.
• Ethnicity, such as African American or South Asian.
• An inactive lifestyle.

Anti-Hyperglycemic Use in the INAVO120 Study - Metformin and Other Agents

Overview of the anti-hyperglycemic medications utilized in the INAVO120 study, with specific focus on metformin and other agents.

• Metformin^a: Recommended as a first-line management option.^b At the investigator's discretion, prophylactic metformin^c could be initiated on Cycle 1, Day 1 for high-risk patients. However, the available clinical data for prophylactic use from the INAVO120 trial is limited to three patients, so no conclusions can be drawn.
  • Precautions: When patients are taking metformin, it is important to monitor for signs and symptoms of renal impairment, metformin toxicity, or lactic acidosis, which can be life-threatening.
  • Common Side Effects: Nausea, vomiting, diarrhea, abdominal pain, and loss of appetite.
  • Hypoglycemia Risk: Metformin does not typically cause hypoglycemia on its own, but it may occur with a missed meal, alcohol consumption, heavy exercise, or when combined with another diabetes medication.
• Other Agents: If metformin was not tolerated or sufficient, other anti-hyperglycemic medications could be added or used in its place. Preferred agents included SGLT2 inhibitors.^d
  • SGLT2 inhibitors: Ensure adequate hydration and monitor for vaginal yeast infections.
  • Pioglitazone: Monitor closely for signs of heart failure, including fluid retention or edema.
  • DPP4 inhibitors: Also used as an option.
• Insulin and Sulfonylureas: These agents should be used with extreme caution. When used to manage hyperglycemia, inavolisib is subsequently interrupted or discontinued,^d as this can lead to a rapid escalation of insulin levels and a risk of hypoglycemia. Short-term insulin use was allowed in the protocol to control blood glucose levels, with the goal of maintaining patients on oral agents once the acute episode resolved.

1. Refer to the local prescribing information for metformin. Metformin was recommended to be titrated to the maximum allowed dosages to achieve control of blood glucose to ≤160 mg/dL or 8.9 mmol/L.
2. Investigators were advised to exercise caution in the dosing and management of patients receiving metformin in combination with inavolisib and to be vigilant for signs of renal impairment and metformin toxicity including lactic acidosis, which may occur in the setting of acute worsening of renal function or cardiorespiratory illness or sepsis and can be life‑threatening. The most frequently reported AEs with metformin are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. Metformin does not produce hypoglycemia, but it may occur with a missed meal, alcohol consumption, or heavy exercise, or when it is taken with another type of diabetes medicine.
3. The available clinical data for prophylactic metformin use are limited (3 patients in INAVO120 and 16 patients in the Phase 1 Arm F), and no conclusions can be drawn.
4. Refer to the local prescribing information for each of these agents.

Summary of Anti-Hyperglycemic Described in the INAVO120 Protocol

1. Metformin was recommended to be titrated to the maximum allowed dosages to achieve control of blood glucose to ≤160 mg/dL or 8.9 mmol/L.
2. Investigators were advised to exercise caution in the dosing and management of patients receiving metformin in combination with inavolisib and to be vigilant for signs of renal impairment and metformin toxicity including lactic acidosis, which may occur in the setting of acute worsening of renal function or cardiorespiratory illness or sepsis and can be life‑threatening. The most frequently reported AEs with metformin are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. Metformin does not produce hypoglycemia, but it may occur with a missed meal, alcohol consumption, or heavy exercise, or when it is taken with another type of diabetes medicine.
3. The available clinical data for prophylactic metformin use are limited (3 patients in INAVO120 and 16 patients in the Phase 1 Arm F), and no conclusions can be drawn.
4. There is a risk of hypoglycemia if insulin or sulfonylureas are used, particularly if these agents are started during periods of inavolisib exposure and doses are not adjusted appropriately during periods of treatment interruption, during which patients’ insulin sensitivity may increase rapidly. Short-term insulin is allowed to control blood glucose levels, but the goal should be to maintain blood glucose on oral agents once acute episode resolves.

When choosing an agent, side effects and onset of action should be considered.

• Insulin: Insulin is listed as a last-line agent. This is because it has a stimulatory effect on PI3 kinase signaling and is associated with an increased risk of hypoglycemia. Therefore, it is considered a last-line of therapy for PI3 kinase inhibitor-associated hyperglycemia.