Dosing and Administration¹

*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)].

The recommended dose of Itovebi is 9 mg orally once daily.
Palbociclib is administered orally at 125 mg daily for 21 consecutive days followed by 7 days off, in a 28-day cycle. Fulvestrant is administered intramuscularly at a dose of 500 mg on days 1 and 15 of cycle 1, and then once every 4 weeks thereafter. Prior to initiating Itovebi, evaluation of fasting plasma glucose and hemoglobin A1c is recommended, and blood glucose should be optimized before starting treatment and monitored regularly during treatment.

INAVO120 Study Design^1-4

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 cancer. 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

1. “Visceral” (yes/no) refers to lung, liver, brain, pleural, and peritoneal involvement.
2. Patients with evaluable bone-only disease were not eligible; patients with bone-only and at least one measurable soft tissue component per RECIST v1.1 were eligible.
3. Defined as ≥1% per ASCO CAP guidelines.
4. Primary resistance: relapse while on the first 2 years of adjuvant ET. Secondary resistance: relapse while on adjuvant ET after at least 2 years or relapse within 12 months of completing adjuvant ET.

A majority of patients had more than three metastatic sites, with visceral liver metastasis being the most common. Approximately one-third of patients had primary endocrine resistance, and two-thirds had secondary endocrine resistance. Notably, there was a low representation of Black or African American patients in the trial. PIK3CA mutation status was primarily determined by ctDNA testing.

Prior Therapies

The majority of patients in both arms had received prior neo-adjuvant or adjuvant chemotherapy and adjuvant endocrine therapy with aromatase inhibitors, tamoxifen, or a combination. Due to the study's enrollment period, only a small percentage of patients had prior exposure to adjuvant CDK4/6 inhibitors.

Efficacy from INAVO 120^1,2

Primary Endpoint: Progression Free Survival (PFS) (Investigator assessed)

Clinical cutoff date: September 29, 2023.

The primary endpoint in INAVO120 was progression-free survival (PFS). At the primary analysis, the results demonstrated a statistically significant reduction in the risk of progression or death with the addition of inavolisib to palbociclib and fulvestrant. The median PFS in the inavolisib arm was 15 months compared to 7.3 months in the placebo arm (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.32-0.59; p < 0.00001). The median follow-up was 21.3 months.

Secondary endpoint: Overall Survival (OS)³

Final overall survival was evaluated as a key secondary endpoint in the study. After a median follow-up of 34.2 months, the results demonstrated a statistically significant reduction in the risk of death in the inavolisib arm compared to the placebo arm (stratified HR=0.67; 95% CI, 0.48-0.94; p=0.0190). Median OS was 34 months in the inavolisib arm compared to 27 months in the placebo arm, translation to a 7 month improvement in median OS.

Clinical cutoff date: 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.^4,5

Safety from INAVO 120^1-6

Hyperglycemia and Elevated Fasting Glucose

CTCAE Grading Criteria for Hyperglycemia in INAVO120

• Hyperglycemia was graded according to CTCAE v5.0 in INAVO120 and as assessed by the investigator.^a
• Glucose (fasting) increased was graded according CTCAE v4.03 in INAVO120.^a

The INAVO120 study start date was January 29, 2020.

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.

The INAVO120 trial utilized CTCAE version 5 for grading hyperglycemia, which is based on clinical assessment without specific numeric ranges.
Hyperglycemia grade 1 is an abnormal glucose above baseline with no medical intervention, and grade 2 is a change in daily management from baseline for a diabetic or oral antiglycemic agent initiated or a workup for diabetes. Grade 3 is when insulin therapy is initiated or hospitalization is indicated, and grade 4 is life threatening consequences or urgent intervention indicated, and grade 5 is death.
In contrast, elevated fasting glucose, a laboratory finding, was graded according to CTCAE version 4, which includes specific fasting blood glucose ranges (increased fasting glucose as a laboratory finding is included in the USPI table 4). A range of the upper limit of normal to 160 is considered a grade 1, and greater than 160 to 250 is grade 2. A fasting glucose of greater than 250 to 500 is grade 3 and a fasting glucose of greater than 500 is a grade 4. Death is grade 5.

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

Table 3 from the USPI for adverse reactions, seen with a higher incidence in inavolisib.

*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 Laboratory Abnormalities (≥10% With ≥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 post treatment 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 posttreatment value.
3. Grading according to CTCAE version 4.03.

Hyperglycemia and Fasting Glucose Rates in INAVO120

Data from the two INAVO 120 study arms were compared side-by-side, analyzing hyperglycemia using CTCAE version 5 and increased fasting glucose using CTCAE version 4

• Hyperglycemia was graded according to CTCAE v5.0 in INAVO120 and as assessed by the investigator.^a

• 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.^b
• Fasting glucose was graded according to CTCAE v4.03 in INAVO120.

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.
2. Section 5.1 of the Itovebi™ US Prescribing Information has important Warnings & Precautions information about hyperglycemia.

Other Key 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).

The incidence of other key adverse events, including diarrhea, rash, and stomatitis/mucosal inflammation, was higher in the inavolisib arm, with the majority of these toxicities being grade 1 or 2. Most adverse events in both treatment groups resolved over time.

Time to Onset of Key Selected Adverse Events^a

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.

Concomitant Medications for Adverse Events

A significant proportion of patients in the inavolisib arm required concomitant medications for the management of key adverse events. Metformin was the most common medication used for hyperglycemia (47%), loperamide for diarrhea (28.4%), topical hydrocortisone cream for rash (16%), and steroid mouthwash for stomatitis (42.6%). Prophylactic steroid mouthwash was used in 20% of patients.

Adverse Event Management for Hyperglycemia^1-19

Mechanism of PI3K Inhibitor-Induced Hyperglycemia

The PI3K pathway is important for regulating glucose homeostasis

• The p110α isoform of PI3K mediates insulin responses in muscle, liver, and adipose tissue
• Activation of PI3K results in a signaling cascade involving AKT and glucose transporters that facilitates glucose uptake

Inhibition of p110α can result in hyperglycemia

• Inhibition of p110α blocks the intracellular response to insulin signaling, leading to…
  • decreased glucose transport and uptake
  • increased glycogenolysis and gluconeogenesis
  • a transitory state of insulin resistance and hyperglycemia, and an increase in circulating insulin
    • preclinical data suggest that the resulting hyperinsulinemia can partially reactivate the PI3K pathway

Warnings and Precautions for hyperglycemia

• Severe hyperglycemia can occur in patients treated with Itovebi.
• The safety of Itovebi in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing antihyperglycemic 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 patients on lifestyle changes.
• Based on the severity of the hyperglycemia, Itovebi may require dose interruption, reduction, or discontinuation.

Updated Safety Information

While no cases of ketoacidosis were reported in the INAVO120 trial, post-marketing surveillance has identified cases of life-threatening ketoacidosis in patients receiving Itovebi. Ketoacidosis is a medical emergency requiring immediate treatment. A Dear Healthcare Provider letter was issued to inform clinicians of this important safety information.

Management Guidelines from INAVO120 Protocol

Evaluate FPG/FBG and glycosylated hemoglobin and optimize blood glucose prior to starting Inavolisib and at regular intervals during treatment.

1. High-risk factors for diabetes include prediabetes, overweight, obese, 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 laboratory value (if patient has 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 agents 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 episodes resolve.
5. It is recommended that the patient is reassessed within 24 hours and preferably the same day for assessments of hydration status and renal function.
6. Fasting glucose should be checked by finger stick or laboratory 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 agents for dosing guidelines.
7. A maximum of two dose reductions was allowed.

The above table illustrates the management guidelines and treatment algorithms that were part of the INAVO120 protocol. This correlates fasting blood glucose ranges in regards to what to do with inavolisib management, as well as medical management and monitoring recommendations that were in the protocol. Treatment decisions are ultimately at the discretion of the treating health care professional and per local institutional guidelines.
Refer to the USPI table 2 for dose modifications for adverse reactions.

High-Risk Factors for Hyperglycemia

Patients considered at high risk for hyperglycemia in the INAVO120 trial included those older than 45 years, with an A1c > 5.7%, pre-diabetes, a family history of diabetes, a BMI > 30, a history of gestational diabetes, and certain ethnicities (African American, South Asian) or an inactive lifestyle.

Anti -Hyperglycemic Agents in INAVO 120 Study protocol

Metformin^a

• Metformin was recommended as first-line for management of^b:
  • sustained fasting glucose >160 mg/dL or >8.9 mmol/L or
  • anytime fasting glucose is >250 mg/dL or >13.9 mmol/L
• At the investigator’s discretion and where allowed by local regulations, prophylactic metformin^c may be initiated on C1D1 for patients at high risk of hyperglycemia
• Monitor for signs and symptoms of:
  • renal impairment
  • metformin toxicity
  • intolerance or 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
• Common side effects of metformin:
  • nausea
  • vomiting
  • diarrhea
  • abdominal pain
  • loss of appetite
• Metformin does not produce hypoglycemia, but hypoglycemia may occur with a missed meal, alcohol consumption, or heavy exercise, or when metformin is taken with another type of diabetes medicine

SGLT2 inhibitors, pioglitazone, DPP-4 inhibitors^d
If metformin was not tolerated or not sufficient, another anti-hyperglycemic medication(s) may be added to or used in place of metformin. Preferred agents included:

• SGLT2 inhibitors
  • Ensure adequate hydration and monitor for vaginal yeast infections
• Pioglitazone
  • Monitor closely for signs of heart failure including fluid retention or edema
• DPP-4 inhibitors
• Patients administered insulin or sulfonylureas should be treated with extreme caution when these agents are used to manage hyperglycemia and inavolisib is subsequently interrupted or discontinued; this can lead to rapid escalation of insulin levels and risk of hypoglycemia
• Short-term insulin is allowed to control blood glucose levels, but the goal should be to maintain them on oral agents once the acute episode resolves

Review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines.

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 (ie, 3 patients on inavolisib in INAVO120), and no conclusions can be drawn.
4. Refer to the local prescribing information for each of these agents.

Metformin was recommended as first-line management for hyperglycemia in the INAVO120 trial. Prophylactic metformin could be considered at the investigator's discretion for high-risk patients, the available clinical data for prophylactic use from the INAVO120 trial is limited to three patients, and no conclusions can be drawn. For patients that are taking metformin, it is important to monitor for signs and symptoms of renal impairment, metformin toxicity, intolerance or toxicity, including lactic acidosis which may occur in the setting of an acute worsening of renal function or cardio respiratory illness or sepsis that can be life threatening. Common side effects of metformin include nausea, vomiting, diarrhea, abdominal pain and loss of appetite. Metformin does not produce hypoglycemia, but hypoglycemia may occur with a missed meal, alcohol consumption, heavy exercise, or when metformin is taken in combination with another type of diabetes medication.
In addition, other agents were used in the INAVO120 trial. If metformin was not tolerated or not sufficient, other anti hyperglycemic medications may be added or used in place of metformin, preferred agents included SGL2 inhibitors (need to ensure adequate hydration and monitor for vaginal yeast infections), pioglitazone (which does require monitoring for signs of heart failure, including fluid retention or edema), as well as dpP4 inhibitors. Patients administered insulin or sulfonylureas should be treated with extreme caution when these agents are used to manage hyperglycemia and inavolisib is subsequently interrupted or discontinued as this can lead to rapid escalation of insulin levels and increase the risk for hypoglycemia. Short term insulin use is allowed to control blood glucose levels, but the goal should be to maintain them on oral agents when once the acute episodes resolve. Review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines.

Summary of Anti-Hyperclycemics Described in the INAVO120 Protocol

When choosing an antihyperglycemic agent, consider possible side effects and onset of action, as well as any adverse events the patient may experience as a result of the PI3K inhibitor treatment. Medications that do not affect the PI3K pathway are preferred. Oral antihyperglycemic medications should be titrated to the maximum allowed dosages to achieve control of blood glucose with a goal of less than or equal to 160 mg per deciliter. For example, metformin may be administered to a maximum dose allowed as per local prescribing information given in divided doses as tolerated. Please see local prescribing information of individual oral antihyperglycemic agents for dosing guidelines.

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 (ie, 3 patients on inavolisib in INAVO120), 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.

Comparison of Hyperglycemia Grading in Clinical Trials

Hyperglycemia was graded using CTCAE version 5 in the INAVO120 trial, while an earlier Phase 1 study (GO39374) utilized CTCAE version 4.^a This difference in grading scales should be considered when comparing safety data across trials.

The INAVO120 study start date was January 29, 2020.

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.

Phase 1 Study (GO39374) Experience with Hyperglycemia

The Phase 1 GO39374 study investigated inavolisib in combination with endocrine therapy and palbociclib. Arm E of this study led to the design of INAVO120. Arm F specifically enrolled high-risk patients for hyperglycemia who received prophylactic metformin. In this arm, a high percentage of patients experienced hyperglycemia despite prophylaxis, highlighting the need for careful monitoring. Overall, a significant proportion of patients in the Phase 1 study required treatment for hyperglycemia, with metformin being the most frequently used agent. The median time to onset of hyperglycemia was 9 days, and the median time to the first antihyperglycemic agent was 15 days. The data on prophylactic metformin from this phase 1 study were limited, and caution is advised when interpreting these results.

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%).

The table below examines arms E and F from the Phase 1 study. It is important to note that the sample size in this study is limited; therefore, formal hypothesis testing was not conducted, and definitive conclusions cannot be drawn. Additionally, the study populations differ from those in the INAVO 120 study. Specifically, arm F comprised a high-risk patient population defined by a BMI exceeding 30 and/or an HBA1c greater than 5.7%. These patients received prophylactic metformin at a dose below 2000 mg daily. As illustrated in the lower right graph, depicted in yellow, these patients commenced metformin at 500 mg on cycle one, day one, concurrently with their fulvestrant. The titration of metformin occurred over a two-week period. Inavolisib treatment initiation was deferred until cycle one, day 15, thereby allowing for a full two weeks of metformin prophylaxis.

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

Patients in Arm F were obese and/or prediabetic and received metformin ≤2000 mg daily; inavolisib was started on C1D15 (Cycle 1 Day 15)

Adverse events were graded according to NCI CTCAE v4.0.

1. 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.

Arm F is a high risk (obese/prediabetic) cohort. Despite initiating metformin prior to inavolisib, hyperglycemia was frequent in this arm. Specifically, 69% of patients experienced hyperglycemia of any grade, and 44% of those on prophylactic metformin developed Grade 3/4 hyperglycemia (CTCAE v4). However, clinical data regarding prophylactic metformin in this context is limited, so these findings should be interpreted with caution.

AEs Of Hyperglycemia Related to Any Study Treatment

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

Results from the phase one study indicated that 43% of patients necessitated treatment for hyperglycemia, with 16% managed with a single medication, most frequently metformin. Insulin was administered to 6% of patients in the acute setting for short-term use. Dose reductions were observed in 9% of patients across all arms. The median time to onset of hyperglycemia was nine days, and the median time to initiation of the first antihyperglycemic agent was 15 days. For patients in arm f, this represented the median time to initiation of the second medication. Given the limited clinical data available regarding prophylactic metformin and its use, these results should be interpreted with caution.