Does insulin work in patients with diabetes taking inavolisib (a phosphatidylinositol 3-kinase (PI3K) inhibitor) due to its mechanism of action?

Does Insulin Work in Patients Taking Inavolisib?

Yes, insulin works mechanistically in patients taking inavolisib, but it should be avoided as first-line therapy because insulin may partially reactivate the PI3K pathway and potentially reduce the anti-cancer effectiveness of inavolisib. 1, 2

Mechanism of the Problem

• Inavolisib is a PI3K inhibitor that blocks the phosphatidylinositol-3-kinase pathway, which is the same intracellular pathway that mediates insulin's action after binding to the insulin receptor 1, 2
• PI3K inhibition leads to decreased glucose transport, increased glycogenolysis, and increased gluconeogenesis, resulting in hyperinsulinemic hyperglycemia 1, 2
• In the INAVO120 trial, 85% of patients developed increased fasting glucose, with 22% experiencing Grade 2 hyperglycemia (FPG >160-250 mg/dL), 12% Grade 3 (FPG >250-500 mg/dL), and 0.6% Grade 4 (FPG >500 mg/dL) 3

Why Insulin Should Be Avoided

• Animal models demonstrate that hyperinsulinemia from exogenous insulin administration results in partial reactivation of the PI3K pathway, which may counter the anti-cancer effectiveness of PI3K inhibitors 1, 2
• The compensatory increase in endogenous insulin release from PI3Ki-induced hyperglycemia has been shown to reduce treatment efficacy by reactivating the PI3K pathway in preclinical models 2
• Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect on PI3K signaling 2

Preferred Treatment Hierarchy for Inavolisib-Associated Hyperglycemia

First-Line Agents (Do Not Affect PI3K Pathway)

• Metformin: Preferred primary agent that does not affect the PI3K pathway 2
• SGLT2 inhibitors: Preferred as they do not stimulate insulin secretion or affect PI3K signaling 1, 2
• Low carbohydrate diet: Essential non-pharmacologic intervention 1

Second-Line Agents

• Thiazolidinediones: Do not affect PI3K pathway but use with caution due to heart failure risk and weight gain 2
• α-glucosidase inhibitors: Alternative agents that do not affect PI3K signaling 2

Agents to Avoid

• Insulin: Last-line only due to PI3K pathway reactivation 1, 2
• Sulfonylureas: May inhibit anti-tumor activity of PI3K inhibitors 1
• DPP-4 inhibitors and GLP-1 receptor agonists: Increase insulin secretion, which may theoretically reduce PI3Ki efficacy 2

Clinical Management Protocol from FDA Label

Pre-Treatment Requirements

• Test fasting plasma glucose (FPG) or fasting blood glucose (FBG) and HbA1c levels before initiating inavolisib 3
• Optimize fasting glucose before starting treatment 3
• The safety of inavolisib has not been studied in patients with Type 1 diabetes or Type 2 diabetes requiring ongoing anti-hyperglycemic treatment 3

Monitoring Schedule After Initiation

• Days 1-7: Monitor fasting glucose once every 3 days 3
• Days 8-28: Monitor once weekly 3
• Weeks 5-12: Monitor once every 2 weeks 3
• After 12 weeks: Monitor once every 4 weeks and as clinically indicated 3
• HbA1c: Monitor every 3 months 3

Dose Modifications for Hyperglycemia

• FPG 160-250 mg/dL (Grade 2): Continue inavolisib, initiate or intensify anti-hyperglycemic medications 3
• FPG 251-500 mg/dL (Grade 3): Withhold inavolisib until FPG ≤160 mg/dL, then resume at one lower dose level (from 9 mg to 6 mg, or from 6 mg to 3 mg) 3
• FPG >500 mg/dL (Grade 4): Withhold inavolisib until FPG ≤160 mg/dL, resume at one lower dose level; if recurs within 30 days, permanently discontinue 3

Real-World Clinical Data

• In INAVO120, only 7% (11/162) of patients required insulin to manage hyperglycemia, while 46% (74/162) were managed with oral anti-hyperglycemic medications 3
• Among patients with hyperglycemia >160 mg/dL, 96% (52/54) had improvement of at least one grade level with a median time to improvement of 8 days 3
• Hyperglycemia led to dose interruption in 28%, dose reduction in 2.5%, and discontinuation in only 1.2% of patients 3
• The median time to first onset of hyperglycemia was 7 days (range: 2-955 days) 3

When Insulin Must Be Used

If insulin becomes absolutely necessary despite the theoretical concerns:

• Use basal insulin regimens that minimize hyperinsulinemia rather than intensive basal-bolus regimens 4
• Start with conservative doses (0.1-0.15 units/kg/day) given the altered insulin sensitivity from PI3K inhibition 4
• Monitor for hypoglycemia risk, as patients may have unpredictable insulin sensitivity 4
• Consider consultation with an endocrinologist experienced in managing PI3Ki-associated hyperglycemia 3, 2

Critical Pitfall to Avoid

Do not reflexively reach for insulin when managing inavolisib-associated hyperglycemia. The standard diabetes management algorithms that prioritize insulin for severe hyperglycemia do not apply in this unique situation where insulin may compromise cancer treatment efficacy. Exhaust all insulin-independent options first, including dose reduction of inavolisib itself if necessary. 1, 2