PI3K/AKT Inhibitor Side Effect Management in Metastatic Breast Cancer

PI3K/AKT Inhibitor in HR+, HER2- Metastatic Breast Cancer

On the Oncology Brothers podcast, breast medical oncologist Neil Iyengar, MD, of Winship Cancer Institute of Emory University, and endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Icahn School of Medicine, joined cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss common side effects of PI3K/AKT inhibitors for HR-positive, HER2-negative, locally advanced or MBC.

The FDA approved three agents for this population: alpelisib with fulvestrant in May 2019, based on the SOLAR-1 trial; capivasertib with fulvestrant in November 2023, based on the CAPItello-291 trial; and inavolisib with palbociclib and fulvestrant in October 2024, based on the INAVO120 trial.

Common Side Effects of Inavolisib and Other PI3K/AKT Inhibitors

With any PI3K/AKT inhibitor, some degree of hyperglycemia is expected, and skin and GI events, such as rash and diarrhea, are common. Counseling patients to reduce carbohydrate intake is essential for managing hyperglycemia risk. Doctors also need to educate patients on potential side effects so they can be proactively managed together to preserve quality of life and prevent higher-grade events. For inavolisib, the prescribing information guides dose reductions due to AEs. In Dr. Iyengar’s experience, rash and diarrhea are often manageable with inavolisib and don’t typically require dose reductions.

Prophylactic metformin is commonly used alongside PI3K/AKT inhibitors to prevent hyperglycemia. Dr. Gallagher recommended initiating metformin before starting one of these agents, with gradual uptitration from a low starting dose to minimize additional GI toxicity. SGLT2 inhibitors can be considered second-line or in patients who can’t tolerate metformin, but they require additional monitoring for urinary tract infections.

AEs Seen With Alpelisibrse Events

Use of alpelisib has declined in favor of l better-tolerated options, such as inavolisib and capivasertib. With alpelisib, rash events can be severe enough to require systemic steroids, which may exacerbate metabolic toxicities, Dr. Iyengar said. He recommended holding alpelisib doses while toxicities resolve, even if intending to rechallenge at a lower dose.

Hyperglycemia with PI3K/AKT inhibitors typically develops early on and can rise quickly. Based on the clinical trial protocols, patients should perform home glucose monitoring using finger sticks at least twice weekly. Continuous glucose monitors, which have become widely available since the trials, may help detect hyperglycemia earlier and allow patients to see the impact of high-carbohydrate foods on glucose levels directly, Dr. Gallagher said. 

Capivasertib Toxicity Management

In addition to PIK3CA-mutated HR-positive, HER2-negative MBC, capivasertib is also approved for patients with AKT or PTEN alterations. Capivasertib shares most of the common toxicities of inavolisib and alpelisib, although it is not associated with alopecia. Rash events also tend to be less common or less severe compared with alpelisib. Capivasertib has an intermittent dosing schedule of 4 days on followed by 3 days off at all dose levels. This schedule requires additional education, but patients may experience less toxicity during the off-treatment days, Dr. Iyengar said.

Overall, when using PI3K/AKT inhibitors in HR-positive, HER2-negative MBC, patient education is key to managing toxicity. “Helping people understand what’s happening to them can really help them work with you to reduce these side effects,” Dr. Gallagher said.