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Efficacy outcomes were numerically higher among patients who experienced inavolisib-associated hyperglycemia, in a post hoc exploratory analysis of the INAVO120 trial. That trial found that patients with PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced breast cancer benefitted from the addition of inavolisib to standard palbociclib and fulvestrant.

The new subgroup analysis also confirmed that the addition of inavolisib to endocrine therapy and cyclin-dependent kinase (CDK)4/6 inhibition improved progression-free survival (PFS) and overall survival (OS) in both patients who did and did not develop hyperglycemia.

Study author Sibylle Loibl, MD, PhD, cautioned that the outcomes by hyperglycemia status are “hypothesis-generating and should not be overinterpreted,” while presenting the new data at ESMO Breast Cancer 2026.

Hyperglycemia is a “well-known on-target toxicity” of PI3K inhibitors, including inavolisib, and these findings raise the possibility that hyperglycemia may reflect “pharmacodynamic target engagement,” explained study discussant Shigehira Saji, MD, PhD, professor and chair, Department of Medical Oncology at Fukushima Medical University in Fukushima, Japan.

The PI3K signaling pathway plays a central role in insulin signaling and glucose regulation. By inhibiting PI3K — particularly the alpha isoform targeted by inavolisib — these drugs can impair glucose uptake and increase blood sugar levels, producing hyperglycemia as a direct pharmacologic effect.

The data do not suggest hyperglycemia itself improves efficacy. Rather, it could be a pharmacodynamic sign that the drug is effectively hitting the PI3K pathway, experts said during the session.

The INAVO120 trial randomized 325 qualifying patients equally to receive either inavolisib 9 mg or placebo orally once daily on a backbone of palbociclib and fulvestrant in 28-day treatment cycles. The main findings from the trial revealed statistically significant improvements in PFS and OS with the addition of inavolisib to endocrine therapy and CDK4/6 inhibition. The FDA approved inavolisib in combination with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence on or after adjuvant endocrine therapy, based on the INAVO120 trial.

At baseline, participants had fasting glucose levels below 126 mg/dL with A1c < 6.0%. Hyperglycemia (any grade) was experienced by 63.4% of those in the inavolisib group and 13.5% of those in the placebo group, and adverse events leading to discontinuation occurred in 6.8% and 0.6% of the trial participants in each of the groups, respectively. Baseline characteristics were generally balanced between patients who did and did not develop hyperglycemia, although higher body weight and BMI were associated with a greater likelihood of hyperglycemia.

The subgroup analysis of the trial, which looked at hyperglycemia and its correlation with outcomes among patients in the inavolisib group who developed hyperglycemia, found that 21.6% had a BMI of at least 30 compared with 11.9% among those who did not experience hyperglycemia.

“PFS was consistently improved with the addition of inavolisib, with a small trend of better PFS with hyperglycemia than without,” reported Loibl, who is a gynecologist at Goethe University Frankfurt in Frankfurt, Germany.

Median PFS was 21.0 months in patients with hyperglycemia and 12.8 months in those without hyperglycemia compared with 7.3 months among those in the placebo group. The hazard ratio vs placebo was 0.38 for patients with hyperglycemia and 0.51 for those without hyperglycemia.

Response rates were higher with inavolisib regardless of hyperglycemia status. Objective response rates were 64.7% among patients with hyperglycemia and 59.3% among those without hyperglycemia compared with 28.0% among those in the placebo group.

Median duration of response was 20.3 months in patients with hyperglycemia and 18.2 months in those without hyperglycemia vs 11.1 months among those receiving placebo.

OS findings followed a similar pattern. Median OS was 34.9 months in patients with hyperglycemia and 32.7 months in those without hyperglycemia compared with 27.0 months among those in the placebo group. Hazard ratios vs placebo were 0.66 and 0.72, respectively.

Overall, efficacy was consistently improved with the addition of inavolisib, with “no significant difference between the groups with and without hyperglycemia,” Loibl said.

Standard management strategies for emergent hyperglycemia, which are clearly outlined in prescribing information, allowed for prolonged treatment with inavolisib, she said.

Echoing Loibl, Saji told attendees “proactive management” of elevated glucose is “important” to allow for sustained dosing.

During the Q&A, Loibl was asked about whether hyperglycemia-related dose adjustments might affect outcome.

“We don’t know exactly, and I think it’s important that we don’t panic,” Loibl told attendees. “We should treat patients for hyperglycemia according to the guidelines, adjust the dose as needed, and keep patients on treatment. They will benefit in the end,” she added.

The study was funded by F. Hoffmann-La Roche. Disclosures for study authors are available with the original publication. Saji disclosed having relationships with Eli Lilly, Chugai, AstraZeneca, Daiichi Sankyo, Pfizer, and other pharmaceutical companies.