Editor’s Note: At the 2026 ESMO Breast Cancer Congress (ESMO BC), Professor Sibylle Loibl from Goethe University Frankfurt presented a post hoc analysis of hyperglycemia in the INAVO120 study. The analysis explored investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS) according to whether patients experienced hyperglycemia of any grade.The findings attracted considerable attention because patients who developed hyperglycemia achieved a median PFS of 21.0 months, significantly longer than the 12.8 months observed in patients without hyperglycemia. Following the presentation, Oncology Frontier interviewed Professor Sibylle Loibl at the ESMO BC meeting to discuss the potential mechanisms underlying the apparent association between hyperglycemia and improved outcomes, as well as practical strategies for transforming metabolic toxicity into sustained clinical benefit through continuous glucose monitoring, early pharmacologic intervention, and lifestyle management.
Study Overview
Background
The INAVO120 study (NCT04191499) previously demonstrated statistically significant improvements in investigator-assessed progression-free survival and overall survival with inavolisib (INAVO) plus palbociclib (PALBO) and fulvestrant (FULV), compared with placebo (PBO) plus palbociclib and fulvestrant, in patients with PIK3CA-mutated, endocrine-resistant HR+/HER2− advanced breast cancer (aBC).
At the final analysis, the incidence of hyperglycemia—a known on-target toxicity associated with PI3K inhibition—was 63.4% in the inavolisib arm compared with 13.5% in the placebo arm. This analysis evaluated efficacy outcomes in patients treated with inavolisib according to whether hyperglycemia occurred.
Methods
Patients received either:
- Inavolisib 9 mg orally once daily, or placebo once daily
- Combined with palbociclib 125 mg orally once daily on Days 1–21 of each 28-day cycle
- Plus fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and approximately every four weeks thereafter
Investigator-assessed progression-free survival, objective response rate, duration of response, and overall survival were analyzed according to hyperglycemia status.
Hyperglycemia was defined as any-grade hyperglycemia adverse event, regardless of severity, duration, or treatment required.
The data cutoff date was November 15, 2024.
Results
Among the 161 patients in the inavolisib arm, 102 developed hyperglycemia of any grade, while 59 did not. The placebo arm included 164 patients.
In the inavolisib arm, the median follow-up was 32.7 months in patients with hyperglycemia and 32.3 months in those without hyperglycemia. Median inavolisib dose intensity was 92.4% and 95.4%, respectively, while median treatment duration was 14.6 months versus 11.2 months.
Baseline characteristics were somewhat imbalanced between patients with and without hyperglycemia in the inavolisib arm, particularly for factors potentially associated with hyperglycemia risk. Median body weight was 64.5 kg versus 60.0 kg, and the proportion of patients with a body mass index (BMI) ≥25 kg/m² was 53.9% versus 30.5%, respectively.
Conclusions
Regardless of hyperglycemia status, patients in the inavolisib arm demonstrated consistently improved efficacy outcomes compared with the placebo arm.
Within the inavolisib-treated population, patients who developed hyperglycemia tended to achieve numerically better outcomes than those who did not, supporting the clinical benefit of inavolisib in these patients.
Although hyperglycemia occurred relatively frequently in the inavolisib arm, proactive glucose management enabled patients to remain on long-term treatment.
Investigator’s Perspective
01
Oncology Frontier: The INAVO120 analysis showed that patients who developed hyperglycemia of any grade appeared to have longer progression-free survival (21.0 months vs. 12.8 months). How do you interpret this seemingly “counterintuitive” efficacy difference? Do you believe it may be related to pharmacokinetics or baseline patient characteristics? In clinical practice, what glucose monitoring and management strategies does your team use to help patients maintain long-term benefit?
Professor Sibylle Loibl:
“The INAVO120 study first demonstrated that adding inavolisib to palbociclib and fulvestrant improves progression-free survival in patients with PIK3CA-mutated HR-positive/HER2-negative breast cancer.
We know that all PI3K inhibitors are associated with hyperglycemia because this is an on-target effect of the drug class.
In the INAVO120 study, we observed that patients who developed hyperglycemia actually appeared to have better outcomes than those who did not, although I would consider this only a very preliminary interpretation of the data. It certainly seems somewhat counterintuitive, and we do not fully understand why patients with hyperglycemia appeared to fare better.
In my opinion, the most likely explanation is that with proactive management, these patients were able to remain on therapy longer—and I think this is the primary and most plausible explanation. These patients did not experience more treatment discontinuations. Although some required dose reductions, treatment intensity remained sufficient to allow prolonged therapy until disease progression.
I believe this was critically important to the success of the study. Hyperglycemia may therefore serve as a signal that these patients are responding well, but from my perspective, what matters most is optimizing management so patients can maintain an adequate dose intensity and ultimately achieve the greatest possible progression-free survival benefit.
That said, active glucose monitoring remains extremely important. Ideally, patients should use continuous glucose monitoring devices so they can monitor glucose levels themselves rather than needing to come to the hospital repeatedly. In my view, this is the best approach, although admittedly it is also more expensive.
At a minimum, blood glucose should be monitored very closely during the first four weeks of treatment to avoid missing the onset of hyperglycemia. Once hyperglycemia occurs, patients should promptly begin treatment with metformin or other glucose-lowering agents, and dose reduction should only be considered if glucose levels cannot be adequately controlled.”
02
Oncology Frontier: Based on these findings, do you believe the inavolisib combination regimen remains appropriate for high-risk patients with preexisting glucose abnormalities or an elevated risk of hyperglycemia in the setting of PIK3CA-mutated, endocrine-resistant advanced breast cancer? What implications do these results have for clinical decision-making?
Professor Sibylle Loibl:
“In most clinical trials, patients at high risk for glucose abnormalities are typically excluded. However, in this study, approximately 18% of patients had a BMI greater than 30 kg/m², representing a higher-risk population.
Among these patients, the incidence of hyperglycemia was around 20%, substantially higher than in other subgroups. Therefore, we need to be especially cautious when treating these patients.
I believe we can still select these patients carefully for treatment. Importantly, in ongoing inavolisib-related studies, the eligibility criteria regarding glycated hemoglobin (HbA1c) have already been relaxed compared with the very strict criteria used in INAVO120.
We need to monitor blood glucose levels carefully, but we also need patients to understand that they belong to a high-risk group and should begin implementing dietary modifications—such as eating whole grains, reducing refined sugar intake, and maintaining a healthy lifestyle. Exercise may also be important because these measures not only help control hyperglycemia but may ultimately benefit breast cancer outcomes overall.”
Professor Sibylle Loibl
