Mafalda Oliveira, MD, PhD, on How Does Hyperglycemia Affect Treatment of Advanced Breast Cancer?

We are presenting an abstract looking at the incidence and management of hyperglycemia in a population of patients with prediabetes and/or obesity enrolled in the phase one trial of inavolisib in combination with endocrine treatment and/or palbociclib in patients with HR-positive HER2-negative PIK3CA-mutated breast cancer. Inavolisib has been approved in patients with this indication, and hyperglycemia is a known side effect of this drug. There is limited experience regarding hyperglycemia management in patients with risk factors for hyperglycemia, and that was the main interest of this study. Among the phase one population, 190 patients were enrolled, and of these, 110 met the definition of prediabetes or obesity. Prediabetes was defined according to the criteria of the American Diabetes Association as the presence of a hemoglobin A1C between 5.7 and 6.4% or a fasting blood glucose between 100 and 126, and obesity was defined as the presence of a body mass index at least or higher than 30 kilograms per meter square. These patients were a subset of the patients enrolled in the phase one trial that included several cohorts of treatments with inavolisib either alone or in combination with endocrine treatment or with triplets with palbociclib. There was a low treatment discontinuation due to adverse events in the overall patient population and also in the prediabetic and obese patients. It was 4% and 6% respectively, as most of the treatment discontinuations were due to disease progression. Hyperglycemia occurred in 68% of the overall patient population treated in the phase one trial. The incidence of hyperglycemia in prediabetes patients was 81%, and it was mainly grade 1 or 2. It is important to note that hyperglycemia was graded in this study according to CTCAE version 4, which means that the grading is related to the absolute number of fasting blood glucose that is determined in this study. Incidence of grade 3–4 hyperglycemia among prediabetic/obese patients was 35%, and within this group, the presence of multiple baseline risk factors appeared to increase the likelihood of developing hyperglycemia, but the numbers in each subgroup are very small and limit the robustness of the observations. An important question when managing patients treated with inavolisib is about the kinetics and outcomes of hyperglycemia, and in this trial the median time to onset of the first all-grade hyperglycemia event was 14 days, both overall and in the patients with the definition of prediabetes or obesity. The median time to resolution or improvement of the first worst event was 8 days, also in both groups, and most hyperglycemia events in both groups resolved or improved with appropriate management. Dose modifications secondary to hyperglycemia were 38% overall and 51% among prediabetic/obese patients. These were mainly dose interruptions; dose reductions occurred in 9% and 14% respectively. Although dose interruptions were common, especially in the prediabetic/obese subgroup, the overall dose intensity remained above 90%, which indicates that the short treatment interruptions were generally sufficient to manage hyperglycemia. Last, let's focus on the treatment of hyperglycemia. Overall, 47% of patients required some form of antihyperglycemia treatment, and among prediabetic and/or obese patients this proportion was 64%. Metformin was the most commonly used medication, and insulin was used in a very small subset of patients—just 8% of prediabetic/obese patients—and note that the use of insulin corresponds to the grade 3 hyperglycemia in CTCAE version 5 that is currently used to grade hyperglycemia. So very similar rates of grade 3 hyperglycemia to more modern trials with inavolisib, and among prediabetic and obese patients most of them had hyperglycemia controlled with metformin with doses that ranged from 1000 to 2000 milligrams. In conclusion, this is a study that informs and gives some more data about the incidence and management of hyperglycemia in patients with risk factors for hyperglycemia, although without a formal diagnosis of diabetes before entering the study. However, this study has some limitations because this is a non–pre-planned analysis of the phase one subset, and more investigation and especially a very thorough management of hyperglycemia is recommended for patients that are starting treatment with inavolisib, especially if they have risk factors for developing hyperglycemia.