Rodon, Jordi, Demanse, David, Rugo, Hope S., Burris, Howard A., Simo, Rafael, Farooki, Aziz, Wellons, Melissa F., André, Fabrice, Hu, Huilin, Vuina, Dragica, Quadt, Cornelia and Juric, Dejan (2024) A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer. Breast cancer research. ISSN 1465-542X

Abstract

Importance: Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib.
Objective: To characterize early grade 3/4 alpelisib-related hyperglycemia, along with associated incidence, management, and outcomes using a machine learning model
Design and Setting: Data for the risk model was pooled from patients receiving alpelisib +/- fulvestrant in the open-label phase 1 X2101 trial and the randomized, double-blind phase 3 SOLAR-1 trial.
Participants: The pooled population (n=505) included patients with advanced solid tumors (X2101, n=221) or HR+/HER2− ABC (SOLAR-1, n=284). Hyperglycemia incidence and management were analyzed for SOLAR-1. Additional external validation was performed using the BYLieve trial (n=340).
Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): Alpelisib +/- fulvestrant/letrozole.
Main Outcome(s) and Measure(s): A machine learning model capable of predicting risk of early grade 3/4 alpelisib-induced hyperglycemia.
Results: A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high- or low-risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib + fulvestrant in SOLAR-1 showed shorter time to grade 3/4 hyperglycemia, higher incidence of hyperglycemia, increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (14.2% vs 2.2% of discontinuations) in the high- vs low-risk group. Among patients in SOLAR-1 with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs 10.9 mo). For external validation, the model was applied to the BYLieve trial, where successful classification into high and low risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed.
Conclusions and Relevance: A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients that may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes.

Item Type:	Article
Date Deposited:	27 Mar 2024 00:45
Last Modified:	27 Mar 2024 00:45
URI:	https://oak.novartis.com/id/eprint/50388