Abstract PS10-35: Early intervention for and management of alpelisib (ALP)-induced hyperglycemia: Case studies from the phase III SOLAR-1 trial
Authors: Mayer Ingrid , Farooki Azeez , Rugo Hope S. , Iwata Hiroji , Ciruelos Eva , Campone Mario , Loibl Sibylle , Conte Pierfranco , Juric Dejan , Ghaznawi Farhat , Lorenzo Ines , Hu Huilin , Gaudenzi Fiorenza , Andre Fabrice 
Published: February 2021

Abstract
Background: In the Phase III SOLAR-1 trial (NCT02437318), ALP (PI3Kα inhibitor) + fulvestrant (FUL) significantly improved progression-free survival vs FUL alone in patients (pts) with HR+/HER2− advanced breast cancer with PIK3CA mutations (André et al. N Engl J Med. 2019;380:1929-1940). Hyperglycemia was identified as an expected adverse event (AE) with ALP and was the most frequent grade (G) 3/4 AE in SOLAR-1 (G3, 32.7%; G4, 3.9%). A protocol amendment was implemented during the study to provide additional detailed guidance on hyperglycemia and rash management. Additionally, conditions at baseline such as prediabetic or diabetic glycemic status, body mass index (BMI) ≥30, and age ≥75 years have been identified as risk factors for ALP-induced hyperglycemia. Here we present a case report highlighting 4 examples of early intervention and different management approaches for ALP-induced hyperglycemia in SOLAR-1. Methods: According to the protocol, glycemic status was assessed at baseline and over time using fasting plasma glucose and glycated hemoglobin. Hyperglycemia was regularly assessed per the National Cancer Institute CTCAE v4.03. In addition to concomitant medications for hyperglycemia, dose interruptions or reductions by one level were recommended for both G3 and G4 hyperglycemia, per protocol. If G4 hyperglycemia had not improved within 24 hours and confounding factors could be excluded, pts should be permanently discontinued from ALP. Pts from this case report were selected on the basis of hyperglycemia events of interest to the community: (1) not well controlled on metformin alone; (2) required hospitalization; (3) no risk factors for hyperglycemia at baseline; (4) no action taken at initial presentation of hyperglycemia. Results: In SOLAR-1, 284 pts were randomized to ALP + FUL and 187 (66%) developed hyperglycemia; 163 of these pts received concomitant medications for hyperglycemia, and most received metformin as part of their treatment (87%). Three cases exhibited examples of early intervention for ALP-induced hyperglycemia. The first pt was prediabetic and had a BMI &gt;30. She presented with G2 hyperglycemia on day 8 and received metformin and a DPP-4 inhibitor but then had a G3 event 2 weeks later, managed by an ALP dose interruption. Another G2 event led to addition of an SGLT2 inhibitor and a sulfonylurea, which allowed her to stay on ALP treatment (&gt;43.3 mo). The second pt was prediabetic and had a BMI &gt;30. She had G3 hyperglycemia leading to hospitalization on day 8, started metformin, and then received rescue insulin. She continued to be managed with dose adjustments of metformin and addition of a sulfonylurea until disease progression (11.2 mo). The third pt had a normal glycemic status at baseline and a BMI &lt;25. She presented with G2 hyperglycemia at 197 days of treatment and immediately received metformin. A DPP-4 inhibitor was also later added, allowing her to stay on treatment (&gt;40.5 mo). A case example of late intervention for ALP-induced hyperglycemia was a pt who had a normal glycemic status at baseline and a BMI &lt;30. She demonstrated G1 hyperglycemia at day 8, no action was taken, and then she presented with G4 hyperglycemia 8 days later, requiring hospitalization leading to discontinuation of ALP. Conclusions: These cases from SOLAR-1 suggest that ALP-induced hyperglycemia is manageable with close monitoring, early detection, and prompt intervention, including concomitant medications and dose modifications where appropriate. This case report should be interpreted with caution due to the limited number and type of pts.
Citation Format: Ingrid Mayer, Azeez Farooki, Hope S. Rugo, Hiroji Iwata, Eva Ciruelos, Mario Campone, Sibylle Loibl, Pierfranco Conte, Dejan Juric, Farhat Ghaznawi, Ines Lorenzo, Huilin Hu, Fiorenza Gaudenzi, Fabrice Andre. Early intervention for and management of alpelisib (ALP)-induced hyperglycemia: Case studies from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-35.