Treatment of alpelisib induced hyperglycemia with sodium-glucose cotransporter-2 inhibitors: A single institution experience.

Abstract

e13041 Background: PIK3CA mutations occur in about 40% of patients with HR+/HER2- breast cancer. The phase III SOLAR-1 trial demonstrated prolonged progression-free survival with alpelisib and fulvestrant compared to fulvestrant alone among patients with HR+/HER2-/ PIK3CA mutant advanced breast cancer previously treated with endocrine therapy. Hyperglycemia was seen in 64% of patients treated with alpelisib and fulvestrant and was treated with metformin. Inhibition of PI3Kα leads to an on-target effect of hyperglycemia and a secondary hyperinsulinemia. This rebound hyperinsulinemia may lead to escape PI3K pathway activation in breast cancer progression via the insulin and IGF1pathways. Concurrent administration of SGLT2 inhibitors may abrogate the PI3K pathway activation effect and delay disease progression. This study reports time on treatment with alpelisib and PFS among patients who received an SGLT2 inhibitor with alpelisib. Methods: A retrospective review of all metastatic breast cancer patients treated with alpelisib was completed from 8/2019 to 5/2021 at the Saint Luke’s Koontz Center for Advanced Breast Cancer. Results: This review included 22 female patients, 11 received an SGLT2 inhibitor for treatment related hyperglycemia (A+SGLT group) and 11 who received metformin/other diabetic agents (A group). Baseline characteristics were not significantly different between the two groups: median age 63, BMI of 29.1, hemoglobin A1C of 6.3 and fasting blood glucose of 119.1mg/dl. PIK3CA mutations included H1047X (40.9%), E545X (31.8%), E542K (13.6%), other (13.6%). The median number of prior treatments for MBC was 3 (range 1-5). Prior treatments included aromatase inhibitors: 100%, fulvestrant: 77%, CDK 4/6 inhibitors: 82%, everolimus: 32% and chemotherapy: 68%. Hyperglycemia grade 2+ was seen in 72.7% of patients. There were no significant differences between the two groups for emergency room visits, hospitalizations, or endocrinology referrals related to hyperglycemia. Median time to initiation of an SGLT2 inhibitor was 13 days following the first dose of alpelisib. PFS was longer in the A+SGLT compared with the A group with a median time to progression of 6.1 months and 3.9 months respectively (HR 0.51; 95% CI 0.16 to 1.63; p = 0.39). Time on treatment was significantly longer for A+SGLT group compared with the A group, with a median time on treatment of 5.8 months, compared with 3.0 months (HR 0.32; 95% CI 0.11 to 0.92; p = 0.03). The primary reason for discontinuation of alpelisb was disease progression in 73%, with no statistically significant difference in the reason for discontinuation between the groups. Conclusions: This study supports a potential clinical benefit of an SGLT inhibitor along with alpelisib in allowing for a longer time on treatment, without significant adverse events. It also suggests a possible favorable impact on PFS for the combination.