The PI3K-alpha inhibitor alpelisib (Piqray) when combined with fulvestrant has been shown to significantly improve progression-free survival compared with fulvestrant alone in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with PIK3CA mutations, in the phase 3 SOLAR-1 clinical trial.1
Hyperglycemia was recognized as an anticipated adverse event associated with alpelisib use, and was the most frequent adverse event, occurring as grade 3 in 32.7% of patients and grade 4 in 3.9% of patients. To provide additional detailed guidance on hyperglycemia and rash management, a protocol amendment was applied. Furthermore, baseline conditions, such as prediabetic or diabetic glycemic status, body mass index (BMI) ≥30, and age ≥75 years were labeled as risk factors for alpelisib-induced hyperglycemia.
Ingrid Mayer, MD, MSCI, Co-Leader, Breast Cancer Research Program, Vanderbilt University, Nashville, TN, and colleagues presented a case report underscoring 4 examples of intervention and different management approaches for alpelisib-induced hyperglycemia in the SOLAR-1 trial.
Throughout the study, glycemic status was regularly assessed by fasting plasma glucose and glycated hemoglobin levels. Grades 3 and 4 hyperglycemia was managed with dose interruptions or reductions by 1 level, along with concomitant medications for hyperglycemia. If within 24 hours, grade 4 hyperglycemia was not improved and confounding factors could be excluded, patients were permanently discontinued from treatment with alpelisib.
In the SOLAR-1 trial, 284 patients were randomized to receive alpelisib, combined with fulvestrant, and 66% of these patients developed hyperglycemia; 163 affected patients received concomitant medications for hyperglycemia.
Three cases of alpelisib-induced hyperglycemia required early intervention. The first female patient, who had a BMI >30 and was prediabetic, presented with grade 2 hyperglycemia on day 8 and was treated with metformin and a dipeptidyl peptidase-4 inhibitor; however, 2 weeks later, she had a grade 3 hyperglycemic event that was managed by interrupting the dose of alpelisib. The patient later had a grade 2 event that led to the addition of a sodium-glucose cotransporter-2 inhibitor and a sulfonylurea; this allowed her to continue treatment with alpelisib for more than 43.3 months.
The second patient was a prediabetic female who also had a BMI >30. She experienced grade 3 hyperglycemia leading to hospitalization on day 8. At this point, the patient began treatment with metformin and then received rescue insulin. Dose adjustments of metformin combined with the addition of a sulfonylurea was the management strategy undertaken, until disease progression occurred at 11.2 months.
The third patient had at baseline a normal glycemic status and a BMI <25. At 197 days of treatment, she presented with grade 2 hyperglycemia and immediately received metformin. The later addition of a dipeptidyl peptidase-4 inhibitor allowed her to continue treatment for more than 40 months.
Lastly, an example of a late intervention for alpelisib-induced hyperglycemia was a patient with a normal glycemic status at baseline and a BMI <30. At day 8, the patient had grade 1 hyperglycemia, with no action taken. Eight days later, she presented with grade 4 hyperglycemia, requiring hospitalization leading to alpelisib discontinuation.
These examples of cases from the SOLAR-1 trial suggest that alpelisib-induced hyperglycemia can be managed with early detection, close monitoring, and prompt intervention, which includes treatment with concomitant antihyperglycemic medications and dose modifications of alpelisib when appropriate. Due to the limited number and type of patients described in this analysis, caution is warranted when interpreting the findings of these case reports.
Reference
- André F, Ciruelos E, Rubovszky G, et al; for the SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940.
