Reviewed by Doreen Pon, Pharm.D., BCOP, BCPS
Associate Professor of Pharmacy Practice and Administration
College of Pharmacy, Western University of Health Sciences

In May 2019, the FDA approved alpelisib (Piqray) for the treatment of metastatic breast cancer that expresses a unique genetic mutation. Alpelisib targets phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in patients with a PIK3CA-mutated tumor.¹ PIK3 is responsible for important biologic functions such as cell survival and proliferation. In PIK3CA-mutated breast cancers, the PIK3CA protein is overactive and leads to increased cellular replication and tumor growth.² The PIK3CA genetic mutation is observed in around 40% of patients with breast cancer.¹

Alpelisib is an orally bioavailable small-molecule medication that was approved for use in combination with fulvestrant, a previously approved hormonal treatment, for the treatment of postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer.³ Current treatment options for these patients include endocrine therapy, chemotherapy, and monoclonal antibodies. In addition, the FDA has approved the therascreen PIK3CA RGQ PCR Kit, which identifies patients with the PIK3CA mutation who might benefit from alpelisib.⁵ Alpelisib was granted FDA approval after the results of the SOLAR-1 trial. The SOLAR-1 was a randomized, double-blind, placebo-controlled, phase III trial conducted in 198 trial centers in 34 countries.³ The trial compared alpelisib plus fulvestrant with placebo plus fulvestrant in patients with HR-positive and HER2-negative advanced breast cancer for whom endocrine therapy had failed. Participants were divided into two cohorts depending on PIK3CA mutation status (PIK3CA mutated vs. not PIK3CA mutated). A total of 572 patients were enrolled in the study and underwent randomization, including 341 patients with confirmed PIK3CA mutations. Each cohort was then divided, with half receiving 300 mg of oral alpelisib once daily plus 500 mg of fulvestrant intramuscular injection on days 1 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle and the other half receiving placebo plus fulvestrant.³ The primary end point was progression-free survival in the patient cohort with PIK3CA-mutated cancer. Patients in the cohort with the PIK3CA mutation were followed for 20 months.³ Median progression-free survival for patients in the PIK3CA-mutated cohort receiving alpelisib plus fulvestrant was 11.0 months (95% CI, 7.5–14.5) compared with the alpelisib plus fulvestrant group, in which the median progression-free survival time was 5.7 months (95% CI, 3.7–7.4).³ Overall, responses among all patients in the PIK3CA-mutated cohort were greater in the alpelisib-fulvestrant group as well. The SOLAR-1 showed a consistent benefit of treatment with alpelisib in combination with fulvestrant.

The SOLAR-1 trial also revealed some troublesome adverse effects associated with alpelisib. The most common adverse effect was hyperglycemia. In the patients who received alpelisib, 63.7% experienced hyperglycemia during their treatment, compared with 9.8% of the patients who received placebo.³ Of the patients in the treatment group with hyperglycemia, 41% had severe (grade 3 or 4) hyperglycemia reaching serum glucose concentrations greater than 250 g/dL.^3,4 Ketoacidosis was reported in 0.7% of patients treated with alpelisib.⁵ Other common adverse effects of significance were diarrhea, increased serum creatinine, hypersensitivity reactions, nausea, decreased appetite, vomiting, and weight loss.⁶ Up to 25% of patients in the treatment group permanently discontinued therapy because of adverse reactions, with hyperglycemia as the most common reason for discontinuation.³ Rash was the next most-common reason for discontinuing therapy. None of the patients in the control group discontinued placebo because of hyperglycemia or rash.³

Alpelisib is an oral medication that is given in combination with fulvestrant. Dosing of alpelisib starts at 300 mg daily. The tablet should be taken at the same time each day with food. Treatment with alpelisib is intended to be continued until disease progression or severe toxicity. If a dose of alpelisib is missed, it can be taken with food up to 9 hours after the regular dose was missed. If more than 9 hours have elapsed, the patient should be instructed to skip the dose and return to taking the medication the next day. Alpelisib comes in blister packaging designed to assist in medication adherence because more than 1 tablet is needed per dose. Dose reduction may be required for some patients with severe adverse reactions. Dose reductions occur in increments of 50 mg, and blister packaging is available in the reduced doses. If a dose reduction below 200 mg/day is required, discontinuation of alpelisib is recommended.⁶

The SOLAR-1 study showed a significant improvement in progression-free survival when alpelisib was used for metastatic PIK3CA-mutated breast cancer. Currently, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology list alpelisib in combination with fulvestrant as a category 1 recommendation for the treatment of HR-positive, HER2-negative, PIK3CA-mutated stage IV or recurrent breast cancer. However, treatment safety concerns remain. The NCCN recognizes that the safety of alpelisib in patients with type 1 or type 2 uncontrolled diabetes has not been established; therefore, use of alpelisib in patients with diabetes has been limited.⁷ The FDA recommends that health care professionals obtain fasting glucose and A1C levels to optimize glycemic control in patients undergoing alpelisib therapy.⁸ This therapy represents an advance in the treatment of metastatic breast cancer, with a phase III study showing a significant statistical improvement in progression-free survival. However, only patients with PIK3CA mutations are eligible, and there are concerns about its use in patients with diabetes. More studies are currently needed to define its optimal use.

References:

1. Markham A. Alpelisib: first global approval. Drugs 2019;79:1249-53.
2. Zardavas D, Wayne P, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res 2014;16:201.
3. Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 2019;380:1929-40.
4. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. November 27, 2017. Available at https://www.fda.gov/medical-devices/recently-approved-devices/therascreen-pik3ca-rgq-pcr-kit-p190001-and-p190004. Accessed September 18, 2020.
5. Piqray [prescribing information]. East Hanover, NJ: Novartis, 2019.
6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 2. 2019 [registration required]. Available at www.nccn.org. Accessed November 28, 2019.
7. Scalzo AJ. Patient with a PIK3CA-positive tumor exhibits hyperglycemia associated with alpelisib. Target Oncol. October 3, 2019. Available at https://www.targetedonc.com/view/patient-with-a-pik3capositive-tumors-exhibits-hyperglycemia-associated-with-alpelisib. Accessed September 18, 2020.