Pharmacist Management of Alpelisib-Associated Hyperglycemia

HR-Positive, HER2-Negative Breast Cancer Treatment

Approximately 70% of invasive breast cancers diagnoses are for disease that is hormone receptor (HR)-positive and HER2-negative. Based on the National Comprehensive Cancer Network guidelines for breast cancer, the standard of care for treatment of HR-positive, HER2-negative metastatic breast cancer is endocrine therapy.¹

Endocrine therapy consists of selective estrogen receptor modulators, such as tamoxifen; selective estrogen receptor degraders, such as fulvestrant; or aromatase inhibitors, such as anastrozole. However, endocrine therapy resistance is present in approximately 50% of tumors, contributing to disease progression or recurrence. The prevalence of disease recurrence indicates that cancers will eventually become resistant to endocrine therapy.² The mechanisms behind the resistance are diverse and complex, so alternative therapies will need to be considered.

CDK4/6 inhibitors (abemaciclib, palbociclib, ribociclib) are novel agents that can be used to treat HR-positive, HER2- negative metastatic breast cancer as well. These medications are highly selective and prevent CDK-mediated cell division by stopping the cell cycle at the DNA synthesis phase. The addition of CDK4/6 inhibitors to endocrine therapy has led to significant improvement in progressionfree survival in metastatic disease. A study of ribociclib reported response rates in 41% to 48% of patients and an increase in overall survival when added to endocrine therapy, compared with endocrine therapy alone.^3-6 This has led to CDK4/6 inhibitors becoming a standard of care for first-line treatment in combination with endocrine therapy in metastatic, HR-positive breast cancer.¹

PI3K Mutations

PI3K mutations occur in 40% of patients with HR-positive, HER-2 negative metastatic breast cancer. A kinase enzyme, PI3K plays an important role in growth-factor signaling. However, the PI3K pathway is susceptible to mutations; the most common mutation leads to amplification of genes encoding the PI3K pathway. Enhanced PI3K activity seen in cancer cells will lead to additional growth of the cells. There are 3 classes of kinase enzymes, but class I PI3K, specifically, has been directly linked to the growth of cancer cells.⁷ When PI3K inhibitors were tested in vitro, they showed inhibition of the tumor cells carrying the mutation and significant tumor growth inhibition.⁸

Alpelisib

Alpelisib is an oral agent that inhibits PI3Kɑ, providing its antitumor effects. When studied in vitro, alpelisib had significant activity against PI3Kɑ mutant cells; it also resulted in antitumor efficacy in mice models. Additionally, synergistic antitumor effects were observed when alpelisib was combined with fulvestrant.⁸ In 2019, Andre et al compared alpelisib 300 mg daily with intramuscular fulvestrant 500 mg on days 1 and 15 of the first 28-day cycle, then monthly thereafter in SOLAR-1, a randomized phase 3 trial.⁹ Of the 572 patients enrolled in the study, 341 patients had detectable PI3Kɑ mutations. Alpelisib demonstrated a significant 35% reduction in risk of disease progression or death in the PI3Kɑ mutation—positive cohort when compared with placebo. When the PI3Kɑ mutation—positive cohort was compared with the non–PI3Kɑ mutation cohort, the positive cohort had a 13.8% greater overall response.

Hyperglycemia Adverse Effect

The SOLAR-1 investigators also found that 63.7% of patients in the treatment group experienced hyperglycemia (compared with 9.8% receiving placebo).⁹ A third of these patients developed a blood glucose level higher than 250 mg/dL, requiring treatment and discontinuation of therapy; 6.3% of patients required therapy interruption due to the effects of hyperglycemia. The 4 different levels of hyperglycemia (Table) have different management recommendations.¹⁰ Hyperglycemia of grade 3 or 4 requires therapy interruption whereas grades 1 or 2 do not, but all grades require antihyperglycemia treatment. In SOLAR-1, a peak in blood glucose was noted at 2 weeks, and discontinuation of alpelisib led to resolution of hyperglycemia.

Normally, the p110ɑ subunit of PI3K plays a role in storing glucose as glycogen when insulin levels increase, which then leads to a reduction in blood glucose levels. When PI3K is inhibited, more glucose is released into the blood, leading to hyperglycemia.⁷ This effect is unique to this targeted agent and is clinically significant due to the incidence and severity of hyperglycemia. Prior to initiating alpelisib, glycated hemoglobin ( A1C) and fasting blood glucose measurements should be taken, and they should be monitored periodically at outpatient appointments. Since patients with type 1 diabetes or uncontrolled type 2 diabetes ( A1C > 6.4%) were excluded from the SOLAR-1 study, the safety of alpelisib use in this patient population is unknown.

If a patient experiences grade 1 or 2 hyperglycemia on alpelisib, an A1C should be taken and appropriate therapy should be initiated based on American Diabetes Association guidelines.¹¹ As long as the patient has no contraindications, metformin can be initiated at a low dose and increased as tolerated. However, alpelisib has been shown to cause diarrhea in about 58% of patients, which can be worsened with the initiation of metformin, which also has a high incidence of gastrointestinal adverse effects.¹⁰ Based on A1C and blood glucose levels, additional therapy may be needed along with metformin.

Some antihyperglycemic agents provide specific benefits, such as improved cardiovascular or renal outcomes, and these can be beneficial in certain patients, depending on their comorbidities. For example, in patients with heart failure or chronic kidney disease, SGLT2 inhibitors will provide benefit; however, the potential adverse effects of polyuria, hypotension, and genital infections should be weighed against the benefits. Additionally, agents are associated with different levels of A1C reduction effects and hypoglycemia effects.

Although insulin is efficacious, it is associated with hypoglycemia and involves daily selfinjection and dedication to consistent blood glucose monitoring. DPP-4 inhibitors have a more modest benefit, but with a low risk of hypoglycemia. GLP-1 analogues provide the benefits of excellent A1C reduction, low hypoglycemia risk, weight loss, and cardiovascular advantages, but initiation requires a careful review of past medical history, since they should not be used in patients with pancreatitis, gastroparesis, or thyroid C-cell tumors. Thiazolidinediones are not frequently used since they are associated with several toxicities.

Impact of Pharmacists in Managing Toxicity

The selection of an agent for hyperglycemia management requires knowledge of both the efficacy and the potential adverse effects of each possible agent, so choosing the best therapy for any given patient can be complicated. Oncology pharmacists can provide therapeutic recommendations for cancer treatment based on guidelines and the medical literature. They will provide dose recommendations and ensure that the patient is premedicated appropriately to help avoid any adverse outcomes.

Pharmacists can also play a key role in toxicity management by providing recommendations for self-treatment or alternative therapies, or by referring patients to specialists. In the case of alpelisib-induced hyperglycemia, an ambulatory care pharmacist trained in diabetes management can help in the selection of antihyperglycemia treatment. Pharmacists who are certified diabetes care and education specialists can provide counseling on the pathophysiology of diabetes and its management, beyond the discussion of medications, to include advice on lifestyle modifications.

It’s not only the selection of treatment that may trouble a patient receiving their orally administered cancer therapy or hyperglycemia therapy. Cost barriers may exist, as may the need to submit prior authorizations; the outpatient pharmacist should assess and facilitate as needed.

Alpelisib must be dispensed from a specialty pharmacy. Specialty pharmacies, highly regulated and accredited, take appropriate steps to ensure safe dispensing of high-risk medications like alpelisib. Patients will be counseled on multiple occasions, from the day they are prescribed a medication to the day they receive it.

Whether employed at a specialty or community pharmacy, the pharmacist remains among the most accessible health care providers, always giving patients an available trained provider to answer their medicationrelated questions. Further, pharmacists are trained to incorporate the patient in every decision made about their health. If a patient is engaged and knowledgeable about their disease, they are more likely to be adherent to their treatment.

The care required for patients taking an oral chemotherapy agent like alpelisib can be complex. A multidisciplinary team approach is ideal for ensuring that the best decisions are made in terms of treatment and monitoring. Pharmacists are an essential part of this team and their participation will improve patient outcomes.

MEISSANE BENBRAHIM, PHARMD is a resident at Boston Medical Center in Massachusetts; DAVID HUGHES, PHARMD, is a clinical pharmacy specialist in Hematology/Oncology and a pharmacy resident preceptor at Boston Medical Center; and KATELYN O’BRIEN, PHARMD, is an ambulatory care clinical pharmacist specialist, General Internal Medicine Clinic and pharmacy resident preceptor at Boston Medical Center, and president of the Massachusetts Pharmacists Association.

REFERENCES

• National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. 2018.
• Liu CY, Wu CY, Petrossian K, et al. Treatment for the endocrine resistant breast cancer: current options and future perspectives. J Steroid Biochem Mol Biol 2017;172:166-75.
• Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017;35(25):2875-2884.
• Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375(18):1738-1748.
• Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016;375(20):1925-36.
• Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018;36(24):2465-2472.
• Goncalves MD, Hopkins BD, Cantley LC, et al. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med 2018;379:2052-62.
• Fritsch C, Huang A, Chatenay-Rivau-day C, et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014;13:1117-29.
• Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PI3KA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med 2019;380:1929-40.
• Piqray (alpelisib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
• American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care 2020;43(1):S98-110.