Alpelisib (ALP) is an alpha-selective phosphatidylinositol- 3-kinase inhibitor and degrader approved, in combination with fulvestrant, for the treatment of patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC). Hyperglycemia and rash are challenging but expected adverse events (AEs) with alpelisib treatment. Current management guidelines for hyperglycemia and rash are based primarily on experience from clinical trials, whose populations may not necessarily represent real-world patients; therefore, detailed guidance remains lacking in certain aspects. The Delphi panel method is a systematic and validated approach to establishing consensus from experts based on real-world experience. The objective of this study is to provide practical recommendations to optimize prevention and management of hyperglycemia (HG) and rash in patients receiving alpelisib. Preliminary expert consensus guidance has been previously presented; here, we present final recommendations following the completion of the study.
Two RAND Corporation/University of California Los Angeles (UCLA) modified Delphi panels were assembled, one focusing on the management of hyperglycemia, and the other focusing on the management of rash, in patients with HR+/ HER2− ABC treated with alpelisib. Each panel comprised 10 experts representing a broad range of backgrounds and expertise, including 4 oncologists, a clinical pharmacist, and a patient advocate; the hyperglycemia panel included 4 endocrinologists whereas the rash panel included 4 dermatologists. No expert participated in both panels. For each panel, a structured questionnaire was developed, in collaboration with the panelists, based on the summary of evidence from the literature review on the mechanism of action, risk factors, and management strategies for hyperglycemia and rash. Experts from each panel reviewed the evidence and rated the appropriateness of clinical interventions for hyperglycemia or rash per hypothetical scenarios in the structured questionnaire in two rounds of review, using a scale of 1 to 9 (highly inappropriate, wherein risks outweigh the benefits, to highly appropriate, wherein benefits outweigh the risks). Median scores and dispersion from the final rating form were used to classify the data into three levels of panel agreement or a single level of disagreement. The consensus statements and treatment algorithms were developed based on the level of agreement.
Per the HG panel, (a) a low-carbohydrate diet is appropriate in all pts starting ALP; a ketogenic diet and/or pre-tx fasting may also be considered; (b) prophylactic metformin is appropriate in pts with baseline HbA1c 5.7%-6.4%; may also be appropriate in pts with HbA1c <5.7%; (c) weekly fasting blood glucose (FBG) monitoring is appropriate for most pts, as is daily monitoring for pts at highest risk for HG (≥70 y old, BMI ≥30, and HbA1c 5.7%-6.4%); (d) metformin is the preferred first-line agent for HG, while insulin is only appropriate for pts with FBG >250 mg/dL at second or later episodes if maximal non-insulin tx is ineffective. Per the rash panel, (a) initiate prophylactic nonsedating (NS) H1 antihistamines at standard dose in all pts starting ALP; (b) for initial management of rash, start/ escalate NS H1 antihistamines and start topical steroids; start oral corticosteroids (OCS) if rash affects ≥10% body surface area and FBG <160 mg/dL; (c) if response to high-dose, NS antihistamine is inadequate, add a sedating H1 antihistamine, and if needed, an H2 antihistamine; (d) for angioedema, either hold ALP and start OCS, or permanently discontinue ALP; if still present upon reevaluation, permanently discontinue ALP.
This practical guidance, based on experts’ recommendations and clinical experience, combined with emerging clinical trial evidence, may help address the challenges that health care practitioners encounter with managing AEs of alpelisib in their routine practice. Although the management of AEs associated with alpelisib can be guided using these recommendations, further studies are needed to establish their effect on patient outcomes. Areas of disagreement identified in this study emphasize a need for further evidence to guide clinical decision-making.
Emily J. Gallagher,1 Heather Moore,2,a Mario E. Lacouture,3 Susan F. Dent,2 Azeez Farooki,3 Marcus D. Goncalves,4 Claudine Isaacs,5 Abigail Johnston,6 Dejan Juric,7 Zoe Quandt,8 Laura Spring,7 Brian Berman,9 Melanie Decker,10 Gabriel N. Hortobagyi,11 Benjamin H. Kaffenberger,12 Bernice Y. Kwong,13 Timothy Pluard,14 Ruta Rao,15 Lee Schwartzberg,16 Michael S. Broder17
1Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
2Duke Cancer Institute, Duke University, Durham, NC.
3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
4Weill Department of Medicine, Weill Cornell Medicine, New York, NY.
5Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
6Surviving Breast Cancer, 305 Pink Pack, Miami, FL.
7Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA
8School of Medicine, University of California, San Francisco, CA
9University of Miami School of Medicine and Center for Clinical and Cosmetic Research, Aventura, FL.
10Woodland Memorial Hospital, Woodland, CA, and Kaiser Permanente, Sacramento, CA.
11Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
12Wexner Medical Center, The Ohio State University, Columbus, OH.
13Department of Dermatology, Stanford University School of Medicine, Stanford, CA.
14St. Luke’s Hospital Koontz Center for Advanced Breast Cancer, Kansas City, MO.
15Rush Hematology, Oncology and Cell Therapy, Rush University Medical Center, Chicago, IL.
16West Cancer Center, Memphis, TN.
17PHAR, Beverly Hills, CA.