A multidisciplinary approach to optimizing care of patients treated with alpelisib

Abstract

Purpose: The oral, α-specific phosphatidylinositol-3-kinase (PI3Kα) inhibitor alpelisib is the first PI3K inhibitor approved for the treatment of advanced breast cancer. As alpelisib is a relatively new therapeutic option, specific guidance and a multidisciplinary approach are needed to provide optimal patient care. The primary objective of this manuscript is to provide comprehensive guidance on minimizing and managing adverse events (AEs) for patients with advanced breast cancer who are receiving alpelisib.

Methods: Clinical studies, prescribing information, published literature, and relevant guidelines were reviewed to provide recommendations on the prevention and management of alpelisib-associated AEs.

Results: The most common AEs associated with alpelisib in the phase 3 SOLAR-1 trial were hyperglycemia and rash (which are considered on-target effects of PI3Kα inhibition) and gastrointestinal AEs, including diarrhea, nausea, and decreased appetite. These AEs require regular monitoring, early recognition, and prompt initiation of appropriate treatment. In addition, there are effective strategies to reduce the onset and severity of frequently observed AEs-in particular, onset of hyperglycemia and rash may be reduced by lifestyle changes (such as reduced intake of carbohydrates and regular exercise) and antihistamine prophylaxis, respectively. To reduce risk of severe hyperglycemia, it is essential to achieve adequate glycemic control prior to initiation of alpelisib treatment.

Conclusion: Overall, alpelisib-associated AEs are generally manageable with prompt recognition, regular monitoring, and appropriate intervention, preferably with a multidisciplinary approach.

Keywords: AE management; Alpelisib; Breast cancer; PIK3CA.

Conflict of interest statement

Declaration of competing interest H.S. Rugo: Institution research funding from Pfizer, Novartis, Eli Lilly, Genentech, MacroGenics, Merck, OBI Pharma, Eisai, Immunomedics, Daiichi, Odonate, and Seattle Genetics; travel support from Daiichi, AstraZeneca, Novartis, Pfizer, Mylan, and Merck; consulting/advisory income from Puma and Celltrion. M.E. Lacouture: Consulting from Novartis, Varsona, Innovaderm, Novocure, QED, Seagen, Lutris, DFB, JnJ, Deciphera, Onquality, TWIBiotech, Azitra, Janssen, EMD Serono, and Bicara; research funding from Novartis, AZ, JnJ, Onquality, and Novocure. M.D. Goncalves: Personal fees from Novartis, grants from Pfizer, and personal fees from Petra Pharma, Scorpion Therapeutics, and Faeth Therapeutics, outside the submitted work; patent (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and patent for The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment pending; and owns stock in Faeth Therapeutics. U. Masharani: Research funding from Clementia Pharmaceuticals. M.S. Aapro: Consulting/advisory role in Amgen, BMS, Daiichi Sankyo, Fresenius Kabi, G1 Therapeutics, Genomic Health, Helsinn Healthcare, Merck, Merck KGaA, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, and Vifor Pharma; speakers' bureau at Accord Research, Amgen, Biocon, Dr Reed, Genomic Health, Helsinn Healthcare, Mundipharma, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Taiho Pharmaceutical, Tesaro, and Vifor Pharma; research funding from Helsinn Healthcare, Novartis, Pierre Fabre, and Sandoz. J.A. O'Shaughnessy: Personal fees from AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eisai, Genentech, Genomic Health, GRAIL, Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck, Myriad, Novartis, Ondonate Therapeutics, Pfizer, Puma Biotechnology, Prime Oncology, Roche, Seattle Genetics, and Syndax Pharmaceuticals, outside the submitted work.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

Management of alpelisib-associated hyperglycemia: [a] Lifestyle modifications and baseline glucose monitoring recommendations prior to initiating alpelisib treatment; [b] monitoring during alpelisib treatment; [c] hyperglycemia management recommendations; and self-monitoring guidelines during alpelisib treatment (severity based on CTCAE v4.03) [d] complications of hyperglycemia including ketoacidosis [10,12,[14], [15], [16]]. 1 L, first-line; 2 L, second-line; BG, blood glucose; BID, twice daily; BMI, body mass index; BP, blood pressure; CTCAE, Common Terminology Criteria for Adverse Events; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; FSBG, fingerstick blood glucose; GA, glycated albumin; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; IV, intravenous; OD, once daily; PCOS, polycystic ovarian syndrome; PI3K, phosphatidylinositol-3-kinase; SGLT2i, sodium-glucose co-transporter 2 inhibitor. aMay be done more frequently as clinically indicated. bAssess eGFR prior to initiation of metformin; do not initiate metformin in patients with eGFR 30–45 mL/min/1.73 m2 but consider 50% dose reduction in patients already on metformin and monitor renal function every 3 months. Metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m2 (see Table 1 [12,[15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]] for further details) [18,19]. Initiate metformin at 500 mg OD before dinner, increasing to 500 mg BID (before breakfast and dinner) as tolerated. May increase to 500 mg at before breakfast then 1000 mg before dinner, and then to 1000 mg BID if tolerated. If not tolerated, reduce to prior tolerated dose.

Fig. 2

Examples of maculopapular rash in the lower extremity [a], and back [b, c] in breast cancer patients treated with alpelisib. All photos are provided courtesy of Mario E. Lacouture, MD, Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York (November 25, 2020).

Fig. 3

Management of alpelisib-associated skin AEs (severity based on CTCAE v5.0) [66,70]. AE, adverse event; BID, twice daily; BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-aminobutyric acid; IV, intravenous; PI3Ki, phosphatidylinositol-3-kinase inhibitor; TID, thrice daily. aTriamcinolone 0.1% or fluocinonide 0.05% BID for ≥28 days. bCetirizine 10 mg or loratadine 10 mg or fexofenadine 180 mg BID. cDiphenhydramine 25–50 mg or hydroxyzine 25 mg at bedtime. dGabapentin 300 mg TID or pregabalin 50 mg BID. ePrednisone 0.5–1 mg/kg/daily or equivalent for 7–10 days for grade 3 rash. fIf feasible, consider a graded rechallenge with alpelisib starting at 50 mg/day, increasing by 50 mg/week until a 250-mg dose is achieved; start trimethoprim/sulfamethoxazole 160 mg/800 mg three times a week plus a proton pump inhibitor during graded rechallenge (continue oral corticosteroid).