Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer

Rugo, Hope S.; André, Fabrice; Yamashita, Toshinari; Cerda, Humberto; Toledano, I.; Stemmer, Salomon M.; Jurado, Josefina Cruz; Juric, Dejan; Mayer, Ingrid A.; Ciruelos, Eva; Iwata, Hiroji; Conté, Pierfranco; Campone, Mario; Wilke, Celine; Mills, David; Lteif, Agnes; Miller, Michelle C.; Gaudenzi, Fiorenza; Loibl, Sibylle

doi:10.1016/j.annonc.2020.05.001

Cited by 123 publications

(164 citation statements)

References 11 publications

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“…Grade 4 should be managed as grade 3. If blood glucose remains above 500mg/dL, permanent discontinuation of the drug is warranted (3). Metformin is the first line treatment (3).…”

Section: Discussionmentioning

confidence: 99%

Diabetic Ketoacidosis Associated With Alpelisib Treatment Of Metastatic Breast Cancer

Farah

Masri

Ghanem

et al. 2020

AACE Clinical Case Reports

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Objective: Alpelisib-induced DKA is a rare, but life-threatening adverse event. There have been only two reported cases in the literature. We describe such a case, with emphasis on the importance of screening and achieving adequate glycemic control prior to and after initiation of therapy. Methods: A 49-year-old woman, known to have advanced breast cancer, presented with a 3-day history of nausea, vomiting and diffuse abdominal pain. She started alpelisib 300 mg/d two months prior to presentation, after failing other options. She was diagnosed with DKA using her clinical and laboratory features, leading to treatment with hydration and IV insulin therapy. Results: Laboratory data showed high anion gap metabolic acidosis, hyperglycemia and ketonemia with negative GAD-65 antibodies, leading to the diagnosis of alpelisib-associated DKA. Alpelisib was held, and she was treated with IV insulin and hydration. When DKA and hyperglycemia resolved, alpelisib was resumed at a lower dose (200 mg/d) and her blood glucose (BG) managed using a regimen combining insulin and metformin. Conclusion: PI3K signaling is important for the metabolic actions of insulin and alpelisib has been associated with severe hyperglycemia. Metformin is the first line treatment, however when DKA is the presenting syndrome, insulin needs to be considered. BG and HbA1c should be checked prior to treatment initiation and monitored closely after drug initiation. DKA, albeit rare, must be considered in an acutely ill, alpelisib-treated patients presenting with metabolic acidosis, and if drug discontinuation is not an option, insulin treatment may be required to control glycemia.

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“…Grade 4 should be managed as grade 3. If blood glucose remains above 500mg/dL, permanent discontinuation of the drug is warranted (3). Metformin is the first line treatment (3).…”

Section: Discussionmentioning

confidence: 99%

Diabetic Ketoacidosis Associated With Alpelisib Treatment Of Metastatic Breast Cancer

Farah

Masri

Ghanem

et al. 2020

AACE Clinical Case Reports

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“…Additionally, PI3K inhibitors have shown some promising efficacy in stage II-III TNBC patients whose tumors have PIK3CA mutations [ 68 , 207 , 225 ]. Following on the efficacy of alpelisib to improve PFS for HR-positive breast cancer [ 228 , 229 , 230 ], alpelisib plus nab-paclitaxel is being assessed in anthracycline-refractory TNBC with PIK3CA or PTEN mutations in a phase II trial [ 225 ]. The addition of everolimus, an mTOR inhibitor, was found to be synergistic with cisplatin and paclitaxel in the treatment of stage II/III TNBC patients.…”

Section: Emerging Targeted Therapies In Tnbcmentioning

confidence: 99%

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Gupta

Collier

Lee

et al. 2020

Cancers

220

160

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Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

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“…In SOLAR-1, in addition to the prediabetic (FPG, 5.6 to <7.0 mmol/L and HbA1c, 5.7 to <6.5%) and diabetic (FPG, ≥7.0 mmol/L or HbA1c, ≥6.5%) status, obesity (defined as body mass index ≥30) and advanced age (≥75 years old) were also associated with higher incidence rates of grade 3/4 hyperglycemia. 80 In the earliest phase of SOLAR-1, before the protocol was amended to exclude patients with diabetes, one patient whose HbA1c was ~8% was enrolled; this patient did have grade 4 hyperglycemia, but after proper dose reduction and supervision by an endocrinologist, she was able to continue study treatment for more than 2 years. Although there are insufficient data regarding the safety of alpelisib in patients with diabetes, they should not be prohibited from using this treatment provided that careful monitoring is implemented and early endocrinologist consultation is sought.…”

Section: Clinical Practice Considerationsmentioning

confidence: 99%

“…Rugo et al reported the time course and management of the key AEs in SOLAR-1 and provided valuable clinical guidance. 80 Eighty-six participants had received prophylactic (before the onset of skin rash) anti-rash medication, among whom, 70% received anti-histamines. Compared with those (n = 198) who did not receive preventive medication, these patients experienced lower rates of any-grade rash (26.7% versus 64.1%) and grade 3 rash (11.7% versus 22.7%).…”

Section: Clinical Practice Considerationsmentioning

confidence: 99%

“…Compared with those (n = 198) who did not receive preventive medication, these patients experienced lower rates of any-grade rash (26.7% versus 64.1%) and grade 3 rash (11.7% versus 22.7%). 80 Therefore, prophylactic antihistamine has been recommended to reduce the frequency and severity of skin rash and is also endorsed by the ABC-5 consensus. 81 Nonetheless, systemic corticosteroid use and treatment interruption are necessary for higher grade events, and it is highly desirable to include a dermatologist in the team.…”

Section: Clinical Practice Considerationsmentioning

confidence: 99%

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Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives

Chang

2021

TCRM

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The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA -mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2– advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2– advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

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Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer

Cited by 123 publications

References 11 publications

Diabetic Ketoacidosis Associated With Alpelisib Treatment Of Metastatic Breast Cancer

Diabetic Ketoacidosis Associated With Alpelisib Treatment Of Metastatic Breast Cancer

Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives

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