Background: Activating mutations in PIK3CA (the gene encoding the p110α catalytic subunit of class I phosphatidylinositol 3-kinase [PI3K] [PI3Kα]) lead to increased activity of the PI3K pathway and play a role in endocrine treatment resistance in breast cancer. Pan-PI3K inhibitors, which inhibit all four isoforms of class I PI3K (α, β, δ, γ), and β-sparing PI3K inhibitors demonstrated modest clinical activity but considerable toxicity,1-3 which precluded further clinical development. Alpelisib (ALP) is a PI3Kα-specific inhibitor. Because it selectively targets a single PI3K isoform, ALP may be associated with less toxicity than broader PI3K inhibitors.
Objectives: The efficacy and safety of ALP+fulvestrant (FUL) versus placebo (PBO)+FUL were evaluated in SOLAR 1 (NCT02437318), a randomized, double blind phase 3 trial in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) who relapsed/progressed on/after prior endocrine therapy.4
Methods: Outcomes from SOLAR-1 are reviewed. Based on clinical experience with ALP in SOLAR-1, management strategies for select adverse events (AEs) are recommended.
Results: ALP+FUL was associated with a statistically significant and clinically meaningful benefit in progression-free survival (PFS) in patients with PIK3CA-mutant disease (median PFS, 11.0 vs 5.7 months with PBO+FUL; hazard ratio, 0.65; 95% confidence interval, 0.50-0.85; P <0.001). In the overall population, hyperglycemia, gastrointestinal toxicities (including diarrhea, nausea, and vomiting), and rash were the most frequent AEs in ALP-treated patients. Rates of grade 3/4 AEs in ALP+FUL versus PBO+FUL arms were as follows: 36.6% versus 0.7% for hyperglycemia, 9.9% versus 0.3% for rash, and 6.7% versus 0.3% for diarrhea. Management of hyperglycemia included dietary/lifestyle modification, early intervention with metformin and other insulin sensitizers,5 and reduction in ALP for grade ≥3 hyperglycemia. Rash may be reduced by prophylactic second-generation antihistamines and treated with topical steroids6 and a hold/reduction in ALP for resistant cases. Management of diarrhea included hydration and use of loperamide7 and a reduction in ALP for grade ≥2 diarrhea. Additional considerations for monitoring/managing AEs in ALP treated patients, as per expert guidance and clinical experience, will be discussed.
Conclusions: ALP+FUL demonstrated efficacy and a generally manageable tolerability profile in SOLAR 1. Awareness and early prevention and management of AEs associated with ALP are important to ensure continued therapy and optimal clinical benefit.
- Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904-916.
- Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:87-100.
- Baselga J, Dent S, Cortés J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. Presented at: 2018 American Society of Clinical Oncology Annual Meeting; June 1-5, 2018; Chicago, IL.
- André F, Ciruelos EM, Rubovsky G, et al. Alpelisib + fulvestrant for HR+, HER2- advanced breast cancer: results of the phase III SOLAR-1 trial. Presented at: ESMO 2018 Congress; October 19-23, 2018; Munich, Germany.
- Goldman JW, Mendenhall MA, Rettinger SR. Hyperglycemia associated with targeted oncologic treatment: mechanisms and management. Oncologist. 2016;21:1326-1336.
- Lacouture ME. Management of dermatologic toxicities associated with targeted therapy. J Adv Pract Oncol. 2016;7:331-334.
- Benson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-2926.