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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The approval of alpelisib was based on the results of the Phase III SOLAR-1 clinical trial (NCT02437318) which reported its results in 2018. This was a randomized study of alpelisib and fulvestrant in 572 postmenopausal women and men with PIK3CA mutated HR-ve/HER2-ve advanced or metastatic breast cancer who had progressed while on (or after receiving) an aromatase inhibitor with or without a CDK4/6 inhibitor. The study demonstrated a median progression-free survival (PFS) of 11 months compared to 5.7 months for fulvestrant alone, with the combination reducing the risk of death or progression by an estimated 35% compared to fulvestrant alone. The overall response rate (ORR) based on a reduction in tumor size of at least 30% was more than doubled in patients who received alpelisib plus fulvestrant.
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
PIK3CA mutations have been found in over 40% of estrogen receptor-positive breast cancers.168 PIK3CA encodes the alpha catalytic subunit of PI3K which is a component of phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway, a pathway with a central role in cell growth, survival, and angiogenesis. Mutations in PIK3CA have been identified as a potential mechanism for endocrine resistance in estrogen receptor-positive breast cancers. Alpelisib is a PI3K inhibitor which has recently been studied in combination with fulvestrant in patients with advanced hormone receptor–positive breast cancers who have received prior treatment with an AI either in the adjuvant or advanced setting. This phase III, randomized study of 572 patients revealed that patients with an identified PIK3CA mutation had a PFS of 11.0 months in the alpelisib plus fulvestrant group compared with 5.7 months in the fulvestrant plus placebo group (HR for progression or death, 0.65; 95%CI, 0.50 to 0.85; p < 0.001). In the cohort without a PIK3CA mutation the hazard ratio was 0.85 (95%CI, 0.58 to 1.25).169 No trial data yet exist on whether the combined use of PIK3CA inhibitors with CDK4/6 inhibitors and AIs would have a synergistic anti-tumor effect.
Pharmacological considerations for lymphatic malformation management
Published in Byung-Boong Lee, Peter Gloviczki, Francine Blei, Jovan N. Markovic, Vascular Malformations, 2019
Therapeutic inhibition of mTOR expression has utility in the PIK3CA-related overgrowth spectrum (PROS) as well. A recent publication details a postnatal murine model of PROS/CLOVES (congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis) that partially recapitulates the human disease.14 The model was useful to demonstrate the efficacy of PIK3CA inhibition, in this case with BYL719/alpelisib, in preventing and improving organ dysfunction. On the basis of the model's prediction, 19 patients with PROS (8 with PROS/CLOVES) were treated with the drug, with symptomatic improvement in all patients.
Alpelisib for the treatment of PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Fanny Leenhardt, Marie Alexandre, William Jacot
Clinical studies evaluating alpelisib in breast cancer patients are summarized in Table 1. The first-in-human phase Ia study evaluating alpelisib monotherapy included 134 patients with PIK3CA-altered advanced solid tumors, including 36 BCs [24]. The maximum tolerated doses were 400 mg once daily and 150 mg twice daily. Dose-limiting toxicities were hyperglycemia (n = 6), nausea (n = 2), and hyperglycemia and hypophosphatemia (n = 1). The most frequent adverse events (AEs) of all grades were hyperglycemia (51.5%), nausea (50.0%), skin toxicities (42.5%), and diarrhea (40.3%). The frequency of AEs tended to increase with the duration of treatment. Fifty-one (38.1%) patients required a dose reduction and 63 (47.0%) a dose interruption due to AEs. The objective response rate (ORR) was 6% among a population of 115 evaluable patients (partial response in one case of BC). Disease control rate was 60.9% and clinical benefit rate (response or stability for more than 24 weeks) was 17.4% in patients with ER+/HER2- BC. Median PFS was 5.5 months.
An evaluation of buparlisib for the treatment of head and neck squamous cell carcinoma
Published in Expert Opinion on Pharmacotherapy, 2021
Nicholas Lenze, Bhisham Chera, Siddharth Sheth
Alpelisib (BYL719), which selectively inhibits p110α, has demonstrated efficacy in advanced breast cancer with PIK3CA mutations. In SOLAR-1, a Phase III trial of 572 hormone positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer patients, individuals randomized to alpelisib plus fulvestrant had superior progression-free survival (PFS; 11 vs. 5.7 months, p < 0.001) compared to placebo plus fulvestrant [18]. As a result, the FDA approved alpelisib for hormone-positive metastatic breast cancer in May 2019. In locally advanced HNSCC, a single-institution study of 11 patients found that the combination of alpelisib with cetuximab and radiation therapy demonstrated promising efficacy [19]. In a mutational analysis for this HNSCC study, one patient had a PIK3CA activating mutation and displayed a rapid response on serial imaging. In a separate phase 1 study, alpelisib was combined with bolus dosing cisplatin and radiation therapy in nine patients [20]. The combination had a manageable safety profile, and a phase 2 dose of 200 mg daily was recommended for further evaluation in this setting.
Emerging serine-threonine kinase inhibitors for treating ovarian cancer
Published in Expert Opinion on Emerging Drugs, 2019
Asaf Maoz, Marcia A. Ciccone, Shinya Matsuzaki, Robert L. Coleman, Koji Matsuo
Alpelisib is a PIK3CA inhibitor which is approved for certain PIK3CA-mutated breast cancer patients. PIK3CA transduces signals from cell membrane-bound receptors to downstream effectors of the PI3K-AKT-mTOR pathway by generating phospholipids [21] that recruit and activate AKT and other proteins. Preclinical work has suggested that alpelisib may induce an HRD phenotype in ovarian cancer, thus sensitizing tumors with proficient homologous recombination to PARP inhibition [85]. Results from a phase Ib clinical trial tested this hypothesis among a predominantly platinum-resistant ovarian cancer cohort. This trial included extensive preclinical and translational work. Subgroup analyses and comparison with historical cohorts suggested a potential benefit of the combination of olaparib with alpelisib for BRCA1/2 wild type, platinum-resistant ovarian cancer with a partial response rate of 36% and a 50% rate of disease stability (n = 34), with the conclusion that further studies are warranted. The combination had an acceptable toxicity profile with hyperglycemia being the most relevant added toxicity of alpelisib to PARP inhibition [85]. Alpelisib lacked the CNS toxicity caused by the pan-PI3K inhibitor buparlisib [86]. Alpelisib has an acceptable toxicity profile when added to PARP inhibitors, but confirmatory studies are needed to demonstrate its efficacy.