Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

Abstract

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

Fig 1.

Alpelisib geometric mean plasma concentration–time profiles.

Fig 2.

Maximum fold increase from baseline in (A) fasting plasma glucose, (B) fasting serum insulin, and (C) fasting serum C-peptide during cycle 1, and (D) best percentage change from baseline in sum of maximum standardized uptake values (sSUVmax) measured by [¹⁸F]-fluorodeoxyglucose positron emission tomography. X represents the geometric mean value.

Fig 3.

Best percentage change in sum of longest diameters according to (A) study treatment dose, (B) primary site of cancer and metformin treatment, and (C) centrally obtained next-generation sequencing results. Dummy sample numbers for each patient correspond with the next-generation sequencing results in the Data Supplement. Of 12 patients with ≥ 30% reduction in tumor size, complete response (demonstrated with two or more scans taken at least 1 month apart) was observed in one patient with endometrial cancer. However, overall response was lower because some patients experienced rapid disease progression. A partial response was observed in one patient with breast cancer, two patients with colorectal cancer, and four patients with other cancers (one patient with endometrial cancer and three patients with cervical cancer). Stable disease was observed in one patient with ovarian cancer, two patients with head and neck cancer, and one patient with breast cancer. (*) Patients with no postbaseline assessment for target lesions or patients with only nontarget lesions were excluded. (†) Patients receiving metformin for hyperglycemia.