Juric D, et al. - The maximum tolerated dose, and safety as well as preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)–selective inhibitor, was investigated in this first-in-human phase Ia study. A tolerable safety profile as well as encouraging preliminary activity of alpelisib was apparent in patients with PIK3CA-altered solid tumors. This finding lends support to the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.

• On a continuous schedule, once-daily or twice-daily oral alpelisib was administered in patients with PIK3CA-altered advanced solid tumors, in the dose-escalation phase.
• In the dose-expansion phase, alpelisib 400 mg once daily was given to patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer.

• Treatment was received by a total of 134 patients.
• Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily.
• In the dose-escalation phase, dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1) were observed in 9 patients (13.2%).
• Hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%) constituted the frequently reported all-grade, treatment-related adverse events.
• Researchers noted that alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation.
• At doses ≥ 270 mg once daily, objective tumor responses were observed; 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).
• In 70 (52.2%) patients, stable disease was achieved and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%.
• The reported median progression-free survival in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer was 5.5 months.
• In addition, frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%).