medwireNews: First-in-human findings raise the possibility of the phosphatidylinositol 3-kinase (PIK3CA)α inhibitor alpelisib as a treatment for advanced solid tumours with a PIK3CA mutation.
“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”, the study investigators write in the Journal of Clinical Oncology.
The dose-escalation stage of the phase Ia trial included 76 pretreated patients, with a further 51 patients in the dose-expansion stage. The most common tumour types were breast, colorectal, and head and neck, and all had a PIK3CA mutation except for seven patients with wild-type tumours, five of whom had oestrogen receptor (ER)-positive, HER2-negative breast cancers.
The maximum tolerated dose of alpelisib was determined to be 400 mg given once daily or 150 mg twice daily, report José Baselga, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors.
Dose-limiting toxicities in the dose-escalation stage of the study included hyperglycaemia (n=6), nausea (n=2), and hyperglycaemia plus hypophosphataemia (n=1). The most frequent treatment-related adverse events across both study phases included hyperglycaemia (51.5%), nausea (50.0%), skin toxicity (42.5%), and reduced appetite (41.8%), with diarrhoea (40.3%) and vomiting (31.3%) also common.
The objective response rate was 6.0% and occurred among patients given at least alpelisib 270 mg once daily; a complete response occurred in one endometrial cancer patient given 150 mg twice daily, while partial responses were reported for three patients with cervical cancer and one case each of breast, endometrial, colon and rectal tumours.
In addition, stable disease occurred in 52.0% of patients, lasting for over 24 weeks in 9.7% of these cases, the researchers say, but they emphasize that none of the four patients with PIK3CA-wild-type breast cancer in the dose-expansion arm derived clinical benefit from alpelisib.
The overall disease control rate was 58.2%; this ranged from 34.3% of 35 colorectal cancer patients to 60.9% of the 23 patients with ER-positive/HER2-negative PIK3CA-mutated breast cancer, 68.4% of the 19 patients with head and neck cancer, and 100% of the five cervical cancer patients.
“Since we observed single-agent activity at ≥ 270 mg, a subsequent phase Ib study tested both 300-mg and 400-mg doses in combination with fulvestrant, with special attention to long-term tolerability of this
agent in patients with breast cancer”, the researchers explain.
“This phase Ib study was used to inform the dose for subsequent phase III trials”, they write, adding: “Ongoing studies are evaluating alpelisib in combination with endocrine therapy and other targeted anticancer agents in a range of tumor types.”
Juric D, Rodon J, Tabernero J, et al. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in human study. J Clin Oncol; Advance online publication 5 February 2018. DOI: 10.1200/JCO.2017.72.7107
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