medwireNews: Researchers report “encouraging” tolerability and efficacy results from a phase Ia trial of the oral phosphatidylinositol 3-kinase α (PI3Kα)–selective inhibitor alpelisib among patients with PIK3CA-altered advanced solid tumors.
José Baselga (Memorial Sloan Kettering Cancer Center, New York, USA) and co-investigators say the data, from what they believe is a first-in-human trial, support “the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.”
In the dose-escalation phase of the study, involving 76 patients with PIK3CA-altered advanced solid tumors and one patient with a PIK3CA-wild-type breast tumor, the researchers established maximum tolerated doses of 400 mg once daily and 150 mg twice daily.
During this phase, nine (13.2%) of 68 evaluable patients experienced dose-limiting toxicities of hyperglycemia (n=6), nausea (n=2), and both hyperglycemia and hypophosphatemia (n=1).
The researchers then moved on to a dose-expansion phase in which an additional 51 patients with PIK3CA-altered advanced solid tumors and four with PIK3CA-wild-type, estrogen receptor (ER)–positive/human epidermal growth factor receptor (HER)2–negative breast cancer received alpelisib 400 mg once daily.
Overall, the most common all-grade, treatment-related adverse events were hyperglycemia (51.5%), nausea (50.0%), skin toxicities (42.5%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%).
Baselga and team note that the incidence of hyperglycemia increased in a dose-dependent manner but was well managed with dose amendments or with the use of metformin and/or insulin. Six (4.5%) patients permanently discontinued alpelisib due to hyperglycemia.
The overall response rate among the 134 study participants was 6.0%. Responses occurred at once daily doses of 270 mg or higher, and included one complete response in a patient with endometrial cancer and seven partial responses in patients with cervical, breast, endometrial, colon, and rectal cancers.
In addition, just over half (52.2%) of patients achieved stable disease, which was sustained for more than 24 weeks in 13 (9.7%) cases.
The resulting disease control rate was 58.2% and was highest among patients with cervical cancer (100% of five patients), followed by those with head and neck (68.4% of 19 patients) and ER-positive/HER2-negative breast (60.9% of 23 patients) cancers.
However, the investigators point out that none of the four patients with PIK3CA-wild-type, ER-positive/HER2-negative breast cancer in the dose-expansion arm derived clinical benefit from the treatment.
Writing in the Journal of Clinical Oncology, Baselga et al conclude: “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.”
They add: “This phase Ib study was used to inform the dose for subsequent phase III trials. Ongoing studies are evaluating alpelisib in combination with endocrine therapy and other targeted anticancer agents in a range of tumor types.”
By Laura Cowen
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