Promising Findings for Alpelisib in Patients With PIK3CA-Altered Metastatic ER+/HER2- Breast Cancer

Findings from a phase Ia, multicenter, open-label, study published in the&nbsp;<em>Journal of Clinical Oncology</em>&nbsp;showed a disease control rate of 58.2% with alpelisib (BYL719) in patients with advanced solid tumors.

José Baselga, MD, PhD

Findings from a phase Ia, multicenter, open-label, study published in theJournal of Clinical Oncologyshowed a disease control rate (DCR) of 58.2% with alpelisib (BYL719) in patients with advanced solid tumors.

Treatment with the oral PIK3CA selective inhibitor led to a stable disease rate of 52.2%. Thirteen (9.7%) patients maintained stable disease for more than 24 weeks.

Investigators reported “encouraging signs of antitumor activity” in patients withPIK3CA-mutant, ER-positive/HER2-negative breast cancer, and otherPIK3CA-altered advanced solid tumors.

Adult patients (N = 134) enrolled in the dose-escalation study at 11 sites from October 2010 to March 2014. Seventy-six patients were included in the dose-escalation phase and 51 patients withPIK3CA-altered advanced solid tumors were included in the dose-expansion phase.

Eligible patients had a ECOG performance score ≤2 with histologically confirmed, unresectable, advanced solid tumors and who had progression of disease per RECIST v1.0 on their last line of therapy within 3 months of screening, or for whom no standard anticancer therapy existed. Patients had at least 1 measurable or nonmeasurable lesion per RECIST v1.0 and fasting plasma glucose <140 mg/dL (7.8 mmol/L).

Patients with diabetes mellitus; a history of gestational diabetes mellitus, or documented steroid-induced diabetes mellitus; and failure to benefit from a prior PI3K, AKT, or mTOR inhibitor were excluded.

Seven patients hadPIK3CA—wild-type tumors including 5 with ER-positive/HER2-negative breast cancer, 1 in the dose-escalation phase and 4 in the dose-expansion phase. The most common primary cancer sites were breast (n = 36; 26.9%), colorectal (n = 35; 26.1%), and head and neck (n = 19; 14.2%).

At initial diagnosis, 86 patients (64.1%) had stage III or IV cancer, and all patients had received prior antineoplastic therapy.

Patients received 30 to 450 mg of oral alpelisib once daily or 120 to 200 mg twice daily on a continuous schedule in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, or investigator’s decision. After MTD/recommended phase II dose determination for the once daily schedule, an expansion arm was opened to further characterize safety and assess preliminary efficacy at this dose.

Overall, 108 patients received alpelisib once daily at doses of 30 to 450 mg, including 65 patients at 400 mg once daily. Twenty-six patients received alpelisib twice daily at doses of 120 to 200 mg, including 15 patients at 150 mg twice daily. As of February 5, 2015, 130 (97.0%) patients had discontinued treatment, most (78.4%) because of disease progression.

MTD for alpelisib monotherapy was established at 400 mg once daily and 150 mg twice daily. In the dose-escalation phase, 9 of 68 evaluable patients experienced dose-limiting toxicity (DLT). At 450 mg once daily, the highest dose, 4 of 9 patients experienced DLTs of grade 3 nausea or grade 3 hyperglycemia. No patients treated at ≤400 mg once daily experienced DLTs. At 200 mg twice daily, 4 of 5 patients had dose-limiting hyperglycemia.

“Overall, single-agent alpelisib demonstrated a wide therapeutic window, with significant pharmacodynamic effects and disease stabilization at ≥180 mg once daily, and objective activity at ≥270 mg once daily, both well below the MTD of 400 mg once daily,” corresponding author Jose ́ Baselga, MD, PhD, Memorial Sloan Kettering Cancer Center, and colleagues wrote. “On the basis of improved tolerability and similar efficacy compared with 400 mg once daily, 300 mg once daily was selected as the dose in the phase III trial of fulvestrant with or without alpelisib (SOLAR-1; NCT02437318).”

The overall clinical benefit rate (CBR) was 15.7%. CBR for patients with PIK3CA-mutant ER-positive/HER2-negative breast cancer was 17.4%.

DCR was highest in patients with cervical cancer (100%; 5 of 5), followed by head and neck cancer (68.4%; 13 of 19), and ER-positive/HER2-negative breast cancer (60.9%; 14 of 23). In colorectal cancer, 2 of 35 patients had a partial response, DCR was 34.3%, and CBR was 8.6%.

One patient with endometrial cancer had a complete response at the 150-mg twice daily dose.

Sixty-nine (51.5%) patients experienced hyperglycemia, including 32 (23.9%) who had grade 3/4 toxicity. A total of 57 patients (42.5%) experienced grade 3/4 adverse events (AEs) considered to be related to the study drug, although that was mostly hyperglycemia. Otherwise, the most common grade 3/4 AEs were vomiting (3.0%) and fatigue (3.0%).

Investigators wrote that hyperglycemia was effectively managed with dose interruption/reduction, or by concomitant metformin, and the addition of insulin in some cases. Six patients (4.5%) permanently discontinued study treatment due to hyperglycemia.


Juric D, Rodon J, Tabernero J, et al. Phosphatidylinositol 3-kinase a—selective inhibition with alpelisib (byl719) in pik3ca-altered solid tumors: results from the first-in-human study [published online February 5, 2018].J Clin Oncol.doi: 10.1200/JCO.2017.72.7107.