The primary endpoint for the phase III SOLAR-1 trial has been met, with improved progression-free survival seen with the combination of alpelisib and fulvestrant compared with fulvestrant alone in postmenopausal women and men with HR-positive, HER2-negative, <em>PIK3CA</em>-mutant advanced or metastatic breast cancer that had progressed after aromatase inhibitor treatment with or without a CDK4/6 inhibitor.
ProSamit Hirawat, MD
The primary endpoint for the phase III SOLAR-1 trial has been met, with improved progression-free survival seen with the combination of alpelisib (BYL719) and fulvestrant (Faslodex) compared with fulvestrant alone in postmenopausal women and men with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutant advanced or metastatic breast cancer that had progressed after aromatase inhibitor treatment with or without a CDK4/6 inhibitor.
According to findings from the phase III SOLAR-1 trial, alpelisib (BYL719) in combination with fulvestrant (Faslodex) improved progression-free survival compared to fulvestrant alone in postmenopausal women and men with hormone receptor (HR)-positive, HER2-negative,PIK3CA-mutant advanced or metastatic breast cancer that progressed after aromatase inhibitor treatment with or without a CDK4/6 inhibitor, meeting the study's primary endpoint.
The findings were announced by Novartis, the company developing the investigational alpha-specific PI3K inhibitor alpelisib, in a recent press release, but no specific data has been provided. Novartis noted that there are no FDA-approved PI3K inhibitors for patients with HR+ advanced breast cancer, despite the established link between the PI3K pathway and tumor progression in these patients.
"BYL719 is the only alpha-specific PI3K inhibitor and the first one to show potential increased benefit and acceptable tolerability for patients," Samit Hirawat, MD, head, Novartis Oncology Global Drug Development, said in a statement. "We are encouraged by the results observed in the SOLAR-1 study and look forward to submitting the data to an upcoming medical congress and starting discussions with health authorities worldwide."
Positive results for single-agent alpelisib were published online in February 2018 in the Journal of Clinical Oncology. In a phase Ia study, alpelisib induced a disease control rate (DCR) of 58.2% in patients with advanced solid tumors. The stable disease rate with alpelisib was 52.2%, and 13 (9.7%) patients maintained stable disease for more than 24 weeks. Investigators reported “encouraging signs of antitumor activity” in patients with PIK3CA-mutant, ER-positive/HER2-negative breast cancer, and otherPIK3CA-altered advanced solid tumors.
Adult patients (n = 134) enrolled in the phase Ia, multicenter, open-label, 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 hadPIK3CAwild-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, of 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).”
The overall clinical benefit rate (CBR) was 15.7%. CBR for patients withPIK3CA-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 aselective 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.