Additional analyses from the SOLAR-1 study show that alpelisib, an investigational alpha-specific PI3K inhibitor, combined with fulvestrant extended progression-free survival compared with fulvestrant alone in patients with PIK3CA-mutant advanced breast cancer regardless of line of therapy or prior CDK4/6 inhibitor treatment.
Dejan Juric, MD
Additional analyses from the SOLAR-1 study show that alpelisib (BLY719), an investigational alpha-specific PI3K inhibitor, combined with fulvestrant (Faslodex) extended progression-free survival (PFS) compared with fulvestrant alone in patients with PIK3CA-mutant advanced breast cancer regardless of line of therapy or prior CDK4/6 inhibitor treatment. An interim overall survival (OS) analysis also demonstrated that the median OS has not been reached in the alpelisib arm.1
The study also demonstrated the potential clinical utility of measuring circulating tumor (ct) DNA to select patients with a PIK3CA mutation and to confirm the robust PFS benefit with alpelisib in patients with plasma ct-DNA-determined mutational status, said Dejan Juric, MD, at the 2018 San Antonio Breast Cancer Symposium.
Approximately 40% of estrogen receptor (ER)-positive breast cancers harbor mutations in the PIK3CA gene, encoding the PI3 kinase alpha form of PI3 kinase.
“This alteration is the most common actionable alteration in ER-positive breast cancer,” said Juric, director, Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital, Boston. “PI3 kinase signaling itself promotes ER-independent growth of ER-positive breast cancer cells, and it’s implicated in resistance to antiestrogens, which is reversed by combined PI3 kinase and ER inhibition.”
There are 4 PI3K isoforms. Alpelisib inhibits just the alpha isoform, which potentially results in a much wider therapeutic index compared with pan-PI3K and beta-sparing CDK4/6 inhibitors, which target multiple isoforms.
Among updated data presented here, the first interim OS analysis after 52% of the planned number of events demonstrated a positive OS trend to the combination in the PIK3CA-mutant cohort, he said, with an HR of 0.73 (95% CI, 0.48-1.10; P = .06). Two additional OS analyses “will shed a lot more light on the potential OS benefit of this combination,” Juric said.
In the PIK3CA-mutant cohort, target lesion diameter decreased by 75.86% from baseline in the alpelisib plus fulvestrant arm, compared with a 43.51% decrease in the fulvestrant-only arm.
Analysis of PFS by prior lines of therapy “reveals increasing benefit of alpelisib as we go from endocrine-sensitive first-line patients, a small portion of patients in this study, to endocrine-resistant first-line patients to second-line patients,” he said.
In the PIK3CA-mutant cohort, median PFS was 22.1 months with alpelisib/fulvestrant versus 19.1 months with fulvestrant in the first-line setting in endocrine-sensitive patients (HR, 0.87; 95% CI 0.35-2.17) and 9.0 months versus 4.7 months, respectively, in endocrine-resistant patients (HR 0.69; 95% CI, 0.46-1.05). In the second-line setting, median PFS was 10.9 months in the alpelisib/fulvestrant arm and 3.7 months in the fulvestrant arm (HR, 0.61; 95% CI, 0.42-0.89). “I suspect that this observation likely reflects temporal evolution of these cancers with decreasing ER dependence and increasing PI3 kinase pathway activation over time,” Juric said.
Only 20 patients had prior CDK4/6 therapy. In this subset, median PFS was 5.5 months with the addition of alpelisib to fulvestrant compared with 1.8 months with fulvestrant alone (HR, 0.48; 95% CI, 0.17-1.36). In the 321 patients without prior CDK4/6 inhibitor therapy, median PFS was 11.0 months in the alpelisib/fulvestrant arm versus 6.8 months in the fulvestrant arm, representing a 33% improvement (HR, 0.67; 95% CI, 0.51-0.87).
In addition to the tissue-based mutation profiling used for the primary analysis of SOLAR-1, plasma ctDNA samples were collected at baseline and analyzed by polymerase chain reaction to retrospectively assess PFS by PIK3CA mutation status as a secondary endpoint. Based on this analysis, combined treatment with alpelisib and fulvestrant resulted in a median PFS of 10.9 months compared with 3.7 months with fulvestrant alone (HR, 0.55) in those with PIK3CA mutation. In the non-mutant cohort, median PFS was 8.8 and 7.3 month, respectively (HR, 0.80).
“This analysis clearly illustrates the potential clinical value of this easily accessible biospecimen, allowing for a rapid determination of PIK3CA mutational status right at the time of initiation of therapy, as opposed to relying on often distant archival tumor material,” he said.
The most common adverse event with alpelisib/fulvestrant is hyperglycemia, experienced by about 65% of patients. It is linked with the on-target activity of alpelisib and insulin resistance associated with PI3 kinase alpha inhibitors, Juric said. Glucose levels >160 mg/dL were generally apparent by day 15 of treatment. Management of hyperglycemia in these patients includes dose interruptions, which occurred in 40.6% of patients; dose adjustments, necessary in 49.3%; and early initiation of insulin sensitizers (used in 76%). These management measures resulted in a median duration of hyperglycemic events of about 10 days, Juric noted.
At baseline, 56% of patients were considered to be prediabetic and 4% were diabetic. These patients were the ones most likely to have glucose spikes, he said, typically occurring by the middle of the first cycle. With initiation of antidiabetic treatment, glucose levels were usually under control by cycle 2, day 1.
In SOLAR-1, 572 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer were randomized to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1). A total of 341 patients had PIK3CA mutations when tumor tissue was tested.
Participants had received 1 or more prior lines of hormonal therapy but no chemotherapy for advanced breast cancer. Patients could have received endocrine therapy in the neoadjuvant or adjuvant setting and then relapsed, followed by endocrine therapy for advanced disease until progression, or received endocrine therapy after diagnosis for advanced disease and then experienced disease progression. Patients who received (neo)adjuvant endocrine therapy and relapsed >1 year were later excluded after a protocol amendment.
In the primary analysis assessed after a median of 20 months, reported previously, in the subset of patients with PIK3CA mutations, the median PFS was 11.0 months for those who received the alpelisib combination compared with 5.7 months for those who received placebo plus fulvestrant, corresponding to a 35% reduction in the risk of progression or death HR, 0.65; P = .00065).2 There was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation.