Addition of alpelisib to fulvestrant significantly prolongs PFS in advanced PIK3CA-mutant breast cancer

SAN ANTONIO — The addition of alpelisib to fulvestrant nearly doubled PFS among patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative advanced breast cancer who progressed on or after prior aromatase inhibitor therapy, according to results of the randomized phase 3 SOLAR-1 trial presented at San Antonio Breast Cancer Symposium.

Researchers observed the benefit with alpelisib (BYL719, Novartis) regardless of line of therapy or prior treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor

“The two most powerful paradigms for developing new drugs are immuno-oncology and precision oncology,” Dejan Juric, MD, director of Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center, told HemOnc Today. “[The precision oncology] paradigm is extremely successful in lung cancer ... and melanoma. ... This is now the first time for breast cancer where a somatic mutation such as PIK3CA can be targeted with a selective PI3 kinase-alpha inhibitor in a biomarker-defined patient population.”

Approximately 40% of patients with hormone receptor-positive advanced breast cancer have a PIK3CA mutation, making it the most common actionable alteration in ER-positive disease.

These mutations overactivate the PI3K pathway, resulting in tumor growth, resistance to endocrine treatment and poor prognosis, according to study background.

PI3K signaling promotes estrogen-independent growth of ER-positive breast cancer cells, but the addition of PI3K inhibitors to antiestrogens can inhibit this growth.

Alpelisib — an investigational, alpha-specific PI3K inhibitor —demonstrated antitumor activity in preclinical models that harbored PIK3CA alterations. Results of a phase 1b trial showed the addition of alpelisib to fulvestrant prolonged median PFS among heavily pretreated patients with ER-positive advanced breast cancer and positive PIK3CA mutation status, according to study background.

The SOLAR-1 trial included 572 patients with hormone receptor-positive, HER2-negative advanced breast cancer who experienced recurrence or progression on or after a prior aromatase inhibitor and underwent up to one additional line of therapy.

All patients had PIK3CA status determined by archival or fresh tumor tissue, measurable disease or at least one predominantly lytic bone lesion, and ECOG performance status of 0 or 1.

Researchers divided patients into two cohorts based on whether they had PIK3CA-mutant disease, also stratifying patients based on visceral metastases and prior treatment with a CDK 4/6 inhibitor.

Within each cohort, investigators randomly assigned patients to fulvestrant 500 mg every 28 days plus either placebo or 300 mg alpelisib daily.

PFS in the cohort of patients with PIK3CA-mutant disease served as the primary endpoint. Secondary endpoints included OS in the PIK3CA-mutant cohort, PFS in the PIK3CA-nonmutant cohort, PFS among patients with PIK3CA-mutant disease as determined by circulating tumor DNA, PFS among patients determined to have PIK3CA-nonmutant disease as determined by circulating tumor DNA, overall response rate and clinical benefit rate in both cohorts, and safety.

The study met is primary endpoint, as locally assessed PFS showed a statistically significant benefit with the addition of alpelisib to placebo (median, 11 months vs. 5.7 months; HR = 0.65; 95% CI, 0.5-0.85).

Researchers determined 75.9% of patients assigned alpelisib experienced at least some tumor shrinkage, compared with 43.9% of patients assigned to the control arm.

Investigators also analyzed PFS in the PIK3CA-mutant cohort by line of therapy. Results showed the greatest absolute PFS benefit with alpelisib for patients who received it as second-line treatment in the metastatic setting (median, 10.9 months vs. 3.7 months; HR = 0.61; 95% CI, 0.42-0.89).

“This observation likely reflects temporal evolution of these cancers with decreasing ER dependence and increasing PI3 kinase pathway activation over time,” Juric said.

The number of patients who received prior CDK 4/6 inhibitor therapy was too small to provide robust assessment of the alpelisib-fulvestrant combination for this group, Juric said. However, results show similar benefit with this regimen among patients who had received prior CDK 4/6 inhibitor therapy (median, 5.5 months vs. 1.8 months; HR = 0.58; 95% CI, 0.17-1.36) and those who had not (median, 11 months vs. 6.8 months; HR = 0.67; 95% CI, 0.51-0.87).

In addition to tissue-based biopsy, Juric and colleagues conducted a polymerase chain reaction-based circulating tumor DNA analysis, and they retrospectively reanalyzed PFS data using circulating tumor DNA PIK3CA mutation status.

Results of this analysis showed the alpelisib-fulvestrant combination resulted in median PFS of 10.9 months compared with 3.7 months with placebo-fulvestrant (HR = 0.55).

“This really suggests that this important biospecimen easily accessible blood sample can provide a rapid way to assess PIK3CA mutation status and can potentially be used also to assess biological activity of the cancer,” Juric told HemOnc Today. “Consistent observation in PIK3CA-mutant patients’ tissue or circulating tumor DNA also points toward the importance of testing PIK3CA status and potentially brings the precision oncology paradigm to breast cancer.”

OS data are immature. However, Juric described what he called “a positive OS trend. Median OS had not been reached in the alpelisib-fulvestrant group but was 26.9 months in the placebo-fulvestrant group (HR = 0.73; 95% CI, 0.48-1.1).

“Two additional OS analyses will shed a lot more light on the potential OS benefit of this combination, and they will be presented once they are mature,” Juric said.

The most common adverse events associated with alpelisib-fulvestrant included hyperglycemia (all grade, 99.4%; grade 3/grade 4, 80.4%), diarrhea (all grade, 65.1%; grade 3/grade 4, 36.7%), nausea (all grade, 54.4%; grade 3/grade 4, 7.7%), rash (all grade, 39.6%; grade 3/grade 4, 13%), decreased appetite (all grade, 33.7%; grade 3/grade 4, 0.6%) and stomatitis (all grade, 26.6%; grade 3/grade 4, 3%).

Hyperglycemia is a reversible on-target effect of PI3K inhibition, and median duration of alpelisib exposure among patients with hyperglycemia was comparable to that of the overall study population (6 months vs. 5.5 months).

Among patients who developed hyperglycemia, 40.6% required dose interruptions and 43.9% required dose adjustments. No sustained induction of diabetic metabolism was observed after discontinuation of alpelisib treatment, Juric said.

The results of this study are particularly important given the development of effective but costly new treatments, Juric said.

“In this era of significant progress, with various agents that are associated with considerable financial toxicity, it is important to find ways to predict which patients are going to benefit from one approach or another,” he told HemOnc Today. “So far, aside from standard markers like ER, PR and HER2, we don’t really have biomarker like PIK3CA that we can use in this predictive way. ... We need to continue to push forward and better understand the genomic complexities of ER-positive breast cancers and determine how to selectively use various agents in genomically predefined patient populations.” – by Mark Leiser

Reference:

Juric D, et al. Abstract GS3-08. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.

Disclosure:

Novartis sponsored this study. Juric reports scientific advisory board fees from Eisai, EMD Serono, Genentech, Ipsen and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.