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Alpelisib prolongs PFS in breast cancer subset
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The addition of alpelisib to fulvestrant significantly extended PFS among certain patients with PIK3CA-mutant breast cancer, according to results of the randomized phase 3 SOLAR-1 trial presented at Miami Breast Cancer Conference.
Alpelisib (BYL719, Novartis) is the first PI3K inhibitor to demonstrate a clinically meaningful, statistically significant benefit in breast cancer, Hope S. Rugo, MD, director of breast oncology and clinical trials education at UCSF Helen Diller Family Comprehensive Cancer Center, and colleagues wrote.
Patients with hormone receptor-positive, HER2-negative advanced breast cancer receive first-line endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. However, more than half (61%) progress within about 2 years, according to study background.
More effective therapies are needed for patients with advanced breast cancer resistant to endocrine therapy. In addition, PI3K pathway hyperactivation has been shown to contribute to endocrine therapy resistance and cancer progression.
Alpelisib — a specific inhibitor of the PI3K alpha-isoform — demonstrated antitumor activity in preclinical models with PIK3CA alterations.
A phase 1 trial that evaluated the addition of alpelisib to fulvestrant for heavily pretreated patients with ER-positive advanced breast cancer showed the combination extended median PFS among patients with PIK3CA-altered tumors (9.1 months vs. 4.7 months).
In SOLAR-1, Rugo and colleagues aimed to determine whether the alpelisib-fulvestrant combination extended PFS compared with fulvestrant-placebo among men and postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who received prior treatment with an aromatase inhibitor, either as neoadjuvant therapy or for advanced disease.
The trial included 572 patients, 341 of whom had PIK3CA-mutant disease and 231 of whom did not.
Researchers assigned 284 patients (PIK3CA mutant, n = 169) to alpelisib 300 mg daily plus fulvestrant 500 mg administered intramuscularly. The other 288 patients received placebo plus fulvestrant.
PFS in the PIK3CA-mutant cohort served as the primary endpoint. Secondary endpoints included OS in the PIK3CA-mutant cohort, PFS in the non-mutant cohort, PFS among patients with PIK3CA mutation in circulating tumor DNA, OS in the non-mutant cohort, overall response rate, clinical benefit rate and safety.
Results showed the addition of alpelisib to fulvestrant significantly improved locally assessed median PFS (11 months vs. 5.7 months). Assessment by blinded independent review committee supported the PFS benefit with alpelisib (median, 11.1 months vs. 3.7 months).
Investigators observed consistent PFS benefit with alpelisib across all subgroups of patients with PIK3CA-mutant disease, including those stratified by lung or liver metastases, bone-only disease, prior CDK 4/6 inhibitor treatment and endocrine status.
Results also showed a significant improvement in ORR among patients with PIK3CA-mutant disease. Among those with measurable disease at baseline, ORR was 35.7% in the alpelisib-fulvestrant group and 16.2% in the placebo-fulvestrant group.
Researchers observed no benefit with alpelisib among patients who did not have PIK3CA-mutant disease.
Investigators observed no unexpected safety concerns. The majority of adverse events were grade 1 or grade 2.
The most frequent adverse event among alpelisib-treated patients was hyperglycemia, which was managed with dose modification.
Alpelisib-treated patients also experienced higher rates of maculopapular rash (all-grade, 14.1% vs. 1.7%; grade 3, 8.8% vs. 0.3%).
Eighteen patients (6.3%) discontinued alpelisib because of hyperglycemia and nine patients (3.2%) discontinued because of rash. No patients assigned placebo-fulvestrant discontinued treatment due to either adverse event.
“Alpelisib plus fulvestrant is a potential new treatment option for patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy with or without a CDK 4/6 inhibitor,” Rugo and colleagues concluded. – by Mark Leiser
Reference:
Rugo HS, et al. Abstract 715. Presented at: Miami Breast Cancer Conference; March 7-10, 2019; Miami.
Disclosure: Novartis sponsored this study. Rugo reports grants to her institution from Eisai, Eli Lilly, Genentech, Macrogenics, Merck, Novartis, OBI, Pfizer and Plexxikon, as well as travel support from Amgen, Eli Lilly, Merck, Mylan, Pfizer and Puma, all outside of the submitted work. Please see the abstract for all other authors’ relevant financial disclosures.