Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.

Abstract

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

“…This was the first trial of a mutant‐selective PI3K inhibitor with ET in a biomarker‐defined population to report safety and efficacy results. The median investigator‐assessed PFS of patients with PIK3CA ‐mutant tumors (assessed by central laboratory) treated with taselisib plus fulvestrant was significantly higher than that of patients treated with placebo plus fulvestrant (7.4 vs. 5.4 months; hazard ratio 0.70; p = .0037) . Taselisib plus fulvestrant also demonstrated improved ORR (28%) versus placebo plus fulvestrant (12%; p = .0002) .…”

“…The median investigator‐assessed PFS of patients with PIK3CA ‐mutant tumors (assessed by central laboratory) treated with taselisib plus fulvestrant was significantly higher than that of patients treated with placebo plus fulvestrant (7.4 vs. 5.4 months; hazard ratio 0.70; p = .0037) . Taselisib plus fulvestrant also demonstrated improved ORR (28%) versus placebo plus fulvestrant (12%; p = .0002) . Both the CBR (52% vs. 37%) and DOR (8.7 vs. 7.2 months) also favored taselisib plus fulvestrant versus placebo plus fulvestrant in patients with PIK3CA ‐mutant tumors .…”

“…At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors . However, phase III trials of investigational PI3K inhibitors suggest patients may derive differential benefit depending on their tumors’ PIK3CA mutation status .

At present, activated PI3K pathway biomarkers in HR+, HER2− ABC do not guide treatment decisions as no CDK4/6 or mTOR inhibitors currently approved for HR+, HER2− ABC have demonstrated superior efficacy in patients with versus without PIK3CA‐ mutated tumors.

…”

“…Improved clinical benefit of taselisib plus fulvestrant in patients with PIK3CA ‐mutant tumors was further demonstrated in the phase III, double‐blind, placebo‐controlled SANDPIPER trial . Postmenopausal women with HR+, HER2− locally advanced or metastatic breast cancer with recurrence or progression during or after AI therapy were randomized 2:1 to receive taselisib plus fulvestrant ( n = 340) or placebo plus fulvestrant ( n = 176) . This was the first trial of a mutant‐selective PI3K inhibitor with ET in a biomarker‐defined population to report safety and efficacy results.…”

ESR1 mutations in breast cancer

“…59 Although combinations exhibited a marginally better PFS (BELLE-2, 6.9 vs 5.0 months; BELLE-3, 3.9 vs 1.8 months) the toxicity profile of buparlisib plus fulvestrant does not support its further development in this setting. 61 Importantly, there has not yet been a retrospective analysis of ESR1 mutations in these patient populations. In the phase 3 SOALR-1 clinical trial, patients with ER-positive MBC who progressed on AI therapy were randomized to fulvestrant with or without the mutant PI3K-alpha specific inhibitor alpelisib.…”