SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors.

Abstract

TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.

KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

“…PI3K inhibitors recently showed good efficacy as single agents in some contexts and acceptable toxicities (37,38). We thus believe that clinical development of G12C inhibitors would benefit from combination with PI3K pathway inhibitor upfront to maximize the response rate and reduce the development of adaptive resistance mechanisms.…”

PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

“…Recently, preclinical evidence suggested that selective inhibition of the p110α isoform of PI3K could provide higher tolerability without affecting treatment efficacy [27][28][29][30]. The randomized phase III SOLAR-1 [31] and SANDIPER [32] trials are currently testing the new potent and selective PI3Kα inhibitors alpelisib and taselisib, respectively, in postmenopausal patients with HR + /HER2 -MBC progressing on or after an AI. Results from these trials are eagerly awaited to determine whether PI3K inhibition can be considered as a valid therapeutic option for luminal BC.…”

Estrogen Receptor-Positive Breast Cancer: Exploiting Signaling Pathways Implicated in Endocrine Resistance

“…This review describes the role of these signaling pathways and the ER in BC, the role of antiestrogens in the treatment of HR+ advanced BC, the development of resistance to antiestrogen therapy, and the use of endocrine and endocrine‐based combination therapy in BC. Supporting evidence for their benefits is provided by completed phase III studies (Table ) and ongoing phase III studies (Table ) .…”