Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial

Abstract

Background: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer.

Patients and methods: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life.

Results: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm.

Conclusion: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Trial registration: ClinicalTrials.gov NCT02340221.

Keywords: PI3K inhibitors; PIK3CA mutations; advanced breast cancer; taselisib.

Conflict of interest statement

Disclosure SD reports research grant funding from Novartis US and honoraria from Novartis. JC reports stock or other ownership in MedSIR; honoraria from F. Hoffmann-La Roche Ltd, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, and Merck Sharp & Dohme; fees from a consultancy or advisory role from F. Hoffmann-La Roche Ltd, Celgene, AstraZeneca, Cellestia, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Lilly, Polyphor, Servier, Merck Sharp & Dohme, and GSK; research funding to his institution from F. Hoffmann-La Roche Ltd, ARIAD Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, Puma Biotechnology, Queen Mary University of London, Seagen; and travel or accommodation expenses from F. Hoffmann-La Roche Ltd, Novartis, Pfizer, Daiichi Sankyo, and Eisai. Y-HI declares no conflicts of interest. VD reports honoraria and fees from a consultancy or advisory role from Pfizer, Novartis, Lilly, F. Hoffmann-La Roche Ltd, AbbVie, Seattle Genetics, AstraZeneca, Daiichi Sankyo, and Merck Sharp & Dohme; and travel, accommodations, or expenses from Pfizer, AstraZeneca, and Novartis. NH has received honoraria for consulting and lectures from Roche and Novartis. IEK reports honoraria from Genentech, AstraZeneca, and Celltrion, fees from a consulting or advisory role from Genentech/Roche, Seattle Genetics, Daiichi Sankyo, MacroGenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, and Ionis, research funding from Genentech and Pfizer, and employment/leadership/stock and other ownership interests (for an immediate family member) from AMAG Pharmaceuticals. TRW is an employee of Genentech, Inc., and holds stock in F. Hoffmann-La Roche Ltd. NC was previously an employee of Genentech, Inc., and is now employed by CStone Pharmaceuticals, and holds stock in both companies. FS is an employee of Genentech, Inc., holds stock in F. Hoffmann-La Roche Ltd, Exelixis, and Teva, and has patent or intellectual property interests with Exelixis. JYH is an employee of Genentech, Inc., and holds stock in F. Hoffmann-La Roche Ltd. JH was an employee of F. Hoffmann-La Roche Ltd/Genentech, Inc., and holds stock in F. Hoffmann-La Roche Ltd/Genentech, Inc. MDL reports honoraria from Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Celgene, Eisai, and Amgen; fees for a consulting or advisory role from Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Eisai, Celgene, Lilly, Genomic Health, MSD Oncology, and Amgen; research funding from F. Hoffmann-La Roche Ltd, Eisai, and Italfarmaco; and fees from speakers' bureau from Novartis and F. Hoffmann-La Roche Ltd. SS reports fees for advisory boards from F. Hoffmann-La Roche Ltd, Novartis, AstraZeneca, Lilly, and Pfizer; fees for speakers' bureau from F. Hoffmann-La Roche Ltd, Novartis, AstraZeneca, Lilly, and Pfizer; and fees for travel, accommodations, or expenses from F. Hoffmann-La Roche Ltd, Novartis, Pfizer, Lilly, Amgen, AstraZeneca, and Pierre Fabre. PD reports research funding from F. Hoffmann-La Roche Ltd and Novartis and NIH/NCI core grant funding (P30CA008798). WJ reports fees for a consulting or advisory role from AstraZeneca, Eisai, Lilly France, MSD, Pfizer, F. Hoffmann-La Roche Ltd, and Novartis; research funding from AstraZeneca; and travel, accommodations, or expenses from AstraZeneca, Chugai Pharma, Eisai, Lilly France, Pfizer, GSK, Pierre Fabre, F. Hoffmann-La Roche Ltd, and Sanofi-Aventis. All authors received support for third-party writing assistance for this manuscript from F. Hoffmann-La Roche Ltd.

Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Kaplan—Meier plots for PFS in patients with PIK3CA-mutant tumors: (A) investigator-assessed PFS; (B) BICR-PFS.

PFS was defined as the time from randomization to first disease progression as determined by the investigator using RECIST v1.1, or death from any cause. BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; INV, investigator-assessed; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

Figure 2.. Forest plot of investigator-assessed PFS in patients with PIK3CA-mutant tumors.

PFS was defined as the time from randomization to first disease progression as determined by the investigator using RECIST v1.1, or death from any cause. CI, confidence interval; CDK, cyclin-dependent kinase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; IxRS, Interactive Voice/Web Response System; MBC, metastatic breast cancer; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

Figure 3.. Kaplan—Meier plots for INV-PFS in patients with PIK3CA mutation status determined by ctDNA analysis: (A) patients with PIK3CA-mutant tumors and (B) patients with MND.

CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; INV, investigator-assessed; MND, mutation not detected; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.