Abstract 352TiP
Background
HER2 overexpression is associated with an aggressive breast cancer phenotype marked by metastatic spread of disease. Hyperactivated PI3K signaling downstream of HER2 promotes resistance to the mainstay anti-HER2 therapy T in advanced disease. Mutations in PIK3CA, which encodes α-PI3K, are reported in ∼40% of HER2+ breast tumours and lead to PI3K pathway hyperactivation. Alpelisib, an α-selective PI3K inhibitor (inh), + fulvestrant (FUL), significantly improved progression-free survival (PFS) vs. placebo + FUL in pts with PIK3CA-mut, HR+, HER2– ABC in the phase III SOLAR-1 trial (hazard ratio 0.65; 95% CI, 0.50-0.85; P<0.001).
Trial design
EPIK-B2 is a 2-part, phase III, multicenter study to assess ALP with T + P as treatment (tx) of PIK3CA-mut HER2+ ABC in women and men. Pts should have no evidence of disease progression on completion of prestudy induction tx with 4-6 cycles of taxane plus T + P, and plan to continue T + P as maintenance tx. Key exclusion criteria include prior tx with PI3K, mTOR, or AKT inh; clinically unstable CNS involvement; and type 1 or uncontrolled type 2 diabetes. Part 1 is an open-label safety run-in to confirm the recommended phase III dose (RP3D) of ALP with T + P. ALP will be administered orally (PO) once daily (QD) in a 21-day cycle, testing up to 3 dose levels (300, 250, and 200 mg) across 3 cohorts. All pts will receive T 6 mg/kg IV + P 420 mg IV on Day 1 of each cycle. Primary endpoint is incidence of dose-limiting toxicities during the first 6 wk of tx for each dose level; secondary endpoints include safety and tolerability, and ALP exposure by timepoint and dose level. Following Part 1 is Part 2, a double-blind, randomised, placebo-controlled evaluation of efficacy and safety of ALP with T + P as maintenance therapy following prestudy induction tx. ALP is administered at RP3D identified in Part 1, PO QD on a 21-day cycle, with T + P given at Part 1 doses. Primary endpoint is PFS. Key secondary endpoint is overall survival; other secondary endpoints include overall response rate, clinical benefit rate, safety and tolerability, exposure, and pt-reported outcomes.
Clinical trial identification
NCT04208178.
Editorial acknowledgement
Medical editorial assistance was provided by Rob M. Camp of Healthcare Consultancy Group, LLC, funded by Novartis Pharmaceuticals.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
S.A. Hurvitz: Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): OBI Pharma; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Dignitana; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Biomarin; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): Cascadian Therapeutics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Ambryx; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Pieris Pharmaceuticals; Research grant/Funding (institution): Radius Health. S.K.L. Chia: Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Hoffmann LaRoche; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Genomic Health. E.M. Ciruelos: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. S-A. Im: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Hanmi. W. Janni: Honoraria (self), Research grant/Funding (self): Novartis. G. Jerusalem: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eli Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AbbVie. M. Lacouture: Advisory/Consultancy: Novartis. R. O'Regan: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Puma; Honoraria (self), Advisory/Consultancy: bioTheranostics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Macrogenics; Honoraria (self), Advisory/Consultancy: Immunogenics; Honoraria (self), Advisory/Consultancy: Genentech; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: Immunomedics; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Cascadian Therapeutics; Honoraria (self), Research grant/Funding (institution): Pfizer. H.S. Rugo: Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution): Merck; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): OBI; Research grant/Funding (institution): Odonate; Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi-Sankyo; Research grant/Funding (institution): Eisai; Research grant/Funding (institution), Travel/Accommodation/Expenses: Macrogenics; Travel/Accommodation/Expenses: Mylan; Research grant/Funding (institution): Immunomedics; Advisory/Consultancy: Samsung; Advisory/Consultancy: Celtrion; Travel/Accommodation/Expenses: AstraZeneca. Y.S. Yap: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca. F. Ghaznawi: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. Y. Han: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. F. Su: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. S. Chandarlapaty: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: Sermonix; Advisory/Consultancy: Revolution Medicine; Advisory/Consultancy: BMS; Advisory/Consultancy: Context Therapeutics; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Genentech. All other authors have declared no conflicts of interest.