Abstract OT-36-01: Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC)
Authors: Turner Nicolas , Jhaveri Komal , Kalinsky Kevin , Loibl Sibylle , Loi Sherene , Im Seock-Ah , Saura Cristina , Schmid Peter , Schutzman Jennifer L , Stout Thomas J , Lei Guiyuan , Hutchinson Katherine E , Thanopoulou Eirini , Juric Dejan 
Published: February 2021

Abstract
Background
HR+/HER2- BC is the most common BC subtype, and adjuvant endocrine therapies (ET) are an integral part of its management; however, ~30% of patients still relapse. Development of ET resistance remains a challenge in HR+/HER2- BC; aberrant phosphoinositide 3-kinase (PI3K) signaling contributes to ET resistance and PIK3CA mutations occur in ~40% of HR+/HER2- BCs. Current research has led to the development of new targeted therapies, including CDK4/6 inhibitors and PI3K inhibitors (alpelisib). Preclinical models have demonstrated synergy between CDK4/6 inhibitors and PI3K inhibitors, with PI3K inhibitors blocking CDK4/6 inhibitor resistance development. GDC-0077 is a potent, selective PI3Kα inhibitor and a mutant p110α-degrader with anti-tumor activity alone and in combination with ET + P in PIK3CA-mutant preclinical models. An ongoing phase I trial showed that GDC-0077 + P + F could be combined at maximum doses. INAVO120 is a phase III, randomized, double-blind, pbo-controlled study that will assess efficacy and safety of GDC-0077/pbo + P + F in patients with PIK3CA-mutant/HR+/HER2- LA/MBC (NCT04191499).
Trial design
Patients are randomized 1:1 to GDC-0077 (9 mg orally; once daily [QD] continuously on a 28-day cycle) + P (125 mg orally; QD, days 1-21 of each 28-day cycle) + F (500 mg intramuscularly every 28 days with a loading dose in Cycle 1) or pbo + P + F. Circulating tumor DNA or tumor tissue must be positive for a PIK3CA mutation.
Eligibility
Patients whose disease progressed during/within 12 months of adjuvant ET completion, and who have not received prior systemic therapy for LA/MBC.
Aims
The primary endpoint is investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include objective response rate (ORR); best overall response (BoR); duration of response (DoR); clinical benefit rate (CBR); overall survival (OS); safety; patient-reported outcomes; and pharmacokinetics.
Statistical methods
Patients are stratified by visceral disease, primary vs secondary resistance, and geographic region. For the primary PFS analysis, the treatment arms will be compared using a two-sided stratified log-rank test. The treatment effect will be quantified via a hazard ratio, computed from a stratified Cox proportional-hazards regression, including a 95% confidence interval. Median PFS will be estimated using Kaplan-Meier methodology.
Accrual
Target enrollment is 400 patients at ~210 sites globally. The study is open for enrollment and, as of 06/04/2020, eight patients have been enrolled.
Contact information For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only).
Originally submitted to the ESMO 2020 Virtual Meeting.
Citation Format: Nicolas Turner, Komal Jhaveri, Kevin Kalinsky, Sibylle Loibl, Sherene Loi, Seock-Ah Im, Cristina Saura, Peter Schmid, Jennifer L Schutzman, Thomas J Stout, Guiyuan Lei, Katherine E Hutchinson, Eirini Thanopoulou, Dejan Juric. Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-36-01.