Abstract OT-28-03: VICKI: A Phase Ib/II, randomized, placebo-controlled, study of venetoclax plus ado-trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (MBC)
Authors: Lindeman Geoffrey J , Hamilton Erika , Krop Ian , Lim Bora , Modi Shanu , Saura Cristina , Desai Rupal , Danner Bradford J , Fernando Tharu M , Kong Shengchun , Legrand Fatema A , Nasroulah Federico 
Published: February 2021

Abstract
Background ~15-20% of primary, invasive breast cancer (BC) overexpresses HER2 and, despite survival improvements, there remains an unmet need for further progress. The antibody-drug conjugate T-DM1 is approved for HER2-positive LA and/or MBC that has previously been treated with trastuzumab and a taxane (separately or in combination), and as adjuvant therapy for HER2-positive early BC, where there is residual invasive disease after neoadjuvant taxane and trastuzumab- or HER2-based treatment. Venetoclax (GDC-0199/ABT-199), an oral, selective small-molecule inhibitor of the antiapoptotic protein BCL-2, is approved for treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. BCL-2 may play a key role in HER2-positive BC, and venetoclax has shown promising activity in estrogen receptor-positive, BCL-2-positive MBC. We describe VICKI (Venetoclax in Combination with Kadcyla), a Phase Ib/II, randomized, double-blind, placebo-controlled, study of venetoclax plus T-DM1 in previously treated HER2-positive LA/MBC (NCT04298918).
Trial design
The study comprises a Phase Ib stage (dose escalation and expansion cohorts) and a randomized Phase II stage. Phase II will be initiated following identification of the recommended Phase II dose of venetoclax in Phase Ib (400 mg or 800 mg). Pts will be randomized 1:1 to T-DM1 (intravenous 3.6 mg/kg q3w) plus venetoclax or placebo. Randomization will be stratified per BCL-2 status (BCL-2 high vs. low), visceral disease (Yes vs. No), and HER2 immunohistochemistry (IHC) 3+ status (Yes vs. No).
Eligibility
Adult pts with HER2-positive (IHC 3+ or IHC 2+/in situ hybridization-positive), previously treated, unresectable, histologically or cytologically confirmed invasive LA/MBC are eligible. Pts will have measurable disease per RECIST v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Pts in Phase II will have BCL-2 expression status by IHC (≥50% of pts BCL-2 high) and will not have received prior treatment with T-DM1, venetoclax, or anti-HER2 drug conjugates.
Aims
The Phase II co-primary efficacy endpoints will be objective response rate (ORR) and progression-free survival (PFS) per RECIST v1.1 (both investigator-assessed). Secondary and exploratory efficacy endpoints will include duration of response, overall survival, clinical benefit rate, and patient-reported outcomes. Non-efficacy endpoints will be pharmacokinetics, immunogenicity, biomarkers, and safety.
Statistical methods
In Phase II, the primary efficacy populations will include all randomized pts according to their assigned treatment arm (intention-to-treat). A point estimate and 95% CI for ORR and the difference in ORR between treatment groups will be calculated using the normal approximation to the binomial distribution. PFS will be defined as time from randomization to the first occurrence of disease progression or death from any cause. Kaplan-Meier methodology will be used to estimate median PFS. An interim analysis is planned when ~56 PFS events have occurred. Primary efficacy analysis will occur when 161 pts have had a PFS event. Cox proportional-hazards models, stratified by the stratification factors, will be used to estimate the hazard ratio with 95% CI. Safety will be analyzed per treatment received in pts who received any study treatment (safety population).
Accrual
Target accrual is ~226-284 pts at 145 sites globally (Phase Ib dose escalation: 6-24 pts; Phase Ib expansion cohorts: ~20-40 pts; Phase II: 220 pts). Accrual is ongoing.
Contact information
For more information or to refer a patient, email global-roche-genentech-trials@gene.com or call 1-888-662-6728 (USA only).
Citation Format: Geoffrey J Lindeman, Erika Hamilton, Ian Krop, Bora Lim, Shanu Modi, Cristina Saura, Rupal Desai, Bradford J Danner, Tharu M Fernando, Shengchun Kong, Fatema A Legrand, Federico Nasroulah. VICKI: A Phase Ib/II, randomized, placebo-controlled, study of venetoclax plus ado-trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-positive locally advanced (LA) or metastatic breast cancer (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-28-03.