Abstract PD1-06: A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2–positive metastatic breast cancer (MBC)
Authors: Lindeman GJ , Lok SW , Whittle JR , Siow ZR , Bergin AR , Dawson S-J , Desai J , Gray DH , Liew D , Mann GB , Murugasu A , Roberts AW , Rosenthal MA , Shackleton K , Sherman P , Silva MJ , Teh C , Travers A , Vaillant F , Visvader JE 
Published: May 2019

Abstract
Background: Venetoclax, a potent and selective inhibitor of the survival protein BCL-2 (recently approved in CLL and in development in other hematopoietic malignancies), has yet to be evaluated in pts with solid tumors. BCL-2 is overexpressed in ˜85% of ER+ breast cancer. Pre-clinical findings using patient-derived xenograft breast tumor models suggest that venetoclax synergizes with endocrine therapy by increasing apoptosis. Here we report mBEP, an investigator-initiated phase 1b study of venetoclax with tamoxifen in 33 pts with ER+ (&gt;1%), BCL-2+ (&gt;10%, 2-3+ intensity) and HER2– MBC.
Methods: We conducted a 3+3 dose escalation study comprising cohorts receiving venetoclax 200, 400, 600 or 800 mg/d with tamoxifen 20 mg/d (continued until progression). The primary endpoint was to determine the maximum tolerated dose (MTD), define dose-limiting toxicities (DLTs) and identify the recommended phase 2 dose (RP2D). In a dose expansion phase (at the RP2D), secondary endpoints including safety and tolerability, response at 24 wks (RECIST v1.1), clinical benefit rate (CBR) and progression-free survival (PFS) were studied.
Results: In the escalation phase (n=15 pts), treatment was well tolerated with no DLTs or high-grade (Gd 3/4) adverse events observed, apart from asymptomatic on-target lymphopenia (Gd 3, 2/15 pts). MTD was not reached. The 800 mg/d dose was selected as the RP2D and the cohort expanded to include 24 pts with ≥24 wks follow up (range 24-105 wks). Fifteen pts had received prior regimens for MBC (median 3, range 1-9) that included tamoxifen in 5/15.
For the RP2D cohort (n=24), overall responses (OR) included 1 CR (4%) and 12 PR (50%), with 5 SD (21%), corresponding to a CBR of 75%. The 9 pts treated in the first line setting experienced a 78% OR (7/9 pts) and 11% SD (1/9 pts), equating to an 89% CBR. The data are immature for determining median PFS for the RP2D cohort (currently 40+ wks).
Treatment responses were pre-empted by metabolic responses (FDG-PET) at 4 wks (seen in 13/16 (81%) pts studied), and correlated with serial changes in circulating tumor DNA (ctDNA). Intriguingly, responses and clinical benefit were observed in pts with plasma-detected ESR1 mutations (4/10 and 7/10, respectively).
The most common treatment-related AEs (CTCAE v4.0) for all pts were lymphopenia in 29/33 (88%; 57% Gd 1-2, 30% Gd 3-4), neutropenia in 24/33 (73%; 67% Gd 1-2, 6% Gd 3), nausea in 22/33 (67%; all ≤Gd 2), anemia in 13/33 (39%; 33% Gd 1-2, 6% G3), thrombocytopenia in 11/33 (33%; all ≤Gd 2), vomiting in 11/33 (33%, all ≤Gd 2), diarrhea in 10/33 (30%; 24% Gd 1-2, 6% Gd 3), infection in 9/33 (27%; 18% Gd 2, 9% Gd 3) and fatigue in 7/33 (21%; all ≤Gd 2). There was one possible treatment-related SAE (infection).
Conclusions: In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits remarkable activity in ER+ and BCL-2+ MBC. These findings support further investigation of combination therapy for patients with BCL-2-positive breast cancer.
Sponsor: The Royal Melbourne Hospital (ACTRN12615000702516)
Citation Format: Lindeman GJ, Lok SW, Whittle JR, Siow ZR, Bergin AR, Dawson S-J, Desai J, Gray DH, Liew D, Mann GB, Murugasu A, Roberts AW, Rosenthal MA, Shackleton K, Sherman P, Silva MJ, Teh C, Travers A, Vaillant F, Visvader JE. A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2–positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-06.