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)

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+ (>1%), BCL-2+ (>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.

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“…It remains to be seen whether the positive results observed in diseases like CLL using anti-apoptotic inhibition will be mirrored in solid tumors, including CRC, that are commonly more difficult to treat in the clinic. Promising results have recently been reported on venetoclax when combined with tamoxifen in ER/Bcl-2-positive metastatic breast cancer with an overall response rate of 61% and a 72% clinical benefit rate 59 , which underscores the importance of testing new combination therapies.…”

Systemic treatment of metastatic breast cancer: SABCS 2018

“…Preclinical data using xenograft models from ER+ breast cancer suggest that venetoclax shows a synergistic effect with tamoxifen to induce apoptosis [14]. Based on these findings, a phase 1b 3 + 3 doseescalation and expansion study was performed and presented in San Antonio [10]. The primary aim was to determine the maximum tolerated dose (MTD), define dose-limiting toxicities (DLTs) and to identify the recommended phase 2 dose (RP2D).…”