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Evaluation of Venetoclax plus Trastuzumab Emtansine in Patients with Previously Treated HER2-Positive Locally Advanced or Metastatic Breast Cancer

Conference Correspondent

There remains a persistent, unmet need for further progress in the treatment of primary, invasive breast cancer because approximately 15% to 20% of cases overexpress human epidermal growth factor receptor 2 (HER2) regardless of survival improvements. The antibody–drug conjugate trastuzumab emtansine has been approved for HER2-positive locally advanced and/or metastatic breast cancer that has previously been treated with a taxane (monotherapy or in combination) and trastuzumab, and as adjuvant therapy for HER2-positive early breast cancer, where there is residual invasive disease after treatment with neoadjuvant taxane and trastuzumab- or HER2-based therapy.

An oral, selective small-molecule inhibitor of the antiapoptotic protein BCL-2, called venetoclax, is indicated for the treatment of a few hematologic malignancies. In HER2-positive breast cancer, BCL-2 may play a key role, and venetoclax has demonstrated favorable activity in estrogen receptor–positive, BCL-2–positive metastatic breast cancer.

Geoffrey J. Lindeman of The Peter MacCallum Cancer Centre, and Walter and Eliza Hall Institute, in Melbourne, Australia, and colleagues provided insight into VICKI (Venetoclax in Combination with Kadcyla), a phase 1b/2, randomized, double-blind, placebo-controlled study of venetoclax plus T-DM1 in patients previously treated HER2-positive locally advanced/metastatic breast cancer.

A dose-escalation and expansion cohorts phase 1b stage as well as a randomized phase 2 stage will comprise the study. Subsequent to the identification of the recommended phase 2 dose of venetoclax in phase 1b (400 mg or 800 mg), phase 2 will be initiated. Patients will be randomized 1:1 to receive placebo or trastuzumab emtansine (intravenous 3.6 mg/kg every 3 weeks) plus venetoclax.

Adult patients are considered eligible for the study if diagnosed with HER2-positive, previously treated, unresectable, histologically or cytologically confirmed invasive locally advanced/metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

In phase 2, patients will not have received prior treatment with trastuzumab emtansine, venetoclax, or anti-HER2 drug conjugates and will have BCL-2 expression status confirmed by immunohistochemistry (≥50% of patients BCL-2 high). Phase 2 will have 2 investigator-assessed co-primary efficacy end points. The first will be objective response rate, and the second will be progression-free survival based on RECIST v1.1 criteria. Overall survival, clinical benefit rate, duration of response, and patient-reported outcomes will be considered secondary and exploratory efficacy end points. The study will also evaluate nonefficacy end points, including biomarkers, immunogenicity, pharmacokinetics, and safety.

All randomized patients according to their assigned treatment arm will be included in the primary efficacy populations in phase 2. Time from randomization to the first occurrence of disease progression or death from any cause will be used to define progression-free survival. At the time when approximately 56 progression-free survival events have occurred, an interim analysis is planned. When 161 patients have had a progression-free survival event, primary efficacy analysis will occur. In patients who received any study treatment, safety will be evaluated per treatment received.

Source: Lindeman GJ, Hamilton E, Krop I, et al. 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). Presented at: 2020 San Antonio Breast Cancer Symposium, December 8-11, 2020. Abstract OT-28-03.

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