In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 15 ( 2022-08-02), p. 3256-3267
Abstract:
Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-21-3811
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2022
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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