Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Clin Cancer Res. 2022 Aug 2;28(15):3256-3267. doi: 10.1158/1078-0432.CCR-21-3811.
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.
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.
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.
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.
尽管 B 细胞淋巴瘤 2（BCL2）抑制剂维奈托克在血液恶性肿瘤中显示出有前景的活性，但它在实体肿瘤中的疗效尚不清楚。我们报告了 VERONICA 的预先指定的主要结果，这是一项随机的 II 期临床试验，评估了维奈托克联合氟维司群在雌激素受体（ER）阳性、HER2 阴性转移性乳腺癌中的应用，这些患者在接受细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂治疗后出现进展。
年龄在 18 岁及以上的绝经前/后女性患者按 1:1 随机分组，分别接受维奈托克（800 mg 口服，每日一次）联合氟维司群（500 mg 肌内注射；第 1 周期：第 1 天和第 15 天；随后的 28 天周期：第 1 天）或氟维司群单药治疗。主要终点是临床获益率（CBR）；次要终点是无进展生存期（PFS）、总生存期和安全性。探索性生物标志物分析包括 BCL2 和 BCL 细胞凋亡抑制蛋白（BCLXL）肿瘤表达以及 PIK3CA 循环肿瘤 DNA 突变状态。
在主要分析时（截止日期：2020 年 8 月 5 日；n = 103），维奈托克并未显著提高 CBR[维奈托克联合氟维司群组：11.8%（n = 6/51；95%置信区间[CI]，4.44-23.87）；氟维司群组：13.7%（7/51；5.70-26.26）；风险差-1.96%（95%CI，-16.86 至 12.94）]。维奈托克联合氟维司群组的中位 PFS 为 2.69 个月（95%CI，1.94-3.71），而氟维司群组为 1.94 个月（1.84-3.55）（分层 HR，0.94；95%CI，0.61-1.45；P = 0.7853）。总生存数据尚未成熟。在肿瘤具有强 BCL2 表达（免疫组化 3+）、BCL2/BCLXL Histoscore 比值≥1 或 PIK3CA 野生型的患者中，观察到 CBR 和 PFS 有非显著性改善。
我们的研究结果表明，维奈托克联合氟维司群在 CDK4/6 抑制剂耐药、内分泌治疗抵抗的转移性乳腺癌患者中没有临床应用价值，但提示在这种情况下可能对 BCLXL 的依赖性增加。
