背景：对于 ER 阳性，HER2 阴性的 MBC 患者，CDK4/6 抑制剂+内分泌治疗（ET）是标准的一线治疗，单用 ET 被认为是二线治疗。然而，大多数患者疾病会进展。一个新的治疗靶点是抗凋亡蛋白 BCL2，它在约 85%的 ER 阳性乳腺癌中过度表达。VEN 是一种有效的选择性 BCL2 抑制剂，在 ER 阳性和 BCL2 阳性接受过内分泌治疗的 MBC 患者中显示出良好的临床活性。我们报告了 VERONICA（NCT03584009）的预先指定的主要和更新的（总生存率[OS]）分析，这是一项关于 ER 阳性、HER2 阴性 LA/MBC 中 VEN+F 与 F 相比较的 II 期研究。

Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC.

方法：患者为≥18 岁，ER 阳性，HER2 阴性，LA/MBC 患者，既往接受过≤2 线 ET 治疗，在 LA/MBC治疗中未接受过化疗，在 CDK4/6 抑制剂治疗期间/之后出现疾病复发/进展（治疗时间≥8 周）。患者按 1：1 的比例随机分为 VEN（口服；每日 800 毫克）+F（肌肉注射；第 1 周期 第 1 天和第 15 天 500 毫克；此后 28 天为一周期的第一天）组或者单用 F 组，治疗至疾病进展、不可接受的毒性、撤回同意、死亡或预先定义的研究终点。根据 LA/MBC 患者既往治疗的线数进行分层设置（1 对 2），并根据 BCL2 状态（高对低）进行分层。主要终点是临床受益率（CBR）；完全缓解，部分缓解，病情稳定≥24 周）。次要终点包括无进展生存期（PFS）和 OS；还进行了安全性和探索性亚组分析。

Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted.

结果：在初步分析时（截止日期：2020 年 8 月 5 日），103 名患者被随机分组（意向治疗[ITT]人群）。VEN+F 组和 F 组的中位年龄分别为 58.0 岁和 59.5 岁。两组的 CBR 相似（VEN+F：11.8%[n=6/51 ； 95% 置信区间（ CI ） 4.44-23.87] ； F ： 13.7%[7/51 ； 5.70-26.26] ；风险差异：-1.96%[95%CI-16.86-12.94]）。VEN+F 组中位 PFS 为 2.69 个月（95%CI1.94-3.71）和 F 组 1.94个月（1.84-3.55）（分层危险比：0.94[95%CI0.61-1.45]）。BCL2 高亚组和低亚组的 CBR 和 PFS结果与 ITT 人群相似。VEN+F 组比 F 组观察到更多 3-4 级不良事件（AE）（n=13/50[26%] vs.6/51[11.8%]）。VEN+F 组观察到的不良事件与他们的个人安全性报告一致。在更新的分析（截止日期：2020 年 10 月 22 日）中，OS 数据不成熟（35.0%事件/患者 比率）；VEN+F 组中位OS 为 16.99 个月，而 F 组中位 OS 未达到（分层危险比：2.06[1.04-4.09]）。

Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]).

结论：从初步分析来看，VERONICA 在接受内分泌和 CDK4/6 抑制剂耐药的 LA/MBC 患者中，与单独使用 F 相比，VEN+F 组未显示出 CBR 或 PFS 的改善。生物标志物分析正在进行中。

Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing.