背景：對於 ER 陽性，HER2 陰性的 MBC 患者，CDK4/6 抑製劑+內分泌治療（ET）是標準的一線治療，單用 ET 被認為是二線治療。然而，大多數患者疾病會進展。一個新的治療靶點是抗凋亡蛋白 BCL2，它在約 85%的 ER 陽性乳腺癌中過度表達。VEN 是一種有效的選擇性 BCL2 抑製劑，在 ER 陽性和 BCL2 陽性接受過內分泌治療的 MBC 患者中顯示出良好的臨床活性。我們報告了 VERONICA（NCT03584009）的預先指定的主要和更新的（總生存率[OS]）分析，這是一項關於 ER 陽性、HER2 陰性 LA/MBC 中 VEN+F 與 F 相比較的 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：患者為≥18 歲，ER 陽性，HER2 陰性，LA/MBC 患者，既往接受過≤2 線 ET 治療，在 LA/MBC治療中未接受過化療，在 CDK4/6 抑製劑治療期間/之後出現疾病複發/進展（治療時間≥8 周）。患者按 1：1 的比例隨機分為 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；此後 28 天為一周期的第一天）組或者單用 F 組，治療至疾病進展、不可接受的毒性、撤回同意、死亡或預先定義的研究終點。根據 LA/MBC 患者既往治療的線數進行分層設置（1 對 2），並根據 BCL2 狀態（高對低）進行分層。主要終點是臨床受益率（CBR）；完全緩解，部分緩解，病情穩定≥24 周）。次要終點包括無進展生存期（PFS）和 OS；還進行了安全性和探索性亞組分析。

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.

結果：在初步分析時（截止日期：2020 年 8 月 5 日），103 名患者被隨機分組（意向治療[ITT]人群）。VEN+F 組和 F 組的中位年齡分別為 58.0 歲和 59.5 歲。兩組的 CBR 相似（VEN+F：11.8%[n=6/51 ； 95% 置信區間（ CI ） 4.44-23.87] ； F ： 13.7%[7/51 ； 5.70-26.26] ；風險差異：-1.96%[95%CI-16.86-12.94]）。VEN+F 組中位 PFS 為 2.69 個月（95%CI1.94-3.71）和 F 組 1.94個月（1.84-3.55）（分層危險比：0.94[95%CI0.61-1.45]）。BCL2 高亞組和低亞組的 CBR 和 PFS結果與 ITT 人群相似。VEN+F 組比 F 組觀察到更多 3-4 級不良事件（AE）（n=13/50[26%] vs.6/51[11.8%]）。VEN+F 組觀察到的不良事件與他們的個人安全性報告一致。在更新的分析（截止日期：2020 年 10 月 22 日）中，OS 數據不成熟（35.0%事件/患者 比率）；VEN+F 組中位OS 為 16.99 個月，而 F 組中位 OS 未達到（分層危險比：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]).

結論：從初步分析來看，VERONICA 在接受內分泌和 CDK4/6 抑製劑耐藥的 LA/MBC 患者中，與單獨使用 F 相比，VEN+F 組未顯示出 CBR 或 PFS 的改善。生物標誌物分析正在進行中。

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.