背景：MONALEESA-3 III 期試驗（NCT02422615）之前在統計學上顯示，細胞周期蛋白依賴性激酶 4/6 抑製劑（CDK4/6i）RIB 聯合 FUL 與安慰劑（PBO）聯合 FUL 比在絕經後 HR+/HER2-的 ABC 患者一線（1L）或者二線（2L）治療中可顯著改善 OS（中位，未達到 vs40.0mo；危險比[HR]，0.72；95％CI，0.57-0.92，P=.00455）。根據研究方案，該分析是最終結果；在這項研究揭盲之後，仍在 PBO 組中接受研究治療的患者可以交叉到 RIB 組。我們報告了對 OS 進行額外中位 16.9 個月的隨訪後的探索性分析，從而可以進一步證明 RIB 的長期生存獲益。

Background:The Phase III MONALEESA-3 trial (NCT02422615) previously demonstrated a statistically significant improvement in OS with RIB, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), plus FUL compared with placebo (PBO) plus FUL as first-line (1L) or second-line (2L) treatment in postmenopausal pts with HR+/HER2-ABC (median, not reached vs 40.0 mo; hazard ratio [HR], 0.72; 95% CI, 0.57-0.92, P =.00455). This analysis was final per the protocol; following the unblinding of the study, pts still on study treatment in the PBO arm were allowed to cross over to the RIB arm. We report an exploratory analysis of OS after an additional median 16.9 mo of follow-up, allowing for further characterization of long-term survival benefits of RIB.

方法：HR+/HER2-絕經後 ABC 患者以 2：1 隨機分配接受 RIB+FUL 或 PBO+FUL 進行 1L 和 2L治療。采用 Cox 比例風險模型評估更新的 OS 並使用 Kaplan-Meier 方法進行了總結。其他進展後終點，例如無進展生存期 2（PFS2），開始化療的時間（CT）和無化療生存期也進行了評估和總結。

Methods:Postmenopausal pts with HR+/HER2-ABC were randomized 2:1 to receive RIB+FUL or PBO+FUL in 1L and 2L settings. Updated OS was evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Additional postprogression endpoints such as progression-free survival 2 (PFS2), time to chemotherapy (CT), and CT-free survival were also evaluated and summarized.

結果：在數據截止（2020 年 10 月 30 日）時，中位隨訪時間為 56.3 個月（最小，52.7 個月），其中 68（14.0％）和 21（8.7％）名患者仍在接受治療，分別在 RIB 和 PBO 組中。通過延長隨訪時間，RIB+FUL 與 PBO+FUL 相比繼續顯示出 OS 獲益（中位，53.7vs41.5 月；HR，0.73；95％CI，0.59-0.90）。RIB+FUL 在 1L 中比 PBO+FUL 的 OS 有延長（中位，未達到 vs51.8 個月；HR，0.64；95％CI，0.46-0.88）和 2L 亞組（中位，39.7vs33.7 個月；HR，0.78；95％CI，0.59-1.04）。亞組分析還顯示，大多數亞組與意向性治療（ITT）人群相比，OS 具有持續的獲益。ITT 人群的PFS2，開始化療的時間 CT 和無化療生存期都傾向於 RIB+FUL（表）。在停止研究治療的患者中，有 81.9％和 86.4％的患者隨後接受了下一線治療抗腫瘤治療，在 RIB 組與 PBO 組分別有 14.0％和 30.0％的患者接受 CDK4/6i 作為後續治療。沒有觀察到新的安全性信號。

Results:At the data cutoff (Oct 30, 2020), the median follow-up was 56.3 mo (min, 52.7 mo) and 68 (14.0%) and 21 (8.7%) patients were still on treatment in the RIB vs PBO arms, respectively. With this extended follow-up, RIB+FUL continued to demonstrate an OS benefit vs PBO+FUL (median, 53.7 vs 41.5 mo; HR, 0.73; 95% CI, 0.59-0.90). RIB + FUL had prolonged OS vs PBO+FUL in the 1L (median, not reached vs 51.8 mo; HR, 0.64; 95% CI, 0.46-0.88) and 2L subgroups (median, 39.7 vs 33.7 mo; HR, 0.78; 95% CI, 0.59-1.04). Subgroup analyses also showed a consistent OS benefit compared with the intent-to-treat (ITT) population for most subgroups. PFS2, time to CT, and CT-free survival for the ITT population favored RIB+FUL (Table). Among pts who discontinued study treatment, 81.9% and 86.4% received a next-line subsequent antineoplastic therapy, while 14.0% and 30.0% received a CDK4/6i as any subsequent line in the RIB vs PBO arms, respectively. No new safety signals were observed.

	RIB + FUL(n=484)	PBO + FUL(n=242)
PFS2, events, n (%)	265 (54.8)	163 (67.4)
Median, mo	37.4	28.1
HR (95% CI)	0.69 (0.57-0.84)
Time to first CT, events, n (%)	215 (44.4)	131 (54.1)
Median, mo	48.1	28.8
HR (95% CI)	0.70 (0.57-0.88)
CT-free survival, events, n (%)	287 (59.3)	178 (73.6)
Median, mo	32.3	22.4
HR (95% CI)	0.69 (0.57-0.83)

結論：對 HR+/HER2-絕經後 ABC 患者進行了將近 5 年的隨訪後，與 PBO+FUL 相比，RIB+FUL先前被證實的穩固且具有臨床意義的 OS 獲益仍然得以維持。在 1L 和 2L 亞組中均觀察到使用RIB 的 OS 獲益，這進一步支持了在這些亞組人群中使用 RIB。結果還表明，在 RIB 與 PBO 組後續開始化療的時間明顯延遲。

Conclusions:The previously demonstrated robust and clinically meaningful OS benefit with RIB + FUL compared with PBO+FUL was maintained after almost 5 years of follow-up in postmenopausal pts with HR+/HER2-ABC. The OS benefit of RIB was observed in the 1L and 2L subgroups, which further supports the use of RIB in these populations. The results also demonstrated a significant delay in the use of subsequent CT with RIB vs PBO.