針對已接受CDK4/6抑制劑之荷爾蒙受體陽性、人類表皮生長因子受體2陰性且無可靶向之基因變異的晚期乳癌患者以標靶藥物合併內分泌療法之系統性文獻回顧、統合分析與臨床試驗計畫書

Abstract

背景： 荷爾蒙受體陽性（HR+）/人類表皮生長因子受體2陰性（HER2−）乳癌佔所有乳癌亞型一半以上。根據多項大型隨機臨床試驗結果，與單獨內分泌療法比較，週期素依賴性激酶4/6（CDK4/6）抑制劑合併內分泌療法（ET）可顯著延長患者無疾病進展存活期（progression-free survival, PFS）達兩倍以上。目前美國食品藥物管理局（FDA）已核准palbociclib（2016年6月）、ribociclib（2017年3月）及abemaciclib（2021年10月）三種CDK4/6抑制劑，自2017年起，國際治療指引將CDK4/6抑制劑合併內分泌療法作為晚期管腔型乳癌之標準一線治療。對於接受CDK4/6抑制劑合併內分泌療法後疾病惡化且未具有特定基因變異的族群，現行二線治療選項包含單獨內分泌療法fulveatrant等或標靶藥物（targeted therapy, TT）mTOR抑制劑合併內分泌療法，此乃根據先前BOLERO-2試驗（2013），一個隨機分派臨床實驗結果。但在 BOLERO-2 試驗中全部的受試者過去並沒有使用CDK 4/6抑制劑，因此無法得知這是否會影響其增進無疾病進展存活期的推估。此外，近期研究指出，在接受CDK4/6抑制劑治療疾病惡化的患者族群中，轉換使用不同的CDK4/6抑制劑合併另一種內分泌療法似乎具療效潛力，但尚未有充足證據證實此策略優於mTOR抑制劑合併內分泌療法。 方法： 本研究依循系統性回顧與統合分析報告準則（Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA），透過PICO架構確認檢索關鍵字，於PubMed、EMBASE及Cochrane進行隨機對照試驗文獻檢索，並納入美國臨床腫瘤學會（ASCO）與歐洲腫瘤學學會（ESMO）國際會議資料。擷取研究中無疾病進展存活期數據，並以考科藍偏誤風險評估工具（Cochrane risk of bias tool）進行文獻品質評估。使用R軟體（版本4.4.1）執行統合分析，以比較標靶藥物合併內分泌療法與單獨內分泌療法在CDK4/6抑制劑治療後疾病惡化的患者之療效差異。納入分析的臨床試驗包含EMBER-3、postMONARCH、MAINTAIN、PACE、PALMIRA以及CapItello-291的亞組資料。此外，亦針對族群特徵，年齡（≥65歲或<65歲）、轉移部位（有無內臟轉移或僅骨轉移），以及前次接受CDK4/6抑制劑治療的時間（≥12個月或<12個月）進行亞組分析，以檢視治療效益的一致性。 結果： 統合分析顯示，標靶藥物合併內分泌療法相較於單獨內分泌療法，可顯著改善無疾病進展存活期（HR=0.71，95% CI：0.55-0.90）。依據標靶藥物的使用策略進行分層分析，患者在接受palbociclib治療疾病惡化後，改為使用其他CDK4/6抑制劑（abemaciclib或ribociclib）合併內分泌療法時（EMBER-3、postMONARCH與MAINTAIN試驗），相較於單獨使用內分泌療法，可顯著提升療效（HR=0.61，95% CI：0.48-0.76）；然而，若接續使用相同的CDK4/6抑制劑palbociclib合併內分泌療法（PACE與PALMIRA試驗），相較於單獨使用內分泌療法，則未觀察到明顯的療效差異（HR=0.91，95% CI：0.70-1.17）。此外，以CapItello-291試驗亞組資料進行敏感性分析，在無特定基因變異（PI3K/AKT pathway alteration）的患者族群中，使用AKT抑制劑capivasertib標靶藥物時，結果趨勢仍與前述分析一致（TT+ET vs ET: HR=0.68，95% CI：0.56-0.82）。針對臨床上具有代表性的族群特徵進行亞組分析，結果亦一致顯示不論年齡差異、轉移位置或先前CDK4/6抑制劑治療時間長短，標靶藥物合併內分泌療法均有較佳的無疾病進展存活期改善趨勢。 結論： 在HR+/HER2− 轉移性乳癌患者接受一線CDK4/6抑制劑治療疾病惡化後，更換標靶藥物治療（包括不同CDK4/6抑制劑或AKT抑制劑）合併內分泌療法能顯著改善無疾病進展存活期。目前尚無直接比較mTOR抑制劑與更換CDK4/6抑制劑作為二線治療的研究。因此，本研究將設計一項非劣性臨床試驗，評估對一線CDK4/6抑制劑（palbociclib及ribociclib）治療後疾病惡化且無特定基因突變的患者，第二線治療使用內分泌療法fulvestrant合併不同CDK4/6抑制劑abemaciclib或mTOR抑制劑everolimus之療效。此研究目的為確認更換CDK4/6抑制劑的療效是否不遜於mTOR抑制劑，同時兼顧毒性較低及保持患者的生活品質，以確立最佳的二線治療策略。由於亞組分析顯示不同族群特徵具有一致的療效改善，因此此研究設計將不特別排除上述亞組患者。

Background: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) accounts for more than half of all BC subtypes. The standard first-line treatment for HR+/HER2− metastatic breast cancer (mBC) has been established as a combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and endocrine therapy (ET) since 2017, based on pivotal phase III randomized controlled trials (RCTs), such as MONARCH 3, MONALEESA-2, MONALEESA-3, MONALEESA-7, and PALOMA-2, which demonstrated significantly improved outcomes, with a median progression-free survival (PFS) of approximately 24 months. The U.S. Food and Drug Administration (FDA) approved three CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—in June 2016, March 2017, and October 2021, respectively. For patients without targetable gene mutations (wild type) who experience disease progression from prior CDK4/6 inhibitor plus ET, treatment strategies include endocrine monotherapy (fulvestrant, etc.) or switching to mTOR inhibitor combined with ET based on the BOLERO-2 RCT result published in 2014. However, none of the trial participants were previously treated with CDK4/6 inhibitor; therefore, its results may have limited relevance to current clinical practice. Recent studies have suggested potential benefit from switching to another CDK4/6 inhibitor combined with ET, but comparative mTOR-based strategies are limited. Therefore, it remains unclear whether prior CDK4/6 inhibitor exposure would impact estimated efficacy of PFS or OS in this population. Methods: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was constructed based on the PICO framework to define keywords, and a comprehensive literature search was performed in PubMed, EMBASE, and the Cochrane Library for RCTs. Abstracts and subgroup data presented at the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) international conferences were also included. The primary endpoint was PFS. Study quality was assessed with the Cochrane risk of bias tool. Meta-analysis was conducted with R software (version 4.4.1) to compare the efficacy of targeted therapy (TT) plus ET versus ET alone in patients with disease progression from prior CDK4/6 inhibitor treatment. Six studies were included in the meta-analysis: EMBER-3, postMONARCH, MAINTAIN, PACE, PALMIRA, and the CapItello-291 subgroup. Subgroup analyses were performed to determine consistency of treatment benefit by clinical characteristics, including age (≥65 vs. <65 years), site of metastasis (visceral metastasis vs. non-visceral or bone-only), and prior duration of CDK4/6 inhibitor use (≥12 vs. <12 months). Result: Meta-analysis of six studies demonstrated that TT plus ET significantly improved PFS compared with ET alone (HR = 0.71; 95% CI, 0.55–0.90). Stratified analyses by treatment strategy indicated that switching to an alternative CDK4/6 inhibitor (abemaciclib or ribociclib) following progression on palbociclib, as investigated in the EMBER-3, postMONARCH, and MAINTAIN trials, was associated with significant PFS benefit compared with ET alone (HR = 0.61; 95% CI, 0.48–0.76). In contrast, continuation of the same CDK4/6 inhibitor (palbociclib) in the PACE and PALMIRA trials yielded no significant difference in PFS compared with ET alone (HR = 0.91; 95% CI, 0.70–1.17). In the sensitivity analysis, subgroup data were analyzed from the CapItello-291 trial with prior CDK4/6 inhibitor exposure and without relevant targetable gene mutations (PI3K/AKT pathway alterations); treatment with the AKT inhibitor capivasertib yielded results consistent with the primary analysis, confirming the benefit of TT+ET (HR = 0.68; 95% CI, 0.56–0.82). Subgroup analyses based on clinically relevant characteristics (age, presence of visceral metastases, bone-only disease, and duration of prior CDK4/6 inhibitor therapy) further confirmed consistent PFS benefit of TT+ET across predefined clinical categories. Conclusions: This meta-analysis demonstrated that TT combined with ET, particularly switching to another targeted agent including an alternative CDK4/6 inhibitor or an AKT inhibitor, was associated with improved PFS in patients with HR+/HER2− mBC who had experienced disease progression from prior CDK4/6 inhibitor treatment. However, there are no randomized trials that have directly compared mTOR inhibition with switching to another CDK4/6 inhibitor as second-line treatment. Accordingly, we propose a non-inferiority randomized clinical trial to determine the efficacy of ET fulvestrant combined with either abemaciclib (an alternative CDK4/6 inhibitor) or everolimus (an mTOR inhibitor) as second-line therapy in patients with prior progression on palbociclib or ribociclib and without relevant targetable gene mutations. The objective of this trial is to determine whether switching to another CDK4/6 inhibitor is non-inferior to mTOR inhibition in terms of PFS, while also considering toxicity profiles and quality of life. Given the consistent benefit of TT+ET among clinical subgroups observed in this meta-analysis, patients will not be excluded based on predefined characteristics in the study protocol.