背景：紫杉醇常用作 HER2 陰性 MBC 的一線化療。然而，由於有效率為 21.5-53.7%，並且周圍神經病變的風險很大，因此需要更有效和耐受性更好的化療（CCT）。

Background: Paclitaxel is commonly used as first line chemotherapy for HER2 negative MBC. However, with response rates of 21.5-53.7% and a significant risk of peripheral neuropathy there is a need for more effective and better tolerated chemotherapy (CCT).

方法：這項開放性隨機（1：1）2 期試驗比較了每 3 周為一個周期的 cabazitaxel （25 mg/m2） 6 個周期與每周紫杉醇（80mg/m2）在 18 周內作為一線 CCT。HER2 陰性和體力狀況評分≤1 的患者符合條件。接受 cabazitaxel 的患者需接受 GCSF 預防治療。主要終點是無進展生存期（PFS），需要 127 個事件來檢測風險比（HR）為 0.65，有 85%的效力。次要終點包括客觀反應率（ORR; RECIST 1.1），出現反應的時間（TTR）、總生存期（OS）、安全性、耐受性和生活質量（QoL）。

Methods: This open label randomised (1:1) phase 2 trial compared 6 cycles of cabazitaxel (25 mg/m2) every 3 weeks, with weekly paclitaxel (80mg/m2) over 18 weeks as first line CCT. HER2 negative and performance status ≤1 patients were eligible. Patients on cabazitaxel received GCSF prophylaxis. Primary endpoint was Progression Free Survival (PFS) with 127 events required to detect a hazard ratio (HR) of 0.65 with 85% power. Secondary endpoints included objective response rate (ORR; RECIST 1.1), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL).

結果：158 名患者來自英國 14 家醫院（每組 79 名）。cabazitaxel 組的中位年齡（範圍）為 56歲（34-81 歲），紫杉醇組為 61 歲（34-79 歲）。61%的患者體力狀態評分為 0。兩組的中位治療時間為 15 周，但紫杉醇治療延遲（61%比 39%）或劑量減少（37%比 24%）的患者較多。比較 cabazitaxel 和紫杉醇在 146 例 PFS 事件後的中位 PFS 分別為 6.7 和 5.8 個月（HR 0.84；95%CI 0.60–1.18, P = 0.3）。在 OS 方麵沒有差異，中位 19.3 vs 20.0 個月（HR 0.94；95%CI 0.63-1.40，P=0.7），ORR（42% vs 37%）或 TTR（HR 1.09；95%CI 0.68-1.74，P=0.7）。cabazitaxel 組和紫杉醇組分別有 42%和 48%發生≥3 級不良事件。腹瀉、發熱性中性粒細胞減少和惡心是cabazitaxel 組最常見的≥3 級事件，發生率分別為 11%、11%和 10%，而紫杉醇組為 1%、1%和0%。紫杉醇組的最高≥3 級事件為肺部感染和周圍神經病變，分別為 6%和 5%，而 cabazitaxel組為 2.5%和 0%。在接受紫杉醇治療的患者中，有 55%的患者報告了任何級別的周圍神經病變，而接受 cabazitaxel 治療的患者報告了 17%的周圍神經病變。紫杉醇組 41%的患者發 脫發，而 cabazitaxel 組為 27%。導致停藥的不良事件紫杉醇（22%）比 cabazitaxel（14%）更頻繁。在整個治療過程中，平均 EQ5D 單指標效用評分（+0.05; 95%CI 0.004-0.09, P = 0.03）和視覺模擬量表評分（+7.7; 95%CI 3.1-12.3, P =0.001）在 cabazitaxel 組高於紫杉醇組，提示 cabazitaxel 組的生活質量更好。

Results: 158 patients were recruited from 14 UK hospitals (79 in each arm). Median age (range) was 56(34-81) in the cabazitaxel arm and 61(34-79) in the paclitaxel arm. 61% of patients were performance status 0. Median time on treatment was 15 weeks for both arms, but more patients on paclitaxel had a treatment delay (61% vs 39%) or dose reduction (37% vs 24%). Comparing cabazitaxel to paclitaxel after 146 PFS events, median PFS was 6.7 vs 5.8 months (HR 0.84; 95%CI 0.60–1.18, P = 0.3). There was no difference in OS, median 19.3 vs 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7), ORR (42% vs 37%) or TTR (HR 1.09; 95%CI 0.68–1.74, P = 0.7). Grade ≥3 adverse events occurred in 42% of patients on cabazitaxel and 48% on paclitaxel. Diarrhoea, febrile neutropenia and nausea were the most common grade ≥3 events in the cabazitaxel arm with rates of 11%, 11% and 10% respectively compared to 1%, 1% and 0% in the paclitaxel arm. In the paclitaxel arm the top grade ≥3 events were lung infection and peripheral neuropathy, 6% and 5% respectively compared to 2.5% and 0% in the cabazitaxel arm. Peripheral neuropathy of any grade was reported by 55% of patients treated with paclitaxel vs 17% on cabazitaxel. Alopecia occurred in 41% of patients on paclitaxel compared to 27% on cabazitaxel. Adverse events leading to discontinuation were more frequent with paclitaxel (22%) than cabazitaxel (14%). Over the course of treatment, mean EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in the cabazitaxel arm compared to paclitaxel suggestive of better QoL on Cabazitaxel.

結論：與每周紫杉醇相比，HER2 陰性 MBC 患者每 3 周 1 次 cabazitaxel 一線化療對 PFS 的改善不明顯，但其周圍神經病變的風險較低，患者總體健康狀況較好。cabazitaxel 對 MBC 患者安全且耐受性良好，且需要較少的醫院就診，這是 COVID 大流行及以後的重要考慮因素。

Conclusions: 3 weekly cabazitaxel as first line chemotherapy in HER2 negative MBC does not significantly improve PFS compared to weekly paclitaxel, though it has a lower risk of peripheral neuropathy with better patient reported overall health outcomes. Cabazitaxel is safe and well tolerated for MBC and requires fewer hospital visits, an important consideration in the COVID pandemic and beyond.