背景：有大量的隨機證據支持在 mCRC 中使用治療間歇期，但盡管毒性降低，但治療間歇期並不普遍適用於患者，對 OS 沒有損害。先前的試驗表明，Cp 和 bevacizumab（貝伐珠單抗）聯合應用可延長 PFS，但不能延長 OS。FOCUS4-N 探討了一線治療疾病控製患者的口服維持 CP單一療法。

Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy.

方法：FOCUS4 是一個分子分層試驗項目，登記來自英國 88 家醫院的新診斷 mCRC 患者。在接受 16 周一線治療的同時，一份腫瘤樣本被送往實驗室檢測，以將其疾病分為分子亞型：MSI、BRAF、PIK3CA、TP53 和 RAS 突變。對於某些分子組，有一個靶向治療亞試驗可用，但 FOCUS4-N 試驗提供給那些沒有靶向亞試驗的人。患者被隨機分為 1:1 維持 Cp 治療組和 AM 組。主要結果是使用 8 周的 RECIST 報告的 CT 掃描評估 PFS，並以生活質量（EQ5D 8 周）和 OS 作為次要結果。毒性和耐受性在 4 周後進行評估。在進展中，從最低點開始，患者重新開始一線治療。 Cox 回歸通過意向治療（ITT）評估療效，並調整腫瘤位置、WHO 狀況、轉移負擔、一線治療和生物標誌物亞型。

Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype.

結果：2014 年 3 月至 2020 年 3 月，254 名患者被隨機分組（127 名為 Cp，127 名為 AM）。兩組的基線特征是平衡的，但 AM 組的事件發生率高於預期最後的分析是由於 COVID-19 大流行的停止招募而提前觸發的。下表列出了全氟辛烷磺酸和全氟辛烷磺酸的結果。治療依從性良好，方案分析結果與 ITT 非常相似（PFS HR=0.38（95%CI 0.28-0.51））。毒性從 Cp 到 AM，與預期一樣，出現 G$2 疲勞（25%v 12%）、腹瀉（23%v 13%）和手足綜合征（26%v 3%）。兩組患者的生活質量無統計學差異。

Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms.

結論：盡管有強有力的證據表明維持治療延長了 PFS，但 OS 仍不受影響，FOCUS4-N 為穩定或對 mCRC 一線治療反應良好的患者提供了額外的證據，以支持使用治療間歇作為安全的管理選擇。不含貝伐單抗的 Cp 可用於在聯合治療 16 周後的間隔期內治療 PFS。

Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy.