大腸直腸癌治療進展新知區

HWT@2022/6/14

June 5, 2022

DOI: 10.1056/NEJMoa2201445

這是一個算是非常重要的前期臨床試驗，簡單來說，在微衛星不穩定性高的第 二 三期直腸癌病人身上，使用免疫治療之後，可以避免手術及放療，文獻上，宣稱的效果非常好，

但是在早期pembrolizumab的研究中，也是有類似的觀察，需要等待後續大規模的研究驗證。

另外，這些病人大多數是(MSH2 MSH6 PMS2)有問題的( some only in somatic?)，事實上，衛星不穩定性高的，還有所謂的散發型(sporadic 甲基化)要很小心的解釋，這樣的資料。

方法:

前瞻性 2 期研究，在錯配修復缺陷型 (MSIH) II 期或 III 期直腸癌患者，單藥 dostarlimab (一種抗 PD-1 單克隆抗體，每 3 週給藥一次，持續 6 個月 )。

接續之後是標準的放化療和手術。患者完成 dostarlimab 治療後臨床完全緩解的患者

將在沒有放化療和手術的情況下進行觀察。

結果

共有 12 名患者完成了 dostarlimab 治療並接受了至少6個月的觀察。所有 12 名患者有臨床完全反應，本報告中，沒有患者後續接受過放化療或手術，並且追蹤期間，未報告進展或復發病例（範圍，6 到 25 個月）。

結論

筆者建議要小心解釋。

摘要沒提: 

共有 "16 名患者入試驗"並接受治療。 在這些患者中，有 12 名患者的入組時間超過 6 個月，並完成了 9 個計劃的周期（6 個月）治療。 

4/16 = 25% 失敗?(有4位尚未評估)，另外將來如果復發，是否死亡??

微衛星不穩定高的病患，本來就對免疫治療有一定的效果，但是有些病患還是對免疫治療沒有效，使用免疫治療，有時候會遇到無法回頭的狀況，也就是超級惡化現象，在二三期的病人(除非無法切除或要保留肛門)，遇到這樣的現象，將來付出的代價就是生命。

因此這樣的臨床設計，事實上是有點瑕疵，為什麼不先做化療，再使用免疫藥物，或者是穿插。

這種研究設計，有時候付出的是生命，但是它提供另外一種治療的想法。

有些人可以保留肛門但是至少可以先打一些化療穩定住，再打免疫更好。因為這樣可以兼顧"轉移"跟"肛門保留"。

這樣的臨床試驗,是非常重要,但是我覺得還是需要比較大規模的是驗證,另外治療模式也值得商榷.

 

HWT@ 2022/5/29

我想這是一個非常重要的雙盲臨床試驗

簡單來說，就是想證明在各種大型資料庫(包括台灣的健保資料庫)一直鼓吹的降血糖藥(Metformin 常見商品名格華止、庫魯化)可以預防癌症的概念是不是真的?

結論先說: 在這篇研究，沒辦法證實這個概念是真的，也警示了我們，做這種所謂的健保資料庫，其實在某方面是會導致醫療觀念的偏差，需要更加審慎小心。

國家應該把資源集中在更前瞻性的研究。

文章中有提到在後續的探索性分析中(Exploratory Analyses in the ERBB2+ Population) 

ERBB2 status did not have a significant impact on the effect of metformin vs placebo on invasive disease-free and overall survival outcomes (P for interaction, .59 and .49, respectively)

但是具有這種特性的病人或許有值得探討的地方。 有興趣的人可以再去看文獻。

#

Metformin (常見商品名格華止、庫魯化)與 安慰劑 對 侵襲性乳腺癌患者，無病生存的影響：MA.32 隨機臨床試驗。

JAMA。 2022 年 5 月 24 日；327(20):1963-1973。

摘要

重要性：

Metformin (常見商品名格華止、庫魯化)是一種常用於治療 2 型糖尿病的藥，在觀察性和臨床前研究中與乳腺癌亞型的潛在有益作用有關。

目的：

確定對”無糖尿病”的乳腺癌患者給予”輔助”Metformin (常見商品名格華止、庫魯化)（與安慰劑相比）是否能改善預後。

設計、設置和參與者：

MA.32 是一項 3 期隨機、安慰劑對照、雙盲試驗，招募了 3649 名接受標準治療的高危非轉移性乳腺癌患者。 患者被隨機分組（根據激素受體 [雌激素受體和/或孕激素受體 {ER/PgR}] 狀態分層，陽性與陰性；體重指數，≤30 與 >30；人表皮生長因子受體 2 [ERBB2，以前HER2 或 HER2/neu]，陽性與陰性；以及任何與無化療）至 850 mg 口服Metformin (常見商品名格華止、庫魯化)每天兩次（n = 1824）或口服安慰劑每天兩次（n = 1825），持續 5 年。

主要結果和措施：

主要結果是激素受體陽性乳腺癌的無侵襲性無病生存。在 8 個次要結局中，分析了總生存期、無遠處復發生存期和無乳腺癌間隔期。

結果：

在 3649 名隨機患者（平均年齡 52.4 歲；3643 名女性 [99.8%]）中，所有 (100%) 均被納入分析。在第二次中期分析後，宣布 ER/PgR- 患者無效，因此對 2533 名 ER/PgR+ 患者進行了初步分析。 ER/PgR+ 組的中位隨訪時間為 96.2 個月（範圍 0.2-121 個月）。 465 名 ER/PgR+ 患者發生侵襲性無病生存事件。Metformin (常見商品名格華止、庫魯化)組侵襲性無病生存事件的發生率為 2.78/100 患者年，安慰劑組為 2.74/100 患者年（風險比 [HR]，1.01；95% CI，0.84-1.21；P = .93），Metformin (常見商品名格華止、庫魯化)組的死亡發生率為 1.46/100 患者年，而安慰劑組為 1.32/100 患者年（HR，1.10；95% CI，0.86-1.41；P = .47 ）。在中位隨訪 94.1 個月的 ER/PgR- 患者中，侵襲性無病生存事件的發生率分別為 3.58 和 3.60/100 患者年（HR，1.01；95% CI，0.79-1.30； P = .92)。在 ER/PgR+ 組中分析的 3 項次要結局均無統計學差異。

服用Metformin (常見商品名格華止、庫魯化)的患者比服用安慰劑的患者更頻繁地發生 3 級非血液學毒性事件（分別為 21.5% 和 17.5%，P = .003）。

結論和相關性：

在無糖尿病的高危可手術乳腺癌患者中，在標準乳腺癌治療中添加Metformin (常見商品名格華止、庫魯化)與安慰劑相比，並未顯著提高無侵襲性無病生存率。

 

HWT@2022/5/22

瑪雅試驗 J Clin Oncol 40:1562-1573

這應該是一個，非常重要的臨床試驗:

簡單來說，在經過治療無效後的"微衛星穩定"且"MGMT被甲基化"轉移性大腸直腸癌病人，先使用:

#第一部分治療2次: Temozolomide (two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks)，如果能夠穩定無惡化，再接續第二部分治療。

#第二部分治療: 雙重免疫治療 (ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks )。

結果:

共篩選716個病人，其中 204(29%)位病人符合條件，但最後只有135個進行第一部分治療。

其中有 102(76%)位病人無法進入第二部分治療 (因為死亡或者是疾病惡化)。

最後只有 33(24%)位病人疾病控制，進入了第二波治療並形成存活資料。

33位病人中，中位無病存活 7個月，中位整體存活 18.4個月，整體反應率是45 %。

簡單來說，這個臨床試驗，驗證這個治療的可行性，但是實務上，真的能夠撐到最後治療的病人，不是那麼多。需要後續的臨床試驗檢驗。

2022/4/24 @hwt

臨床試驗 Eur J 癌症。 2022 年 3 月；163:152-162

對BRAF突變的大腸直腸癌，或許雙標靶(anitEGFR antiBRAF)加上化療是另一選擇

臨床試驗 Eur J 癌症。 2022 年 3 月；163:152-162
西妥昔單抗和威羅非尼加 FOLFIRI（5-氟尿嘧啶/亞葉酸/伊立替康）治療 BRAF V600E 突變的晚期結直腸癌（改進）：一項開放標籤、單臂、II 期試驗
抽象的
背景：目前針對 v-raf 鼠肉瘤病毒癌基因同源物 B1 (BRAF) V600E 突變的結直腸癌患者的治療方案顯示出不令人滿意的療效。為了改善該領域的結果，我們評估了使用威羅非尼和西妥昔單抗聯合 FOLFIRI（5-氟尿嘧啶/亞葉酸/伊立替康）治療 BRAF V600E 突變的結直腸癌患者的新方案的安全性和有效性。

方法和材料：這是一項由研究者發起的、開放標籤、單臂、II 期試驗，在 BRAF V600E 突變的晚期結直腸癌患者中進行。患者有資格接受 FOLFIRI 聯合威羅非尼和西妥昔單抗。主要終點是客觀緩解率，次要終點包括疾病控制率、無進展生存期、總生存期和安全性。該試驗已在 ClinicalTrials.gov 註冊，NCT03727763。

結果：在 2018 年 1 月 12 日至 2021 年 6 月 18 日期間，我們篩選了 27 名患者，其中 21 人參加了本研究。療效分析顯示，意向治療人群的客觀緩解率為 81.0%（17/21；95% CI 57.4-93.7），而意向治療人群的客觀緩解率為 85.0%（17/20，95%CI 61.0-96.0）。符合協議的人群； 2名患者獲得完全緩解，15名患者獲得部分緩解。在整個隊列中，中位無進展生存期為 9.7 個月（95%CI 6.3-10.9），所有患者的中位總生存期為 15.4 個月（95%CI 8.5-15.4）。最常見的不良事件（3 至 4 級）是中性粒細胞減少症（8/21）、貧血（3/21）和皮疹（3/21）。

結論：Vemurafenib和西妥昔單抗可以安全地與FOLFIRI方案聯合使用，在BRAF V600E突變的晚期結直腸癌患者中顯示出良好的抗腫瘤活性和可耐受的毒性。該方案需要在 III 期臨床試驗中進行進一步的隨機研究。

西妥昔單抗和威羅非尼加 FOLFIRI（5-氟尿嘧啶/亞葉酸/伊立替康）治療 BRAF V600E 突變的晚期結直腸癌（改進）：一項開放標籤、單臂、II 期試驗
抽象的
背景：目前針對 v-raf 鼠肉瘤病毒癌基因同源物 B1 (BRAF) V600E 突變的結直腸癌患者的治療方案顯示出不令人滿意的療效。為了改善該領域的結果，我們評估了使用威羅非尼和西妥昔單抗聯合 FOLFIRI（5-氟尿嘧啶/亞葉酸/伊立替康）治療 BRAF V600E 突變的結直腸癌患者的新方案的安全性和有效性。

方法和材料：這是一項由研究者發起的、開放標籤、單臂、II 期試驗，在 BRAF V600E 突變的晚期結直腸癌患者中進行。患者有資格接受 FOLFIRI 聯合威羅非尼和西妥昔單抗。主要終點是客觀緩解率，次要終點包括疾病控制率、無進展生存期、總生存期和安全性。該試驗已在 ClinicalTrials.gov 註冊，NCT03727763。

結果：在 2018 年 1 月 12 日至 2021 年 6 月 18 日期間，我們篩選了 27 名患者，其中 21 人參加了本研究。療效分析顯示，意向治療人群的客觀緩解率為 81.0%（17/21；95% CI 57.4-93.7），而意向治療人群的客觀緩解率為 85.0%（17/20，95%CI 61.0-96.0）。符合協議的人群； 2名患者獲得完全緩解，15名患者獲得部分緩解。在整個隊列中，中位無進展生存期為 9.7 個月（95%CI 6.3-10.9），所有患者的中位總生存期為 15.4 個月（95%CI 8.5-15.4）。最常見的不良事件（3 至 4 級）是中性粒細胞減少症（8/21）、貧血（3/21）和皮疹（3/21）。

結論：Vemurafenib和西妥昔單抗可以安全地與FOLFIRI方案聯合使用，在BRAF V600E突變的晚期結直腸癌患者中顯示出良好的抗腫瘤活性和可耐受的毒性。該方案需要在 III 期臨床試驗中進行進一步的隨機研究。

 

 

2022/4/24 @ HWT

#微衛星不穩定穩定的結直腸癌患者中，其中具有"外切核酸酶域突變" (EDM)的POLE 突變，對免疫治療似乎有效。重點是POLE基因突變需是"外切核酸酶域突變" (exonuclease domain mutation (EDM))的POLE 突變

臨床試驗國際 J 癌症。 2022 年 6 月 15 日；150(12):2038-2045。

durvalumab 單藥治療先前治療的微衛星不穩定性高/錯配修復缺陷或 POLE 突變的轉移性或不可切除的結直腸癌患者的 II 期研究

抽象的

我們研究的目的是評估 durvalumab 在微衛星不穩定性高/錯配修復缺陷 (MSI-H/dMMR) 或聚合酶ε (POLE) 突變的轉移性或不可切除的結直腸癌 (mCRC) 患者中的臨床療效標準化療後疾病進展。

這項前瞻性、開放標籤、多中心、II 期研究納入了患有 MSI-H/dMMR 或 POLE 突變的 mCRC 患者，這些患者接受了至少一種先前的治療。參與者每 4 周靜脈內接受一次 durvalumab（1500 毫克）。主要終點是客觀反應率（ORR）。

在 33 名患者中，30 名患有 MSI-H/dMMR，3 名患有 POLE 突變的微衛星穩定 (MSS) CRC。中位隨訪時間為 11.2 個月（95% 置信區間 [CI]：7.3-15.0），ORR 為 42.4%（95% CI：25.5-60.8）。

在三名 POLE 突變的 CRC 患者中，一名具有外切核酸酶域突變 (EDM) 的患者獲得了客觀反應，但其他具有非外切酶域突變的患者疾病進展。

總體而言，未達到響應的中位持續時間，並且 85.7% 的響應在數據截止時仍在進行。 12個月無進展生存率為58.2%（95% CI：39.0-73.1），12個月總生存率為68.3%（95% CI：48.8-81.7）。 36.4% 的患者發生了 3 級治療相關的不良事件並且是可控的。總之，durvalumab 在患有 MSI-H/dMMR 或 POLE EDM 的 mCRC 患者中顯示出有希望的臨床活性，具有令人鼓舞的反應率和令人滿意的生存結果。在 POLE 突變的 mCRC 患者中，對 durvalumab 的臨床反應可能僅限於 EDM 患者

2021/5/24

2021/ASCO abstract 

====

>>Vactosertib is an orally bioavailable inhibitor of the serine/threonine kinase, transforming growth factor (TGF)-beta receptor type 1 (TGFBR1), also known as activin receptor-like kinase 5 (ALK5),

#Efficacy and safety of vactosertib () and pembrolizumab combination in patients with previously treated microsatellite stable metastatic colorectal cancer.

Background:

Microsatellite stable metastatic colorectal cancer (MSS mCRC) represents a high unmet need since there are currently no approved immunotherapy options. Since the inhibition of the transforming growth factor-β (TGF-β) pathway is known to contribute to the enhancement of immunotherapy efficacy, here, we report the results of vactosertib, a potent and selective TGF-β receptor I kinase inhibitor, combined with pembrolizumab in patients with MSS mCRC.

Methods:

In this phase 2, open label trial, patients have received vactosertib (300 mg BID, 5 days on / 2 days off) and pembrolizumab (200 mg, every 3 weeks) until confirmed progressive disease (PD), unacceptable toxicity or consent withdrawal. Patients with histologically confirmed mCRC who had disease progression after treatment with all available therapies including fluoropyrimidine and oxaliplatin or irinotecan were enrolled. Eligible patients were ≥19 years old, had ECOG status ≤1, and had no prior exposure to immunotherapy. The objectives were to evaluate the safety and efficacy (objective response rate (ORR) per RECIST v1.1).

Results:

Thirty-three patients with MSS mCRC were enrolled. Median age was 60 (range 33-72), 55% were male, median number of previous lines of chemotherapy was 3 (range 1-7), and 82% were consensus molecular subtype (CMS) 4. The ORR was 15.2% including 5 partial responses (PRs), 7 stable diseases, and 17 PDs as best overall responses; 12 patients remain on treatment. Among 5 patients with PR, 3 patients had confirmed PR and median duration of response was not reached yet. As of 04 Jan 2021, the most common treatment related adverse events (AEs) were increased amylase (21.2%), pruritus (21.2%), rash (21.2%), and increased lipase (18.2%). There were 3 treatment-related SAEs reported; drug induced pneumonitis (3%), nausea (3%), and vomiting (3%).

Conclusions:

The combination treatment with vactosertib and pembrolizumab showed favorable safety profile with promising efficacy in patients with MSS mCRC. Updated data including pharmacodynamic markers will be presented at the meeting. Clinical trial information: NCT03724851

====

#使用 樂衛瑪(lenvatinib) 20 mg QD 加上 Keytruda(吉舒達/pembrolizumab) 200 mg Q3W 於微衛星穩定抗藥大腸直腸癌，LEAP-005 資料: 反應率22%。

#LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

Background:

Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort.

Methods:

In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter.

Results:

32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]).

Conclusions:

In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326

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#短程電療加上化療應該是現在治療局部深度侵犯直腸癌主流。

#A multicenter, randomized, phase III trial of short-term radiotherapy plus chemotherapy versus long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR): The final reports.

Background:

It’s presented the results of a phase III trial of short-term radiotherapy (SCRT) combined with chemotherapy versus long-term chemoradiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC).

Methods:

Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinomas diagnosed by MRI, were randomly assigned to experimental group or control group. In experimental group, patients received SCRT (25 Gy / 5 fractions / 5 days), followed by four courses of CAPOX. In control group, patients received LCRT (50 Gy / 25 fractions / 35 days with concurrent capecitabine). Surgery was recommended in both groups and performed 6-8 weeks after preoperative treatment. Two or six courses of CAPOX was prescribed as the postoperative chemotherapy in experimental group and control group, respectively. This trial was a multicenter, open-label, randomized, noninferior, phase III study, and all the patients were from 16 hospitals of China. The primary endpoint for this study was 3-year disease-free survival (DFS).

Results:

From Aug 30, 2015 to Aug 27, 2018, 599 patients were enrolled and entered random. Finally, 591 intention-to-treat (ITT) populations were included in the analysis, 298 patients assigned to SCRT followed by chemotherapy and 293 to CRT. For the experimental group and control group, cT3 and cT4 accounted for 82.3% vs. 84.6% and 15.4% vs. 12.3%, respectively, and approximately 85% were mrN positive (85.6% vs. 84.0%). As a whole, the completion and full-dose completion rates of preoperative treatment were 82.6% vs. 95.2% (p＜0.001) and 74.8% vs 93.2% (p＜0.001) in the experimental and control groups, respectively. Among the 465 patients who received surgery, 16.6% and 11.8% of them achieved pCR (p=0.134), respectively. Accounting for cCR after preoperative treatment, the total rate of pCR+cCR in experimental group was 22.5% and significantly higher than control group (12.6%, p=0.001). With median follow-up 35.0 months, the HR between experimental and control of DFS was 0.883, with 1-sided noninferiority p-value <0.001, so the noninferiority hypothesis was confirmed. The probability of DFS and OS at 3 years was 64.5% and 86.5% in the experimental group compared with 62.3% and 75.1% in control group. It’s observed the OS rate of the experimental group was significantly higher than that of the control group (p=0.036) and no significant difference in metastasis-free survival or loco-regional recurrence was observed.

Conclusions:

For LARC with high risk factors, SCRT combined with sequential chemotherapy was noninferior to CRT and could be used as an alternative to LCRT. Meanwhile, SCRT combined with chemotherapy presented a higher cCR+pCR and 3-year overall survival rates as compared with CRT. However, the long term results need to be further followed up. (ClinicalTrails No.: NCT02533271). Clinical trial information: NCT00833131

 

2021/5/25

KEYNOTE-177這個研究，非常重要。

對於有"微衛星不穩定高"的大腸直腸癌病患，是否使用傳統的標靶化學治療或者是免疫治療當第一線治療。有最完整的回答。依目前最新的存活分析很明確的指出:

相對上，使用免疫治療在微衛星不穩定性高的大腸直腸癌病患的確有比較高的比例，得到好處(像是反應率或者是無惡化存活率 ，PFS中位數為16.5 mo vs 8.2 mo ORR為45.1％（20 CR，49 PR），而33.1％（6 CR，45 PR）)；但是如果能夠交叉使用，也就是說，標靶化學治療後也有免疫藥物的使用的話，對生命其實並沒有達到顯著的差別。

也就是說晚點用或許還是可以接受的方式，換成健保的話來說，先打標靶化學的藥，沒效之後再使用免疫治療，是一個可以被接受的方式。當然如果沒有經濟的壓力，提早在第一線使用免疫治療也是一個很正確的選擇。

Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).

背景：

在III期階段，隨機開放標籤KEYNOTE-177（NCT02563002）研究將1L pembrolizumab（pembro）與化療（chemo）進行比較，在患有MSI-MS的患者（pts）的第二次中期分析（IA2）中提供了更高的無進展生存期（PFS）。 H / dMMR mCRC。 該研究繼續進行了總生存期（OS）的最終分析，該分析計劃在190個OS事件或IA2後12個月（以先到者為準）進行。 我們介紹了IA2後12個月的OS最終分析結果。

方法：

總共307名患有MSI-H / dMMR mCRC和ECOG PS 0或1的患者隨機分配1：1至1L 彭布羅(PEMBROLIZUMAB) 200 mg Q3W，最多2年，或研究者選擇mFOLFOX6或FOLFIRI Q2W±AVASTIN(貝伐單抗)或CETUXIMAB(西妥昔單抗)。繼續治療直至PD，不可接受的毒性，病人 /研究者決定退出治療或完成35個週期（僅pembro）。確診PD後，接受化學治療的患者可能會過渡到Pembro長達35個週期。

主要終點是OS(OVEREALL SURVIVAL)和PFS (PROGRESSION FREE SURVIVAL)（RECIST v1.1，集中審查）。次要終點包括ORR (反應率)，反應持續時間（DOR）（RECIST v1.1，集中審核）和安全性。對於OS重要意義，p值必須滿足0.0246的預定α（單側）。進行靈敏度分析以調整交叉效應。最終分析的數據截止日期為2021年2月19日。

結果：

Pembro的研究中位追蹤（範圍）隨訪為44.5 mo（36.0-60.3），而化學治療的中位（範圍）隨訪為44.4 mo（36.2-58.6）。從化學療法過渡到pembro療法的受試者為56名（36％），另有37名接受抗PD-1 / PD-L1療法的患者不在研究範圍內（ITT中有效的交叉率為60％）。 

OS的HR偏愛於pembro與chemo，並有降低死亡風險的趨勢（HR 0.74； 95％CI，0.53-1.03； P = 0.0359；中位數未達到[NR]對36.7 mo）；這種差異沒有達到統計學意義。

通過保持等級的結構失效時間模型的敏感性分析和審查加權的逆概率顯示OS HR分別為0.66（95％CI 0.42-1.04）和0.77（95％CI 0.44-1.38）。 Pembro vs chemo符合IA2規定的PFS優越性標準。最終分析時，PFS中位數為16.5 mo vs 8.2 mo（HR 0.59； 95％CI，0.45-0.79），但未根據每個分析計劃進行正式測試。確認的ORR為45.1％（20 CR，49 PR），而33.1％（6 CR，45 PR）。中位（範圍）DOR分別為NR（2.3+至53.5+）與10.6 mo（2.8至48.3+）。與治療相關的不良事件（TRAEs）發生率為79.7％，而患者為98.6％。 ≥3級TRAE分別為21.6％和66.4％。

結論：

作為用於MSI-H / dMMR mCRC pts的1L治療，pembro vs chemo提供了統計學上優越的PFS，而TRAE卻更少，並且與死亡率降低的趨勢相關，該趨勢未達到統計學意義，這可能是由於從chemo到anti的高交叉率所致。 -PD1 / PD-L1治療。這些數據一起證實了Pembro是MSI-H / dMMR mCRC患者1L的新護理標準。

ackground:

In the phase III, randomized open-label KEYNOTE-177 (NCT02563002) study 1L pembrolizumab (pembro) versus chemotherapy (chemo) provided superior progression-free survival (PFS) at second interim analysis (IA2) in patients (pts) with MSI-H/dMMR mCRC. The study continued to final analysis of overall survival (OS), planned after 190 OS events or 12 months after IA2, whichever occurred first. We present results of the final analysis of OS, 12 months after IA2.

Methods:

A total of 307 pts with MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to 1L pembro 200 mg Q3W for up to 2y or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab. Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Pts receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were OS and PFS (RECIST v1.1, central review). Secondary end points included ORR, duration of response (DOR) (RECIST v1.1, central review), and safety. For OS significance, the p-value had to meet a prespecified α of 0.0246 (one-sided). Sensitivity analyses to adjust for crossover effect were performed. Data cut-off for final analysis was Feb 19, 2021.

Results:

Median (range) study follow-up was 44.5 mo (36.0-60.3) with pembro vs 44.4 mo (36.2-58.6) with chemo. 56 (36%) pts crossed over from chemo to pembro, with 37 more receiving anti-PD-1/PD-L1 therapies off study (60% effective crossover rate in the ITT). The HR for OS favored pembro vs chemo with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359; median not reached [NR] vs 36.7 mo); this difference did not reach statistical significance. Sensitivity analysis by the rank-preserving structure failure time model and inverse probability of censoring weighting showed OS HRs of 0.66 (95% CI 0.42-1.04) and 0.77 (95% CI 0.44-1.38), respectively. Pembro vs chemo met the prespecified criteria for PFS superiority at IA2. At final analysis, median PFS was 16.5 mo vs 8.2 mo (HR 0.59; 95% CI, 0.45-0.79), but was not formally tested per analysis plan. Confirmed ORR was 45.1% (20 CR, 49 PR) vs 33.1% (6 CR, 45 PR). Median (range) DOR was NR (2.3+ to 53.5+) vs 10.6 mo (2.8 to 48.3+), respectively. Treatment-related adverse events (TRAEs) occurred in 79.7% vs 98.6% of pts; 21.6% vs 66.4%, respectively, had grade ≥3 TRAEs.

Conclusions:

As 1L therapy for pts with MSI-H/dMMR mCRC, pembro vs chemo provides statistically superior PFS with fewer TRAEs, and is associated with a trend toward reduced mortality that did not meet statistical significance likely due to the high crossover rate from chemo to anti-PD1/PD-L1 therapies. Together these data confirm pembro as a new standard-of-care in the 1L for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02563002

 

 

2021/3/11

使用Pemetrexed/Erlotinib作為EGFR高表達的轉移性結直腸癌患者，在標準化學療法失敗後的挽救性治療：II期單臂。

反應率 10.3%

疾病控制率 62.1%

2021/3/11 Pemetrexed/Erlotinib as a Salvage Treatment in Patients with High EGFR-Expressing Metastatic Colorectal Cancer Following Failure of Standard Chemotherapy: A Phase II Single-Arm Abstract Background: Despite new agents to treat metastatic colorectal cancer (CRC), patients eventually progress and additional therapies are needed. Objective: We intended to evaluate the combination of pemetrexed/erlotinib in patients with high epidermal growth factor receptor (EGFR)-expressing (2+ or 3 on immunohistochemistry) metastatic CRC who experienced disease progression after standard chemotherapy. Patients and methods: We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1-21) as a salvage treatment, given every 3 weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). Results: From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who had previously received standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of grades 1 or 2 only. In an intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had a tumor EGFR expression of 3+. Among the eight patients with EGFR 3+ expression, the RR and DCR were 37.5% and 75.0%, respectively. Conclusion: This phase II trial using pemetrexed/erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response.