Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
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durvalumab（抗pd - l1）和trametinib （MEKi）在微卫星稳定（MSS）转移性结直肠癌（mCRC）中的II期研究。
DOI：
10.1136/jitc-2022-005332
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发表时间：
2022-08
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells. Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4. Twenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively). T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials. NCT03428126.
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围手术期Durvalumab和Tremelimumab的试验临床试验在可切除的结直肠癌肝转移治疗中。
DOI：
10.1158/1078-0432.ccr-21-0163
发表时间：
2021-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Kanikarla Marie P;Haymaker C;Parra ER;Kim YU;Lazcano R;Gite S;Lorenzini D;Wistuba II;Tidwell RSS;Song X;Foo WC;Maru DM;Chun YS;Futreal A;Kee B;Menter D;Solis L;Tzeng CW;Parseghian C;Raghav K;Morris V;Chang CC;Jenq R;Tam A;Bernatchez C;Kopetz S;Vauthey JN;Overman MJ
通讯作者：
Overman MJ
DOI：
10.1158/1078-0432.ccr-20-2403
发表时间：
2021-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Morris JS;Luthra R;Liu Y;Duose DY;Lee W;Reddy NG;Windham J;Chen H;Tong Z;Zhang B;Wei W;Ganiraju M;Broom BM;Alvarez HA;Mejia A;Veeranki O;Routbort MJ;Morris VK;Overman MJ;Menter D;Katkhuda R;Wistuba II;Davis JS;Kopetz S;Maru DM
通讯作者：
Maru DM
影响因子：
30.5
作者：
Verma, Vivek;Jafarzadeh, Nazli;Boi, Shannon;Kundu, Subhadip;Jiang, Zhinuo;Fan, Yiping;Lopez, Jose;Nandre, Rahul;Zeng, Peng;Alolaqi, Fatmah;Ahmad, Shamim;Gaur, Pankaj;Barry, Simon T.;Valge-Archer, Viia E.;Smith, Paul D.;Banchereau, Jacques;Mkrtichyan, Mikayel;Youngblood, Benjamin;Rodriguez, Paulo C.;Gupta, Seema;Khleif, Samir N.
通讯作者：
Khleif, Samir N.
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
影响因子：
11.5
作者：
Liu, Li;Mayes, Patrick A.;Hoos, Axel
通讯作者：
Hoos, Axel