部分靶向药的前期试验信息，以备参考

贝伐单抗长时间曝光伴有EGFR激活在结直肠癌（CRC）的模型，以提供合理的贝伐单抗和厄洛替尼在GERCOR三DREAM期临床试验的组合

背景： 表皮生长因子受体和血管内皮生长因子（R）的组合-targeted代理商一直表明至少有添加剂的活性在临床前的CRC模型时，有针对性的代理人单独给药（Larsen等。药理学Therap 131：80，2011; Poindessous等。 ，临床癌症研究 17：6522，2011）铺平了道路GERCOR梦幻OPTIMOX3 III期临床试验的转移性CRC校验码。虽然使用表皮生长因子受体单克隆抗体导向是反显示结直肠癌患者的突变的KRAS，对于EGFR靶向酪氨酸激酶抑制剂如厄洛替尼的情况不太清楚。 方法： 表达重量三人间的CRC异种移植模型的KRAS / BRAF基因，突变的KRAS基因或突变的BRAF人成立于裸鼠体内。动物用贝伐单抗和埃罗替尼，单独或组合，并且对肿瘤生长，存活和磷酸化的ErbB / HER家族成员的存在下测定的影响。治疗相关性毒性估计重量损失。 结果： 贝伐单抗和厄洛替尼的组合是显著更积极比单独代理三种异种移植模型虽然两种药物相结合的优势尤为引人注目的KRAS / BRAF的重量移植瘤模型。没想到，厄洛替尼单显示，在强大的抗肿瘤活性BRAF基因突变的HT-29异种移植物模型。贝伐单抗联合厄洛替尼的组合是毒性较低，通过减肥来确定，相比单独厄洛替尼。有趣的是，免疫组化分析表明，贝伐单抗激活表皮生长因子受体在所有三个异种移植模型。 结论： 我们在这里报告，贝伐单抗和厄洛替尼的组合是显著比单独代理的CRC模型不同的更积极的KRAS和BRAF基因状态。我们还表明，贝伐单抗激活EGFR信号类似于已经描述为伊立替康和电离辐射。两者合计，我们的研究结果表明，突变的KRAS和BRAF基因对表皮生长因子受体靶向酪氨酸激酶抑制剂的敏感性较小的影响比对表皮生长因子受体单克隆抗体导向的情况下，并为贝伐单抗和厄洛替尼结合的活性增加一种机械的基础。

http://meetinglibrary.asco.org/content/123095-143

Background: Combinations of EGFR and VEGF(R)-targeted agents have consistently shown at least additive activity in preclinical CRC models when the targeted agents were administered alone (Larsen et al., Pharmacol Therap. 131:80, 2011; Poindessous et al., Clin Cancer Res. 17:6522, 2011) paving the way for the GERCOR DREAM-OPTIMOX3 phase III trial in metastatic CRC. Although use of EGFR-directed mAbs are counter-indicated in CRC patients with mutant KRAS, the situation is less clear for EGFR-targeted TKIs like erlotinib. Methods: Three human CRC xenograft models expressing wt KRAS/BRAF, mutant KRAS or mutant BRAF were established in nude mice. Animals were treated with bevacizumab and erlotinib, alone or in combination, and the influence on tumor growth, viability and the presence of phosphorylated ErbB/HER family members was determined. Treatment-related toxicity was estimated by weight loss. Results: Combinations of bevacizumab and erlotinib were significantly more active than either agent alone for all three xenograft models although the advantage of combining the two agents was particularly striking for the KRAS/BRAF wt xenograft model. Unexpectedly, erlotinib alone showed strong antitumor activity in the BRAF mutant HT-29 xenograft model. The bevacizumab plus erlotinib combination was less toxic, as determined by weight loss, compared to erlotinib alone. Interestingly, IHC analysis showed that bevacizumab activates EGFR in all three xenograft models. Conclusions: We here report that bevacizumab and erlotinib combinations are significantly more active than either agent alone in CRC models with different KRAS and BRAF status. We further demonstrate that bevacizumab activates EGFR signaling similar to what has been described for irinotecan and ionizing radiation. Taken together, our findings suggest that mutant KRAS and BRAF have lesser influence on the sensitivity to EGFR-targeted TKIs than is the case for the EGFR directed mAbs and provide a mechanistic basis for the increased activity of the bevacizumab and erlotinib combination.

nintedanib中晚期难治性结直肠癌的前瞻性I期亚组分析。


摘要
背景：
Nintedanib是一种有效的，口服angiokinase抑制剂，针对血管内皮生长因子，PDGF和FGF信号，以及RET和Flt3的。最大耐受剂量nintedanib在我研究治疗难治性晚期实体瘤的阶段进行了评估。在此预先计划的亚组分析，效果nintedanib上的肿瘤血管，伴随着的疗效和安全性，评估30例结直肠癌（CRC）。
方法：
晚期患者的CRC谁没有常规治疗，或对他们来说，没有治疗证明疗效的存在，都与治疗nintedanib范围从50-450毫克每日一次（N = 14）或150-250毫克每日两次（N = 16 ）为28天。经过1周的休息，进一步课程，允许在无进展或不适当的毒性。的主要目的是利用动态对比增强磁共振成像（DCE-MRI）在肿瘤血管的效果秒和60秒（iAUC60）或音量转印后表示为DCE-MRI造影剂的浓度-时间曲线下的初始区域恒血浆和血管外细胞外空间（KTRANS）之间。
结果：
患者接受的4.0课程（范围：1-13）的中位数。间21可评估的患者中，14（67％）为从基线KTRANS和13（62％）的降低≥40％有减小≥40％从基线iAUC60，代表对肿瘤血流和通透性，分别与临床相关的效果。从基线的减少KTRANS≥40％呈正非进行性的肿瘤状况相关（Fisher确切概率：P = 0.0032）。一名患者达到250毫克每日两次和24（80％）部分反应达到疾病稳定≥8周。肿瘤进展时间（TTP），4月为26％，中位TTP为72.5天（95％可信区间为65-114）。常见的药物相关不良事件（AE）包括恶心（67％），呕吐（53％），腹泻（40％）; 3例患者发生药物相关的不良事件≥3级。4 ​​例治疗nintedanib每日一次有丙氨酸氨基转移酶和/或3天门冬氨酸氨基转移酶升高≥级无增加> 2级主要出现在每天两次的组。
结论：
Nintedanib调节肿瘤的血流和通透性的晚期患者，难治性儿童权利，同时实现抗肿瘤活性，并维持可接受的安全性。

http://www.ncbi.nlm.nih.gov/pubmed/25012508

结论： bibf1120     40%出现缩小  1例部分反映，24例稳定》8周  中位疾病进展 77天   26% 稳定超过4个月   在末线适用，有一定的效果

JAK1 / 2-STAT3的作用为急性抗性机制的MEK抑制BRAF突变的结直肠癌细胞系。

摘要：

背景： 癌基因突变的BRAF发生在治疗晚期结直肠癌（CRC）的8％，并已证实与预后较差。在对比BRAF突变（MT）黑色素瘤，其中所述的BRAF抑制剂Vemurafenib（PLX4032）已经显示显著增加反应率和总生存期，只有轻微的反应Vemurafenib治疗已经报道了在BRAF MT CRC校验。的弱点了然BRAF MT的CRC是很重要的，并确定唯一需要的成药目标的BRAF吨的CRC肿瘤必须填写晚期CRC的治疗设备缺口的潜力。本研究的目的是确定在新的耐药机制，以MEK抑制BRAF吨CRC校验码。 方法： 配对BRAF MT / WT雷电华和VACO432大肠癌细胞和非等基因BRAF MT LIM2405，WiDR，用于HT-29和COLO205大肠癌细胞。改变蛋白的表达/活性免疫印迹进行了评估。MEK1 / 2和JAK1 / 2或c-Met的抑制之间的相互作用采用MTT法细胞活力检测和流式细胞仪评估。利用蛋白质印迹法对PARP，裂解的caspase 3，图8和9，和caspase 3/7和8活性测定细胞凋亡的测 ​​定。 结果： 治疗与MEK1 / 2抑制剂AZD6244，trametinib，UO126和PD98059导致急性增加STAT3的活性在在BRAF MT RKO和VACO432细胞，但不是在他们的BRAF基因野生型的克隆，这与增加JAK2活性有关。利用基因特异性siRNA或小分子JAK / STAT3的活化的抑制抑制剂TG101348或AZD1480，废除这种生存反应，导致协同效应和显著增加细胞死亡时MEK1 / 2抑制剂AZD6244或trametinib结合的BRAF吨大肠癌细胞。RTK的c-Met的是STAT3以下MEK1 / 2的抑制上游激活。抑制c-Met的和MEK1 / 2，采用药理学抑制剂（crizotinib和AZD6244），导致协同效应，增加细胞死亡的BRAF吨大肠癌细胞。 结论： 我们已经确定了JAK / STAT3的活化，作为一个重要的逃逸机制的BRAF吨的CRC以下MEK1 / 2的抑制体外。JAK / MEKi或MET / MEKi的组合可以是一个潜在的新的治疗策略预后不良的BRAF MT先进的大肠癌患者。

http://meetinglibrary.asco.org/content/131690-144

大肠癌 的基因驱动的临床试验

                               
登录/注册后可看大图

vemurafenib组合与伊立替康和西妥昔单抗的患者的阶段1B研究BRAF -mutated晚期癌症和转移性结肠直肠癌。

背景： BRAF V600突变，存在于转移性结直肠癌（转移性结直肠癌）的病人（PTS）5-10％，被认为是预后不良的标志，和<10％的BRAF -mutated转移性结直肠癌点西妥昔单抗的结合反应（C）和伊立替康（一）。Vemurafenib（五），口服激酶抑制剂BRAF基因的突变V600亚型，表现出5％的响应率在I期临床试验有BRAF基因 -mutated转移性结直肠癌。在大肠癌细胞系体外实验的结果显示突变的BRAF由vemurafenib是阻断表皮生长因子受体触发的代偿激活。表皮生长因子受体结合vemurafenib导致在临床前模型中的协同细胞毒性的抑制，通过伊立替康进一步增强。组合的点的安全性和有效性的BRAF -mutated晚期恶性肿瘤尚未研究。方法： 在这个3 +3 I期研究分，分难治的BRAF收到升级结合剂vemurafenib的西妥昔单抗与伊立替康在-mutated癌症14天为一周期。通过RECIST 1.1影像学反应进行了评估，每4个周期。不良事件（AE）是由CTCAE 4.0评估。结果： 通过二千零十四分之一，10分都被录取：7剂量水平1（DL）（V-480mg PO BID，C-250毫克/ m2每周和I-180毫克/ m2，每14天）和三个在DL 2（提高到V-PO为720mg BID）。一个剂量限制性毒性，观察到DL1（3级关节痛），并解决了与减少剂量。最常见的不良反应为皮疹，恶心，腹泻等。在DL 1治疗6个评价患者中，5例转移性结直肠癌，1例阑尾腺癌。四转移性结直肠癌5例（80％）获得了部分缓解。为5的mCRC点，中位数最好的反应是减少了44％（范围为0％-70％）为5，5 +，8 +，12 +和14 +个循环的反应时间。阑尾癌PT疾病进展。PK和PD的分析计划。结论： vemurafenib的结合与伊立替康和西妥昔单抗似乎耐受性良好，在点与BRAF -mutated转移性结直肠癌。即使是低剂量的vemurafenib，永久居民则见于4分评价的转移性结直肠癌点在第一队列。附加分继续在vemurafenib的高剂量水平进行注册。一名美国协作组随机的BRAF基因突变的转移性结直肠癌（SWOG1406）这个组合的II期试验计划。临床试验信息：NCT01787500。

Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are considered poor prognostic markers, and <10% of BRAF-mutated mCRC pts respond to a combination of cetuximab (C) and irinotecan (I). Vemurafenib (V), an oral kinase inhibitor to the mutated V600 isoform of BRAF, demonstrated a 5% response rate in a phase I trial with BRAF-mutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAF-mutated advanced malignancies have not been studied. Methods: In this 3+3 phase I study, pts with refractory BRAF-mutated cancer received escalating doses of vemurafenib in combination with cetuximab and irinotecan over a 14-day cycle. Radiographic responses were evaluated every 4 cycles by RECIST 1.1. Adverse events (AEs) were assessed by CTCAE 4.0. Results: Through 1/2014, 10 pts have been enrolled: 7 at dose level 1(DL) (V- 480mg PO BID, C-250 mg/m2 weekly and I- 180mg/m2 every 14 days) and three at DL 2 (increased to V-720mg PO BID). One dose-limiting toxicity was observed at DL1 (grade 3 arthralgia) and resolved with dose reduction. The most common AEs were rash, nausea, and diarrhea. Of the 6 evaluable pts treated at DL 1, 5 had mCRC and 1 had appendiceal adenocarcinoma. Four of the 5 mCRC pts (80%) achieved a partial response. For the 5 mCRC pts, median best response was a reduction of -44% (range, 0% to -70%) with duration of responses of 5, 5+, 8+, 12+, and 14+ cycles. The appendiceal carcinoma pt had disease progression. PK and PD analysis is planned. Conclusions: The combination of vemurafenib with irinotecan and cetuximab seems well tolerated in pts with BRAF-mutated mCRC. Even with a low vemurafenib dose, PRs were seen in 4 of 5 evaluable mCRC pts in the first cohort. Additional pts continue to be enrolled at higher dose levels of vemurafenib. A US cooperative group randomized phase II trial of this combination in BRAF-mutated mCRC (SWOG1406) is planned. Clinical trial informatio

http://meetinglibrary.asco.org/content/132589-144

结论： 5例可评价mcrc 4例缩小   中位最好效果缩小44% 并持续 2.5，2.5+ 4+ 6+ 7+ 个月   

     vemurafenib组合与伊立替康和西妥昔单抗  效果不错.. 并且进一步进行下一期临床试验                   http://clinicaltrials.gov/show/NCT01787500

效果nintedanib，三angiokinase抑制剂，EGFR和HER2在结直肠癌（CRC）的车型，合理的组合，其与ErbB家族阻滞剂afatinib。

背景： 我们最近表明，afatinib的组合，泛他/她的ErbB受体阻滞剂和nintedanib，三angiokinase（VEGFR，FGFR，PDGFR）在CRC模型抑制剂协同表演活动（Poindessous等，临床癌症研究，17 ：6522，2011）。然而，对于该组合的协同作用的机理的基础被完全理解。在暴露于多种治疗方法，包括电离辐射和依立替康的表皮生长因子受体被激活。我们推测，nintedanib曝光也能激活EGFR信号这或许可以解释组合的协同活性。方法： 小鼠与人类的CRC异种移植物分别用nintedanib和afatinib单独或组合使用，并在肿瘤生长，存活和磷酸化的存在的影响家人被确定。不同的调度方案进行了探讨，以确定哪些组合最佳的抗肿瘤活性以最小的毒副作用的给药方案。 结果： 我们在这里表明，nintedanib处理导致在多个CRC异种移植模型中的活化的EGFR和HER2的以剂量依赖性的方式。在所测试的不同的治疗方案，连续nintedanib与afatinib每第二周的施用证实几乎一样有效，这两种药剂一起连续给药并且是低毒性。最后，nintedanib加afatinib优于单独nintedanib在三个不同的肿瘤异种移植物具有突变的KRAS。 结论： 我们在这里报告，长时间暴露于nintedanib，小分子血管生成抑制剂，是伴随着激活的EGFR和HER2的。因此，afatinib，一种ErbB家族阻滞剂，是协同与nintedanib。我们随后确定了一种新的方案以优化有限毒性副作用的组合的抗肿瘤效果，并表明，该方案是活跃在四个不同的CRC肿瘤模型，包括3与突变的KRAS。这些发现两个小分子的临床试验提供了理论基础，甚至在患者的突变的KRAS。

http://meetinglibrary.asco.org/content/123071-143

Background: We have recently shown that combinations of afatinib, a pan-HER/ErbB blocker, and nintedanib, a triple angiokinase (VEGFR, FGFR, PDGFR) inhibitor show synergistic activity in CRC models (Poindessous et al., Clin Cancer Res. 17:6522, 2011). However, the mechanistic basis for the synergistic effects of the combination is incompletely understood. EGFR is activated following exposure to a wide variety of therapeutic modalities including ionizing irradiation and irinotecan. We speculated that nintedanib exposure could also activate EGFR signaling which might explain the synergistic activity of the combination. Methods: Mice with human CRC xenografts were treated with nintedanib and afatinib alone or in combination and the influence on tumor growth, viability and the presence of phosphorylated HER family members was determined. Different scheduling regimens were explored to identify an administration schedule which combined optimal antitumor activity with minimal toxic side effects. Results: We here show that nintedanib treatment results in activation of EGFR and HER2 in multiple CRC xenograft models in a dose-dependent manner. Among the different regimens tested, continuous nintedanib with administration of afatinib every second week proved almost as efficient as continuous administration of the two agents together and was less toxic. Finally, nintedanib plus afatinib was superior to nintedanib alone in three different tumor xenografts with mutant KRAS. Conclusions: We here report that prolonged exposure to nintedanib, a small molecule angiogenesis inhibitor, is accompanied by activation of EGFR and HER2. Accordingly, afatinib, an ErbB family blocker, was synergistic with nintedanib. We subsequently identified a novel regimen for optimizing the antitumor effects of the combination with limited toxic side effects and showed that this regimen is active in four different CRC tumor models including three with mutant KRAS. These findings provide a rationale for clinical trials of the two small molecules, even in patients with mutant KRAS.


结论： 在体外培植的肿瘤中，bibf 1120 的长期使用，导致 her2 和 egfr 的激活， 联用  bibf1120 + 阿法替尼  可以有很好的协同作用，该联合疗法对部分kras突变的模型也有效

贝伐单抗（BEV），带或不带厄洛替尼作为维持治疗的患者（PTS）转移性结直肠癌（转移性结直肠癌）：根据在gercor梦III期临床试验KRAS基因状态的探索性分析。

背景： 在GERCOR-DREAM试验，维持治疗（MT）与BEV +表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼（E）一线贝伐单抗为基础的诱导治疗（IT）在点单用贝伐单抗相比，转移性结直肠癌显著改善PFS之后。在这里，我们探讨KRAS基因状态厄洛替尼疗效的影响。 方法： 分初治和不可切除的转移性结直肠癌均符合要求。过了贝伐单抗为基础的IT与FOLFOX或XELOX方案或FOLFIRI分，分无疾病进展，随机吨贝伐单抗单（BEV 7.5毫克/千克Q3W; A组）之间或贝伐单抗+ E（BEV 7.5毫克/千克Q3W，E 150毫克/连续天; B组）。KRAS基因决定成立由各中心的地方评估。 结果： 其中452例患者随机分组，KRAS基因状态是403分（89％）可供选择：234例（58％）的KRAS野生型和169例（42％）的KRAS MUT。临床特点是两个群体之间的相似。对于随机患者的全人群（n = 452），中位PFS从列入A组和B，分别为9.33米和10.55米（HR = 0.76 [0.61-0.94]，p值= 0.011）。对于KRAS重量人群，中位PFS从列入为9.66米，10.94米在A组和B，分别为（HR = 0.80 [0.59-1.08]，p值= 0.141）。对于KRAS基因MUT人口，中位PFS从包容是9.79米9.79米的臂A和B，分别为（HR = 0.86 [0.61-1.22]，p值= 0.393）。在厄洛替尼治疗的KRAS基因重点，皮肤毒性预测的PFS：MPFS是9.66米以点带0级（N = 101）和10.91米以点带级≥1（N = 114）（HR = 0.69 [0.51- 0.95]，P = 0.0186）。 结论： 添加厄洛替尼的贝伐单抗维持治疗的一线转移性结直肠癌显著提高从包含无进展生存期。然而，在WT和MUT嘉仕点，差异无统计学显著。不像抗EGFR单克隆抗体，加入厄洛替尼对贝伐单抗并不显得拮抗剂在KRAS基因突变的患者。临床试验信息：NCT00265824。

http://meetinglibrary.asco.org/content/106173-133

In the GERCOR-DREAM trial, maintenance therapy (MT) with bev + EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC significantly improved PFS compared with bev alone. Here we explore the influence of KRAS status on erlotinib efficacy. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (Bev 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). KRAS determination was established by local assessment in each center. Results: Among the 452 randomized patients, KRAS status was available in 403 pts (89%): 234 pts (58%) KRAS wt and 169 pts (42%) KRAS mut. Clinical characteristics were similar between both populations. For the whole population of randomized patients (n=452), median PFS from inclusion were 9.33m and 10.55m in arm A and B, respectively (HR=0.76 [0.61-0.94], p=0.011). For KRAS wt population, median PFS from inclusion was 9.66 m and 10.94 m in arm A and B, respectively (HR=0.80 [0.59-1.08], p=0.141). For KRAS mut population, median PFS from inclusion was 9.79 m and 9.79 m in arm A and B, respectively (HR=0.86 [0.61-1.22], p=0.393). In KRAS wt pts treated with erlotinib, cutaneous toxicity was predictive of PFS: mPFS was 9.66m in pts with grade 0 (n=101) and 10.91m in pts with grade ≥1 (n=114) (HR=0.69 [0.51-0.95], p=0.0186). Conclusions: The addition of erlotinib to bevacizumab as maintenance treatment in first-line metastatic colorectal cancer significantly improves progression-free survival from inclusion. However, in both wt and mut KRAS pts, difference was not statistically significant. Unlike anti-EGFR monoclonal antibodies, the addition of erlotinib to bevacizumab does not appear to be antagonist in KRAS mutant patients. Clinical trial information: NCT00265824.

结论： 贝伐单抗 和 厄洛替尼 联合维持治疗   对比 贝伐单抗 单独 维持治疗   中位PFS 分别是 10.55月对比 9.33 月  显示有效益，而且不分 kras 状态  

一个要点：口服egfr 抑制剂，对krsa突变也有效，跟单抗不一样

1-2阶段试验的BRAF抑制剂dabrafenib（四）加MEK抑制剂trametinib（T）的BRAF V600突变的大肠直肠癌（CRC）的：更新功效和生物标志物分析。


背景： BRAF V600突变发生在转移性结直肠癌5-15％，并预测预后较差。虽然非常有效的BRAF突变的黑色素瘤，BRAF抑制剂单药治疗已经显示出疗效不佳的BRAF突变的CRC。临床前数据表明，改进的MAPK途径抑制与BRAF和MEK的结合抑制可以提高疗效。 方法： 43名患者（分）与BRAF V600突变体的IV期的CRC进行与D（为150mg BID）和T（2毫克QD），17的处理其中被纳入药效队列与肿瘤活检前处理和2周的治疗后。档案组织的微卫星不稳定性（MSI），PTEN丢失和487-基因测序（Illumina公司）进行了分析。 结果： 43分，5（12％）达到部分缓解（PR）或更好（有或没有确认），包括1（2％），PT完全缓解（CR）持续> 22个月 一个额外的22（51％）在第一再分期实现疾病稳定（SD）患者，其中11（26％）患者有轻微反应（肿瘤缩小10％～30％）。10（23％）患者留在研究> 6个月。所有9个可评价给药后活检减少了相对的磷酸化ERK的水平，以预剂量（平均下降47％±24），然而，％pERK的抑制和反应不相关成比例。的15名受试者的突变分析已经完成为止。3评价患者与美的与CR和2角有PIK3CA突变。与疗效都不PTEN丢失，也不微星相关。 结论： 对D + T中的组合具有活性的一个子集BRAF V600突变的CRC点，有几个PR和持久的CR。MAPK信号被抑制在评估所有患者，但在较小的程度比观察到BRAF突变的黑色素瘤的D单药。PIK3CA突变被确定在应对病人，因此不排除针对这一方案，但PIK3CA突变与疗效之间的确切关系不能建立在有限的PT样本。生物标志物的细化和额外的治疗组合可改善临床活性。临床试验信息：IND号：113557。

http://meetinglibrary.asco.org/content/131743-144

Background: BRAF V600 mutations occur in 5-15% of metastatic CRC and predict poor prognosis. Although highly effective in BRAF mutant melanoma, BRAF inhibitor monotherapy has shown poor efficacy in BRAF mutant CRC. Preclinical data suggest that improved MAPK pathway suppression with combined inhibition of BRAF and MEK may improve efficacy. Methods: 43 patients (pts) with BRAF V600 mutant stage IV CRC were treated with D (150mg BID) and T (2mg QD), 17 of whom were enrolled in a pharmacodynamic cohort with tumor biopsies pre-treatment and after 2 weeks of therapy. Archival tissues were analyzed for microsatellite instability (MSI), PTEN loss, and 487-gene sequencing (Illumina). Results: Of 43 pts, 5 (12%) achieved partial response (PR) or better (with or without confirmation), including 1 (2%) pt with complete response (CR) ongoing >22 months. An additional 22 (51%) pts achieved stable disease (SD) at first restaging, of which 11 (26%) pts had a minor response (10% to 30% tumor reduction). 10 (23%) pts remained on study >6 months. All 9 evaluable post-dose biopsies had reduced levels of phospho-ERK relative to pre-dose (average decrease 47% ±24), however, the % pERK inhibition and response did not correlate proportionally. Mutational analysis of 15 subjects has been completed to date. The pt with CR and 2 of 3 evaluable pts with PR had PIK3CA mutation. Neither PTEN loss nor MSI correlated with efficacy. Conclusions: The combination of D + T has activity in a subset of BRAF V600 mutant CRC pts, with several PRs and a durable CR. MAPK signaling was inhibited in all pts evaluated, but to a lesser degree than observed in BRAF mutant melanoma with D as a single agent. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen, but a definitive correlation between PIK3CA mutations and efficacy cannot be established given the limited pt sample. Biomarker refinement and additional therapeutic combinations may improve clinical activity. Clinical trial information: IND No: 113,557.

结论：  dabrafenib + trametinib  对 BRAF V600突变   42患者   5个pr 其中一个完全缓解   22个稳定，其中 12个  缩小10%-30%   

疗效和耐受性的开放标签阶段的I / MEK抑制剂trametinib（T）的BRAF抑制剂dabrafenib（D）和抗EGFR抗体帕尼单抗（P）的组合患者（PTS）与BRAF V600E II研究突变的大肠癌（CRC）

http://meetinglibrary.asco.org/content/131642-144

背景： BRAF V600突变发生在CRC的5-10％，并赋予预后差。不像在BRAF突变体（BRAFm）黑色素瘤，BRAF和MEK抑制剂显示BRAFm CRC有限的活动。临床前数据表明，表皮生长因子受体可以在BRAFm CRC，它可以通过BRAF基因和EGFR的结合的抑制来克服介导抗性。因此，BRAF基因通路的结合抑制（与D或D + T和抗EGFR剂P），以防止表皮生长因子受体介导的耐药是一种理性的，有前途的方法来治疗BRAFm CRC校验码。 方法： 用BRAFm CRC校验合格的报名点在配件1和2持续3部分的研究，剂量递增的（DE;第1部分），队列扩展（CE认证，第2部分），并有计划的随机比较（第3部分），不论是接受双峰（D + P）或三联（ D + P + T）的组合。 结果： 19分接收到的D + P±吨DE或CE。双峰：6点收到完整的双重剂量（D 150毫克，每天两次[投标] + P 6毫克/公斤，每2周[Q2W]）在队列1德3点收到的双峰在第2部分CE认证。三重：3点收到三元（D 150毫克BID + P 4.8毫克/千克Q2W + T 1.5毫克，每天一次[QD]）的最低剂量组合在队列2 DE各县3A（D 150毫克BID + P 4.8毫克/公斤Q2W + T 2毫克每日一次），N = 4，3B（D 150毫克BID + P 6毫克/公斤Q2W + T 1.5 mg每日一次），n = 3时同时被打开。没有剂量限制性毒性已见于任何世代。最常见的药物相关不良事件（AE）是痤疮样皮炎的双峰（5月9日点，所有等级[GR] 1）和三（5月10日分3石墨1和2的Gr 2）点。在二重集团，没有可能与药物有关的Gr> 3的事件进行了报道。在三联组，GR> 3事件至少可能与药物有关的，包括呕吐（n = 1时），皮疹（N = 1）和皮肤裂隙组（n = 1）。在初步的疗效数据，部分反应已经看到在三重剂量4/6评价患者（四分之三正在进行，1> 7个月），2分与疾病稳定（SD，持续1和1，由于停产，以自动曝光）。在双重剂量的8个可评价的，7月8日实现标清（持续6-26周，2点进行中）作为最佳的整体响应。更新的结果将提交。 结论： P能够被安全地结合D或D / T。临床活动的令人鼓舞的证据已经显现。临床试验信息：NCT01750918。

这么专业的资料，太值得收藏了，谢谢楼主分享！

谢谢分享！