KRAS资料汇总

橙子KARS突变 · 发表于 2015-11-10 18:10:33

Summary on KRAS mutation driven nsc lung cancer - a patient’s perspective
hhhdai
Oct. 31, 2015

The infamous KRAS is a common driver oncogene in NSCLC. In adenocarcinoma of the lung, it accounts for nearly 1/5 – 1/4 of all cases, next only to EGFR positive cases.

Lack of targeted inhibition made KRAS positive NSCLC a very tough cancer to treat and prognosis rather poor. Fortunately since 2010, this is slowly but surely changing, as more and more inhibitors along the RAS/RAF/MEK/ERK pathway are discovered and made into human trials, with some already showed promising outcomes.

Here I summarized a number of targeted therapy trials relevant to KRAS in NSCLC, As always; I am a mere patient, with limited or no knowledge but lots of opinions and strong bias. So, be pre-warned, you might get real harm believing in the wrong guy, though the wrong guy never meant to do so.

1)
MEK inhibitor Trametinib, aka GSK1120212, by GSK. Commercial name is Mekinist

I list this one at 1st place, because it is an approved drug, which means you could get it prescribed off label for lung cancer. In 2013, FDA approved it for the treatment of melanoma with BRAF V600 mutated melanoma. RAF, as in BRAF is immediately downstream of (c- or v-) RAS oncogene (as in KRAS) signaling pathway, which in turn passes signal down to MEK kinases, so it is quite relevant to KRAS positive cancer.

Although earlier clinical trials of Trametinib single agent showed its efficacy to be similar to that of chemotherapy agent docetaxel, improvement could come in further biomarker selection and in drug combination. It is said that KRAS G12C mutation in smokers had the best response to Trametinib, so I wonder if commercial gene tests nowadays provide detailed point mutation information. Also since a year ago, GSK started a combination trial using JAK2 inhibitor momelotinib and trametinib. Momelotinib is in phase 3 clinical trial for myelofibrosis, a type of blood cancer. Why does GSK want to inhibit JAK2, which seems has nothing to do with lung cancer? My guess is, momelotinib probably also has strong inhibition on TBK1, TANK-binding kinase 1, which is a component of the NFkB pathway (accidentally relevant to my wustl project in the past). There have been clear indications in the literature that inhibition of TBK1, which cuts off an autocrine cytokine circuit, significantly blocks KRAS driven tumorigenesis. So, if my guess is right, or shall I say, if GSK betted right, we might see a long-legged (or -footed?) improvement in KRAS positive NSCLC therapy. At this point I have not seen or heard any data from GSK’s combo trial of momelotinib and trametinib.

NCT02258607
Efficacy and Safety of Momelotinib Combined With Trametinib in Adults With Metastatic KRAS-mutated Non-Small Cell Lung Cancer (NSCLC) Who Have Failed Platinum-Based Chemotherapy Preceded by a Dose-finding Lead-in Phase
NCT01912625
Trametinib, Combination Chemotherapy, and Radiation Therapy in Treating Patients with Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

2)
MEK inhibitor Selumetinib, aka AZD6244, by AZD.

Well, Selumetinib is the most famous KRAS path inhibitor as of today, especially outside US. As early as 2012 ASCO, the then AZD6244 already received attention worldwide for its superiority over docetaxel in KRAS positive NSCLC from phase 2 results. Understandably, it was AZD6244 + docetaxel vs docetaxel alone. So, I would say, not a terrific design, but clearly there was survival advantage for AZD6244. Their phase 3 trial worldwide has been ongoing since 2013, and it’s exactly Selumetinib + docetaxel vs placebo + docetaxel.

NCT01933932 – worldwide phase 3, randomized
Assess Efficacy & Safety of Selumetinib in Combination with Docetaxel in Patients Receiving 2nd Line Treatment for v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Positive NSCLC (SELECT-1)

AZD, a global pharma giant, like a rotten-rich gambler, spares no chance in collecting from all bets, no matter what the odds. Look at what they have put out for NSCLC:

NCT01586624 – combo with Vandetanib, an approved thyroid cancer drug by AZD, which inhibits VEGFR, EGFR and RET kinase. My question is, why? I don’t see any apparent synergism in the combo of VEGFR-TKi and MEKi. OK maybe you know more? Please correct me.
A Phase I Trial of Vandetanib (ZD6474) and Selumetinib (AZD6244)for Solid Tumours Including Non Small Cell Lung Cancer (VanSel-1)
NCT02025114 – combo with iressa. Oh, how inspirational?
Selumetinib in Combination With Gefitinib in NSCLC Patients
NCT01750281 - combo with taxol. All I can say is, good luck.
Assess Efficacy and Safety of AZD6244 in Combination With Docetaxel in Patients Receiving Second Line Non Small Cell Lung Cancer Treatment. (SELECT-2)
NCT02503358 – combo with taxol again. Good luck again
Selumetinib and Nab-Paclitaxel (Albumin-stabilized Nanoparticle Formulation) as Second-Line Treatment in Treating Patients With Stage IIIB-IV Non-small Cell Lung Cancer
NCT02143466 – combo with the famous AZD9291. Good luck 3rd time, AZD!
AZD9291 in Combination With Ascending Doses of Novel Therapeutics
NCT02337530 – combo with Alimta + Cisplatin, ouch! You think anyone is going to sign into this horrific triple combo, AZD?
Selumetinib in Patients Receiving Pemetrexed and Cisplatin in Advanced or Metastatic KRAS Wildtype or Unknown Non-Squamous Non-Small Cell Lung Cancer
NCT02583542 - AZD2014 is an mTORC inhibitor, something like rapamycin?
A Study of AZD2014 in Combination With Selumetinib in Patients With Advanced Cancers (TORCMEK)
NCT02450656 –EGFR-TKi again. Good luck 4th time!
Afatinib and Selumetinib in Advanced KRAS Mutant and PIK3CA Wildtype Colorectal, Non-small Cell Lung and Pancreatic Cancer (M14AFS)

3)
MEK inhibitor, Cobimetinib, aka XL518 by Exelixis, + ERK inhibitor GDC-0994 by Genentach

Cobimetinib, combo with vemurafenib (Zelboraf), a Raf inhibitor, is expected to receive FDA decision on melanoma in 2 weeks. Based on what I know, it is likely going to be an approval. Vemurafenib, also by Genentech, is already on the melanoma market.

So, why did Genentech decide to use cobimetinib, in combo with ERK inhibitor GDC-0994, not Raf inhibitor vemurafenib in their “advanced solid tumor including NSCLC” trial, is beyond me. But this trial surely will be interesting to watch.

Did I say I am biased? Here it goes, anything Genentech does, I pay attention. Alright?

NCT02457793
A Study of the Safety, Tolerability, and Effects of Cobimetinib and GDC-0994 in Patients With Locally Advanced or Metastatic Solid Tumors

4)
MEK inhibitor, PD0352901 + CDK4/6 inhibitor Palbociclib, by Pfizer

Palbociclib, aka PD-0332991, is already approved for ER (estrogen receptor) positive breast cancer, under commercial name Ibrance.

Pfizer has already conducted a phase 2 NSCLC trial using Palbociclib – “A phase II clinical trial of the CDK 4/6 inhibitor palbociclib (PD 0332991) in previously treated, advanced non-small cell lung cancer (NSCLC) patients with inactivated CDKN2A”. CDKN2A (p16) inactivation is closely related to CDK4 activation, I believe. This is from ASCO 2014 – “Palbociclib therapy alone was well-tolerated, and stable disease (SD) was achieved in 50% of evaluable patients, suggesting the induction of cellular senescence.”

Eli Lilly has also developed a rather potent CDK4 inhibitor called Abemaciclib, aka LY2835219, and latest data showed that it achieved disease control rate of 58% in KRAS positive NSCLC.

So, Pfizer decided to put CDK4 inhibitor together with MEK inhibitor, I guess if Pfizer could push effectiveness rate to about or beyond 70%, it will be as big a success as their recent blockbuster crizotinib, which gave me an extra one and half year survival despite some significant but tolerable body damages.

NCT02022982
PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors

5)
MEK inhibitor, binimetinib, aka MEK162, by Array BioPharma

Just like Roche/ Genentech has cobimetinib + Vemurafenib, Array BioPharma has binimetinib + encorafenib, in both cases, a MEK inhibitor combo with a Raf inhibitor, against BRAF V600 mutated melanoma.

My trial sponsor, Ariad, under financial stress since couple years ago, still has a market cap of about $1.3b. Look at Array BioPharma, just a little more than half of Ariad. Yet, can you believe they are conducting 4 brand new clinical trials on MEK162, two involving NSCLC. And, they are ditching world #1 pharma pirate Novartis! What a show of confidence. I wish this Colorado company and KRAS NSCLC patients best of luck.

NCT02185690
A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung
NCT02451865
Binimetinib With Docetaxel in Treating Patients With Previously Treated, Stage IV Non-small Cell Lung Cancer

6)
TBK1 inhibitor, momelotinib, already covered above

7)
ERK inhibitor, GDC-0994 , already covered above

8)
Raf inhibitor, encorafenib and vemurafenib, already covered above

9)
CDK4 inhibitor, Palbociclib and Abemaciclib , already covered above

I’m sure there are things I missed or mistaken so please help append / correct all you can, thanks.

https://www.inspire.com/groups/a ... &asat=317910285

橙子KARS突变 · 发表于 2015-11-10 18:35:07

Abemaciclib in NSCLC (Abstract #8026)
KRAS genes, when mutated, are known to turn normal cells into cancerous cells. And existing studies suggest that the presence of KRAS mutation in NSCLC patients is indicative of a poor prognosis, which makes this an important area of research.[1] In preclinical research, there was evidence for greater sensitivity to abemaciclib in reducing the growth of cancer cells when used in NSCLC models with KRAS mutations. In the Phase I study, 57 patients with advanced NSCLC who progressed or relapsed after standard treatments were enrolled. The patients enrolled received a median of four prior regimens, 29 patients had KRAS mutations while 24 were KRAS wild-type, and KRAS status was unknown for 4 patients. Patients received abemaciclib twice daily during the study.

Disease control rate – defined as patients demonstrating either a complete response, partial response or stable disease – was 49 percent for patients on abemaciclib, including two partial responses and 26 patients with stable disease. Consistent with preclinical data, the disease control rate was higher for patients with KRAS mutant type (55%) versus those with KRAS wild-type (38%).

The most common grade 3 adverse events (greater than 5% incidence) were leukopenia (14%) and neutropenia (9%). No patients in the lung cancer cohort experienced grade 4 adverse events. Less than two percent of patients discontinued due to adverse events in this study cohort.

"KRAS mutations are common in patients with NSCLC, but there have been few clinical advances in our treatment for these patients," said Jonathan W. Goldman, M.D. of UCLA's Jonsson Comprehensive Cancer Center, investigator of the trial's lung cancer cohort and study presenter. "The results of the lung cohort of this study – which showed that abemaciclib could decrease tumor size in this patient population – suggest further clinical investigation of abemaciclib as a single agent for the treatment of NSCLC is warranted, with a particular focus on those tumors with KRAS mutations."

LY2835219.pdf (1.82 MB, 下载次数: 230)

最爱菜园子 · 发表于 2015-11-10 22:17:16

英文基本忘光了，希望加入群多了解知识。

qianlong · 发表于 2015-11-11 16:11:31

内容很全面啊，谢谢分享。

秋天1012 · 发表于 2015-12-31 01:20:50

谢谢分享

橙子KARS突变 · 发表于 2016-1-3 16:39:52

Triple Lung Cancer Therapy With Experimental Drugs And Radiation Targets Most Resistant Cancers

Jan 1, 2016 12:00 AM By Lecia Bushak

Researchers developed a triple whammy treatment in defeating a lung cancer gene mutation that's resistant to most drugs and radiation. Pixabay, public domain

The four most common gene mutations that occur in lung cancer include KRAS, TP53, STK11, and EGFR, These are often what make those cancers treatment-resistant. As a result, it’s far more difficult to choose the right therapy for lung cancers with genetic mutations.

One new study out of Thomas Jefferson University in Philadelphia, however, has been experimenting with a triple therapy that has proved effective for KRAS gene mutations in mice. The triple therapy involves two experimental drugs in combination with radiation therapy.

“Currently, there is a clinical trial underway to evaluate the combination of two cancer drugs, trametinib and palbociclib, made by two pharma companies for patients with solid tumors and melanoma,” said Dr. Bo Lu, professor of radiation oncology at Thomas Jefferson University and an author of the study, in the press release. “Although further research in human subjects is needed to confirm the finding, our study suggests that we may be able to identify non-small cell lung cancer patients who are likely to benefit most from this combination of therapies.”

Past research has focused on EGFR mutation treatments, but not much has been developed to target the KRAS mutation. Lung cancers in general have about a 54 percent survival rate of five years — but only if the cancer is detected early, when it’s localized in the lungs. According to the new research, only about 2 percent of lung cancer survivors live past the five-year mark.

For the study, the researchers examined non-small cell lung cancer (NSCLC) cells, and applied a KRAS-targeting drug to them. They found that some cells were more resistant to the drug than others, and that a certain other mutation called p16 contributed to their resistance. In addition, after reviewing lung-cancer patient genotypes, the authors found that people who had the p16 mutation were less likely to survive, compared to those without the mutation.

This is what helped the researchers decide to use a double drug: The first one targets the KRAS mutation, while the second one unravels the p16 mutation resistance. This would weaken the cancer cells enough to make them fall prey to radiation. Though the treatment proved effective in mice, the researchers will need to repeat the experiment in a clinical trial before moving forward.

“If you hit one target another can take over,” Lu said. “If you hit two, it becomes a lethal bullet.”

Source: Lu B, et al. Clinical Cancer Research, 2015.

trametinib（曲美替你）联合palbociclib（帕博西尼），小鼠实验效果还可以。

http://www.medicaldaily.com/trip ... mp;isappinstalled=0

橙子KARS突变 · 发表于 2016-1-3 16:42:09

本帖最后由橙子KARS突变于 2016-1-3 16:43 编辑

Palbociclib是CDK4/6 是细胞分裂周期的重要调节蛋白，诱发细胞从 G1 到 S 阶段的转化。抑制这两个酶应该阻断细胞的继续分裂，但实际上 CDK4/6 不仅能叫停细胞分裂，甚至可以杀死已有的癌细胞，临床上已经观测到淋巴癌、肺癌、和乳腺癌病人使用 CDK4/6 抑制剂后肿瘤缩小。这是立项当初没有预测到的附加治疗价值。礼来和诺华的同类药物预计在 2016-2017 年左右有望上市。CDK4/6 抑制剂除了乳腺癌至少还在 5 种其它肿瘤的临床实验中，其中黑色素瘤和肺癌已有一些积极的结果。

PD-0332991是口服，细胞周期蛋白依赖性激酶（CDK4选择性抑制剂4 / 6 / 6），细胞生长的一个关键调节器。临床前数据表明特异性PD-0332991的有效目标。PD-0332991显示肿瘤细胞在肝癌细胞株的生长有明显的抑制作用，以及动物和异种移植模型系统，并比目前批准的药物更有效，在这些系统中，索拉非尼。初步临床试验已经证明，并可接受的药物的毒性。因此，PD-0332991代表晚期肝癌患者的治疗的一个理想的候选人。
This trial is an open-label non-randomized single-institution study for subjects with inoperable, recurrent/refractory, advanced hepatocellular carcinoma (HCC). Subjects must have failed or be intolerant of standard first line therapy, sorafenib (Nexavar[表情]). Eligible subjects will receive 125 mg PD-0332991 capsules orally once daily, administered on days 1-21 of a 28-day cycle, in repeated cycles. The primary objective of the study is to assess the time to disease progression (TTP). Secondary objectives include assessment of safety and tolerability, and determination of overall survival (OS) and response rate (RR).
这项试验是一项开放标签的非随机的单一机构研究者不能手术，复发性/难治，晚期肝细胞癌（HCC）。受试者必须有失败或不能耐受标准的一线治疗药物，索拉非尼（多吉美[表情]）。合格的受试者将接受125 mg每日一次服用PD-0332991胶囊口服，1-21天一个28天的周期，反复循环。

Palbociclib辉瑞制药，国内有两家仿制，齐鲁的叫帕布昔利布，豪森的叫帕博西尼。

Palbociclib 澳门有成品药，约50000澳元。

橙子KARS突变 · 发表于 2016-1-3 16:47:19

Three hits to fight lung cancer

(PHILADELPHA) - Although the most common type of lung cancer - non-small cell lung cancer (NSCLC) - has recently seen major treatment advances in some genetic subtypes, other subtypes continue to evade effective treatment. (New therapies exist for NCCLC patients whose cancers harbor mutations in the ALK or EGFR genes, for example.) Now, a new study in mice has shown that cancers with KRAS-related gene mutations might benefit from a triple therapy with two experimental drugs plus radiation therapy. The results were published [TKTK date] in the journal Clinical Cancer Research.

"Currently there is a clinical trial underway to evaluate the combination of two cancer drugs, trametinib and palbociclib, made by two pharma companies for patients with solid tumors and melanoma," (clinical trial number, NCT02065063) says Bo Lu, M.D., Ph.D., Professor of Radiation Oncology at Thomas Jefferson University. "Although further research in human subjects is needed to confirm the finding, our study suggests that we may be able to identify non-small cell lung cancer patients who are likely to benefit most from this combination of therapies."

Roughly 85 percent of all lung cancers belong to the NSCLC type. Although there have been some advances in treating this disease, only two percent of survivors live five years beyond treatment. Drugs have been developed to target the ALK- and EGFR-mutated subtypes, and are to some degree effective, however, one genetic subset, NSCLCs with mutations in the gene KRAS have been resistant to conventional and targeted therapies.

Here Dr. Lu and colleagues investigated the KRAS-mutant subset in NSCLC cells and found that there was variation within this subset; some were more resistant to a drug that targeted the KRAS gene pathway than others. An additional mutation in a protein called p16 appeared to be responsible for this difference. After scanning a database of lung-cancer patient genotypes, the researchers saw that patients with the p16 mutation had a lower overall survival rate than those without the mutation.

In order to help make these resistant KRAS mutants more susceptible to therapy, the researchers combined the KRAS-targeting drug with another drug that would undo the effects of the p16 mutation. Together, Dr. Lu's group showed, the combination of the two drugs make these resistant cancer cells susceptible to radiation treatment. "If you hit one target another can take over. If you hit two, it becomes a lethal bullet," says Dr. Lu.

Currently, neither of two drugs that target KRAS and proteins in the p16 pathway are approved for use in lung cancer. However, Dr. Lu hopes that this research will help identify the patients who could potentially benefit from a triple-therapy treatment.

费城的吕波医生给KRAS 肺癌推荐 trametinib and palbociclib + 放疗. 当然他是放疗医生, 没法不推荐放疗.

http://www.eurekalert.org/pub_releases/2016-01/tju-tht122215.php