讨论肺腺癌相关靶点，对应药物及新药临床进展(新增PF-299804））

KRAS确实没有有效的药啊！谢谢您的信息。

来自2011ASCO：


However, in my mind there was one presentation that stood out above the others in terms of real hope for a particularly frustrating subset of lung cancer patients, namely those with EGFR activating mutations that develop resistance to Iressa (gefitinib) or Tarceva (erlotinib). The presentation was the initial results of a phase II trial combining afatinib (Tomtovok; BIBW 2992) with the anti-EGFR antibody cetuximab in TKI-resistant NSCLC patients.

This is a very frustrating group to treat. They tend to be younger, and most have never smoked or for only a short while, and they tend to respond wonderfully to TKIs like Tarceva. However, most patients will eventually go on to progress despite the TKI, and the reasons behind this progression have been a very active area of research. We know that about 50% of them, for example, will develop a second EGFR mutation in exon 20 called the T790M mutation.

There have been a number of strategies tested to overcome this resistance. The two major strategies have been to use a better TKI, such as the irreversible inhibitors BIBW 2992 and HKI 272, or to add a second drug to the TKI that inhibits a parallel pathway. One example of this strategy is the trial testing the addition of a MET inhibitor (ARQ 197) to Tarceva, which is now open all over the globe.

However, to date none of these strategies have proven to be particularly effective. One disappointing example was the LUX LUNG 1 study, which randomized patients who had failed chemotherapy and then progressed after benefit from a first-generation TKI (enriching the group for EGFR mutant cancers) to either afatinib or placebo. The goal of this study was to test if the irreversible TKI (afatinib) could overcome resistance by itself.  Unfortunately, this trial failed to show a survival benefit from afatinib over placebo as a single agent.  There were also only 7.4% of TKI-resistant patients who responded to afatinib.

So why not jump one step and try the strategy of combining afatinib with another agent in TKI resistant patients? Knowing the LUX LUNG 1 results, I would not have been very excited by this strategy. And now knowing the results of the phase I/II trial by Dr. Janjigian testing the combination of cetuximab and Tarceva in TKI-resistant patients, I would be even less enthusiastic. This trial, recently published in online form showed no hint of efficacy (zero of 13 patients responded to the combination).

So it is not surprising that this presentation was stuck in the poster discussion session at ASCO rather than in the more prestigious oral presentations. I spoke to one of the scientific program organizers who told me that this abstract had no results available yet at the time of submission, so it was lucky to make it in at all!

Enough build-up: how about the results, you ask? OK fine, you win. In another study by Dr. Janjigian, 26 patients with NSCLC with acquired resistance to TKIs were originally enrolled and treated with afatinib and escalating doses of cetuximab. At the maximum tolerated dose they began to enroll an additional 80 patients, and this poster described the first 45 pts on the trial. All of the patients but two had mutation status tested, and almost all of them had EGFR mutations. Over half had T790M mutations, as would be expected. The schema is pasted below.



开始剂量，BIBW每天40mg， 爱必妥250mg/㎡；预先估计的最大剂量，BIBW每天40mg，爱必妥500mg/㎡

The confirmed overall response rate in the first 45 evaluable NSCLC patients was 40%, with the response rate in the T790M patients being 50% unconfirmed (unconfirmed means they had not yet done a second set of scans to see if the tumor was still responding over 2 time points). The waterfall plot for all the 45 patients is below, with the red bars representing the T790M patients.



上图红色代表 T790M 有突变者，确定反应率为40%，临床收益率为90%

This is the first time anyone has described activity for any targeted drug in the T790M EGFR population, and this provides the first glimmer of hope for the many patients out there who face the reality of knowing that their tumors are still dependent on EGFR mutations but for whom Tarceva simply doesn’t work anymore

Why does the combination work? Cetuximab binds to the outside of the EGFR protein while afatinib binds the inside, so perhaps it takes 2 to make a thing go right. Cetuximab binding tends to make the EGFR protein move from the outside of the cancer cell to the inside, which might interrupt signaling somehow. The truth is we don’t know why just yet, but this has to be considered one of the most promising trials in recent years.

1：特/易耐药后仅有7.4%的人群对BIBW有反应

2：爱必妥联合特罗凯治疗TKI耐药后的病人，反应率0%（完全无效）

3：爱必妥联合BIBW治疗 晚期非小细胞肺癌（80人入组，几乎全部带有EGFR突变，超过半数带有T790M 突变），45个可评估的患者中，确定有效率为40%，带有T790M 突变患者中，有50%效果还未确定（还未确定是指需要第二次CT来确定他们的肿瘤是否连续两次又缩小）。  

痛恨癌症 发表于 2011-6-13 09:39

                               
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来自2011ASCO：

1：特/易耐药后仅有7.4%的人群对BIBW有反应

这是不是说特，易耐药，也不用考虑用bibw2992了？不是针对特，易耐药而出的药么？

痛恨癌症 发表于 2011-6-13 09:39

                               
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来自2011ASCO：

对bibw的期待不是很乐观啊。有些失望。

瓶子 发表于 2011-6-13 11:29

                               
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1：特/易耐药后仅有7.4%的人群对BIBW有反应

这是不是说特，易耐药，也不用考虑用bibw2992了？不是针对 ...

Unfortunately, this trial failed to show a survival benefit from afatinib over placebo as a single agent.  There were also only 7.4% of TKI-resistant patients who responded to afatinib.

是这么说的 ，相比于安慰剂并没有明显优势。 只有7.4%的TKI耐药人群对阿法替尼有反应

哪里有得卖？

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting . The overall solid tumor Phase 2 safety and tolerability data refers to six deaths, including two ovarian cancer patients.

On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.

Ovarian Cancer Patient Population & Overall Response Rate


(Image Source: Exelixis, Inc.)
The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.

The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacy endpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).

Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.

Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.

The baseline patient tumor histologic characteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)

More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).

Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.

Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded.  At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.

“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”

Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease


Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union

(Image Source: Exelixis, Inc.)
Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).

In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.

Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.

A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.

“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”

General Safety & Tolerability Data

Safety data are available for the 70 patients in the Lead-In phase of the cabozantinib study. The most common CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), palmar-plantar erythrodysesthesia  syndrome (also referred as “hand-foot syndrome”)(7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all CTCAE grades, 0% CTCAE grade 3 or 4), venous thrombosis (6% all CTCAE grades, 4% CTCAE grade 3 or 4), and gastrointestinal perforation (6% all CTCAE grades, 0% CTCAE grade 3 or 4).

To access the cabozantinib clinical study data information, please visit www.exelixis.com/sites/default/f ... 1-XL184-Ovarian.pdf

Six Deaths Reported (Including Two Ovarian Cancer Patients)

If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer – Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.”  Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”

We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.

The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”

Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.

Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”

“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.

In a note to investors, Piper Jaffray analyst Edward Tenthoff said: ”The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”

Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.

Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial



XL184起始服用剂量：100mg

Molecular Profiling Defines New Potential Targets for Lung Cancer Treatment
Appropriate patient selection might influence cost of care, further study needed

The collaborative efforts of members of the Lung Cancer Mutation Consortium (LCMC) demonstrate that although lung cancer may be a disease with one name, genetically it is very heterogeneous. Preliminary results of a study conducted by the LCMC (Abstract CRA7506) are the initial reports of the occurrance of 10 driver mutations for lung adenocarcinoma in 1,000 patients.

Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, presented findings at yesterday’s Oral Abstract Session: Lung Cancer — Metastatic/Non-small Cell. In addition to quantifying the presence or absence of driver mutations, the information was used in real time either to select erlotinib for patients with EGFR mutations or to recommend an appropriate clinical trial of an agent targeting the specific mutation identified. "Understanding the biology of the tumor can lead to better, more effective treatment for the patient," Dr. Kris said.

Investigators tested tumors from patients with lung adenocarcinoma in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using standard multiplexed assays and FISH for EML4-ALK rearrangements and MET amplifications. All patients had stage IIIB/IV lung cancer and a performance status of 0 to 2.

"Understanding the biology of the tumor can lead to better, more effective treatment for the patient."  
— Mark G. Kris, MD


In this group of 516, a single driver mutation was detected in 54% (280) of tumors. The most common mutations found were KRAS (114, 22%), EGFR (89, 17%), and EML4-ALK rearrangements (38, 7%). Other mutations found included BRAF (9), PIK3CA (6), MET amplifications (3), HER2 (3), MEK1 (2), NRAS (2); no AKT1 mutations were found. Ninety-seven percent of mutations were mutually exclusive.

The network of 14 participating institutions was established quickly, and the ability to test for these mutations consistently around the United States is a benefit that will outlive the grant.

"Our goal was to develop testing capability at every site," Dr. Kris said. He noted that seven of the 14 sites developed this capability specifically for the trial, and that this testing will continue. "This is the only time that every test for every mutation on every sample was done.”

In his discussion, Ramaswamy Govindan, MD, of the Alvin J. Siteman Cancer Center and Washington University School of Medicine, noted that knowledge in the area of cancer genetics is growing rapidly, as is the number of targeted therapies. An appropriate match between the two is critical, and the work of the LCMC is an important step.

"If you give targeted drugs to targeted patients, they do quite well," he said.

The link between patients with mutations and appropriate trials is an important component, as is the development of trials testing targeted agents. Only 8% of non-small cell lung cancer studies are currently biomarker driven.

The cost of cancer care might be contained if targeted agents are used only for patients who are appropriate candidates. A French study of EGFR testing for patients prior to treatment with gefitinib showed a cost savings, even with the cost of testing factored in. More studies of new potential targets and personalized adjuvant therapy also are needed, Dr. Govindan concluded.


肺癌中可探查到的基因突变（54%）：


KRAS (114, 22%)
EGFR (89, 17%)
EML4-ALK rearrangements (38, 7%).
BRAF (9), PIK3CA (6), MET amplifications (3), HER2 (3), MEK1 (2), NRAS (2);

也就是说还有46%肺癌患者是检测不到明确基因突变的。。

　在2011年美国临床肿瘤学会（ASCO）年会上，无论是医学科学还是癌症教育的报告，均贯穿了今年的会议主题——“患者，路径，进展”（Patients, Pathways, Progress）。在包括肺癌在内的各类肿瘤研究领域，基于分子标志物的转化性研究和临床研究均取得了重大进展。表皮生长因子受体（EGFR）基因突变及间变性淋巴瘤激酶（ALK）基因融合变异与相应靶向抑制剂的关系均已得到临床研究的证实，而针对肺癌中MET等分子靶点的治疗研究也取得了初步进展。其他相关分子变异的鉴定和药物研发的速度越来越快，肺癌的临床诊治模式也将发生较快的改变。

　　会上，ASCO主席斯莱奇（Sledge）及美国国立癌症研究所（NCI）主任瓦默斯（Varmus）都指出：“基于遗传变异的肿瘤治疗时代已经到来。” 并且，他们均表示未来要加强分子标志物的研究，加深对肿瘤发生发展分子机制的理解，从而促进肿瘤驱动分子突变（driver mutation）的鉴定及相关药物的研发。Varmus表示，尽管NCI 2011年的预算缩减，但NCI仍然愿意将有限资金用于全基因组测序等研究计划，以便从临床样本中发现新的靶点用于药物临床试验从而寻找可能的治疗策略。下面，本文就2011年ASCO会议上肺癌相关的转化性研究进展作一报道。

　　ALK分子突变型肺癌治疗：疗效显著，仍需进一步探索

　　在今年ASCO年会上，坎布里奇（Cambridge）对肺癌中ALK小分子抑制剂crizotinib的Ⅰ期临床试验（NCT00585195或A808-1001）结果进行了更新。

　　目前该研究入组的非小细胞肺癌（NSCLC）患者例数已达119例，中位无进展生存（PFS）期达到10个月，客观反应率达61%，中位反应时间为48周，而中位生存时间达1年的患者比例为81%。该研究的数据仍在不断更新中。

　　综合去年、前年ASCO年会上的报告不难看出，ALK抑制剂在ALK融合型肺癌中一直保持着良好的疗效。患者耐受性较佳，主要不良反应为视觉障碍等。疾病进展（PD）主要表现为脑转移和肺部靶病灶进展。目前，该领域的相关后续Ⅲ期临床研究（二线、三线、一线）也正在进行中。

　　不过，有关crizotinib的这项研究也同样给我们提示了一些值得关注的问题。首先，已有专家提出，对不同的ALK融合变异体，crizotinib的疗效也可能不同。如果这在未来研究中得到证实的话，那么基于荧光原位杂交（FISH）检测技术的ALK融合检测分析将必须要经过逆转录聚合酶链式反应（RT-PCR）和（或）测序技术分析，以明确变异体的类型，这无疑还须开展进一步研究以确立相关临床检测适用技术。

　　其次，患者接受ALK抑制剂治疗后出现耐药的机制是什么？目前已知的可能机制包括ALK酪氨酸激酶（TKI）区L1196M、C1156Y的二次位点突变及潜在的F1174L突变，而其他的耐药机制类型仍需进一步展开鉴定和研究。

　　此外，耐药后的处理对策又将如何？目前已知热休克蛋白（HSP）90是ALK等多种激酶受体或胞内激酶蛋白的辅助分子，HSP90抑制剂（IPI-504）已初步显示出对ALK抑制剂耐药的肺癌患者具有一定的疗效。

　　目前，其他较crizotinib具更强结合力的ALK抑制剂也正在研发过程中，有望为将来肺癌的治疗提供更多的选择。而在各国学者的努力下，围绕ALK融合型肺癌亚型的鉴定，靶向患者检测技术的建立，ALK抑制剂的研发、相关耐药机制和耐药后治疗策略等一系列科学问题正得到快速的确立、发现和研究。可见，有关ALK的一系列科学进展速度之快令人称赞，这些探索都将为最终真正根治这种分子亚型的肿瘤提供各种条件。