ALK抑制劑：可能是肺癌的新治療

作者：Roxanne Nelson  
出處：WebMD醫學新聞

　　January 15, 2010 (科羅拉多) — 標靶治療，包括單株抗體與小分子抑制劑，改變了癌症的治療，現在，很快會新增一種治療方式— ALK抑制劑。
　　
　　最近在非小細胞肺癌(NSCLC)的研究中，提及間變性淋巴瘤激酶(ALK)基因的致癌性重組。而發表於「美國癌症研究協會與國際肺癌研究協會之肺癌分子起源聯合研討會：個人化預防與治療的前景」中的一篇第1期研究提出正面的結果指出，ALK代表NSCLC的分子治療新目標。
　　
　　PF02341066、輝瑞藥廠研發的一個口服ALK抑制劑，在ALK陽性病患顯示有效，迄今為止，有31個具有ALK基因重組的 NSCLC病患被納入研究，觀察到的反應率為65%。
　　
　　科羅拉多大學癌症研究James Dudley講座醫學教授Paul A. Bunn Jr.醫師表示，現在至少有12種可以容易辨識的致癌基因，可能有新的治療製劑可以對抗它們，ALK是一種致癌基因，而且，對肺癌而言，它不是因為突變造成，而是與另一個基因融合。
　　
　　這個染色體重組會打斷ALK基因且將它與另一個基因融合，導致造成致癌性的ALK融合基因，然後，這些基因會促進細胞增生與存活。
　　
　　未參與該研究的Bunn醫師表示，就我的觀點，根據這些資料，這個藥物應可被准許在全球使用，但是美國食品藥物管理局認為，資料還不夠而無法核准，所以現在正在美國開始一個隨機試驗，在該試驗中，將隨機讓病患接受此研發中的藥物或標準化療。
　　
　　Bunn醫師也指出，雖然PF02341066顯示可以比標準化療誘導更多反應，但是它不具治癒性，他推測，想必病患很快就會發生抗藥性。
　　
　　【正確的藥物用於適合的病患】
　　根據研究作者表示，ALK是一個「受體型酪胺酸激酶」，在發育中神經系統的分離區域正常表現，在10多年前，異生性大細胞淋巴瘤上首次描述染色體2的短臂上的致癌性ALK重組，之後，在其他惡性腫瘤也有發現，包括瀰漫性大B細胞淋巴瘤以及惡性組織球增多症，還有多種實質腫瘤也有，包括發炎性肌纖維母細胞瘤、食道鱗狀上皮細胞癌、神經母細胞瘤以及最近提出的NSCLC。
　　
　　第一作者、科羅拉多大學胸腔腫瘤計畫臨床主任D. Ross Camidge博士解釋，NSCLC上的ALK重組相對較罕見，在不特定的NSCLC病患中，ALK基因重組的發生頻率約為3%至5%。
　　
　　Camidge博士解釋，除了聚焦在特定的分子標靶，本研究代表藥物從實驗室轉到人類試驗的計畫轉變。
　　
　　他向Medscape Oncology表示，當正確的標靶製劑被適當地用於有該標靶的適當病患時，可以在首次用於人類的第1期試驗中即有效地檢測分子效果假設，這樣聚焦在可以從藥物獲得最大利益的病患，將可以大幅地縮短藥物獲得核准的時間。
　　
　　ALK基因重組幾乎都發生在腺瘤，各種族之間似乎沒有變異，Camidge博士表示，但是幾乎沒有在鱗狀細胞癌或其他類型肺癌發現過，此外，抽菸量少的戒菸者或未曾抽菸者，發生ALK基因重組的頻率顯著較高。
　　
　　【早期結果顯示有效】
　　Camidge醫師等人在2006年開始第1期試驗，該試驗原本聚焦在有cMET活化標記(人類癌症中最常見的基因改變型酪胺酸激酶)的腫瘤，不過，在劑量調升期時，發現在NSCLC也有ALK基因重組，當時，將證實有ALK基因重組腫瘤的肺癌病患開始被納入研究。
　　
　　Camidge博士解釋，迄今為止，31名有ALK基因重組、可評估的治療前NSCLC病患被納入研究，在這個世代中，19人有部份反應、1人有完整反應；病患維持治療的中位數為24週。
　　
　　他表示，還沒有到達無惡化存活的程度。
　　
　　根據PF02341066的效果，證實了在這類特定的NSCLC病患中，致癌性ALK重組的確是可治療的標靶，這使得PF02341066可以進行隨機的第3期試驗，而不需要另一個第2期研究。
　　
　　Bunn醫師表示，有其他藥廠也在研究ALK抑制劑，但是進度遠遠落後於此研究，這個特殊的藥物抑制了ALK以及MET，這也是首次發展出的藥物。
　　
　　【多數腺瘤的基因檢測】
　　Bunn醫師指出，這個研究顯示的是，只要有正確的環境設定，研究可以更迅速，肺癌的融合基因在2007年被首次報告，2009年時，對於病患的幫助就被提出，有時候，癌症研究被批評為進展過於緩慢，但是，這是一個可以在兩年後就讓實驗室中的發現對病患產生幫助的例證。
　　
　　田納西州Vanderbilt-Ingram癌症研究中心肺癌精進研究專案計畫主任、Harold L. Moses講座David Carbone醫師強調，基因檢測的重要性與日俱增，就更廣的方面看來，藉由對這些抑制劑的瞭解，我們認為，多數肺腺癌病患應進行例行性基因檢測的重要性日益清晰。
　　
　　未參與該研究的Carbone醫師表示，這是相當重要的觀點；這些病患都無法用臨床參數確認，而是需藉由檢視某種突變來辨識病患，這類藥物在將來也會越來越多。
　　
　　美國癌症研究協會與國際肺癌研究協會(AACR-IASLC)之肺癌分子起源聯合研討會：個人化預防與治療的前景：摘要A24。發表於2010年1月13日。


ALK Inhibitors: Possible New Treatment for Lung Cancer

By Roxanne Nelson
Medscape Medical News

January 15, 2010 (Coronado, California) —Targeted therapies, which include monoclonal antibodies and small-molecule inhibitors, are altering the treatment of cancer. A new therapy — ALK inhibitors — might soon be added to the list.

Oncogenic rearrangements of the anaplastic lymphoma kinase (ALK) gene have recently been described in nonsmall-cell lung cancer (NSCLC). Promising results from a phase?1 study, presented here at the American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.

PF02341066, an oral ALK inhibitor being developed by Pfizer, has demonstrated efficacy in ALK-positive patients. Thus far, 31 NSCLC patients with the ALK rearrangement have been enrolled in the study, and a response has been observed in 65% of this cohort.

"There are at least 12 easily identifiable oncogenes now for which there are new therapeutic agents," said Paul A. Bunn Jr., MD, professor of medicine and James Dudley chair in cancer research at the University of Colorado, Denver. "ALK is an oncogene and, in lung cancer, is activated not by mutation but by fusion with another gene."

The chromosomal rearrangements that interrupt the ALK gene and fuse it with another gene result in the creation of oncogenic ALK fusion genes. In turn, these enhance cell proliferation and survival.

This drug should be approved for use worldwide, based on these data.

"In my opinion, this drug should be approved for use worldwide, based on these data," said Dr. Bunn, who was not involved in the study. "But the [US Food and Drug Administration] has deemed that there are not enough data to approve it, so there is now a randomized trial — just starting in the United States — in which patients will be randomized to either the experimental agent or standard chemotherapy."

Dr. Bunn also noted that although PF02341066 appears to induce more responses than standard chemotherapy, it is not curative. Presumably, he surmised, patients will become resistant to it sooner or later.

Right Drug to the Right Patient

ALK is a receptor tyrosine kinase, which is normally expressed in discrete regions of the developing nervous system, and oncogenic rearrangements of ALK on the short arm of chromosome?2 were first described in anaplastic large-cell lymphomas more than 10 years ago, according to the study authors. Subsequently, they have been observed in other malignancies, including diffuse large B-cell lymphomas and malignant histiocytosis, and in several solid tumors, including inflammatory myofibroblastic tumors, squamous cell carcinomas of the esophagus, neuroblastoma and, most recently, in NSCLC.

ALK rearrangements in NSCLC are relatively rare, explained lead author D. Ross Camidge, MD, PhD, clinical director of the Thoracic Oncology Program at the University of Colorado, Denver. In an unselected NSCLC population, ALK gene rearrangements occur with a frequency of 3% to 5%.

Aside from the focus on a specific molecular target, Dr. Camidge explained, this study represents a paradigm shift in the way drugs are moved from the laboratory into human trials.

"When the right targeted agent is appropriately matched with the right target in the right patient, molecular efficacy hypotheses can now be tested effectively within first-in-human phase?1 studies," he told Medscape Oncology. "This can dramatically shorten the drug approval time by focusing on patients who may derive the most benefit from the drug."

ALK gene rearrangements occur almost exclusively in adenocarcinoma, and there doesn't seem to be any variation by ethnicity. But it is almost never seen in squamous cell or other types of lung cancer, said Dr. Camidge. In addition, light exsmokers or never-smokers appear to have significantly higher frequencies of ALK gene rearrangements.

Early Results Promising

Dr. Camidge and colleagues began the phase?1 trial in 2006, and the trial was originally focused on tumors with markers of cMET activation, one of the most common genetically altered tyrosine kinases in human cancers. However, during the dose-escalation phase, it was reported that ALK gene rearrangements also occur in NSCLC. At that time, lung cancer patients with proven ALK-gene-rearranged tumors were recruited into the study.

To date, 31 evaluable heavily pretreated NSCLC patients with ALK rearrangements have been recruited into the study, and they are continuing to enroll patients, explained Dr. Camidge. Within this cohort, there have been 19 partial responses and 1 complete response; patients remain on therapy for a median of 24 weeks.

"We have not yet reached progression-free survival," he said.

The effectiveness of PF02341066 validates oncogenic ALK rearrangements as a therapeutic target in this molecularly defined subset of NSCLC patients, and has allowed for the evaluation of PF02341066 in a randomized phase?3 setting without the need for a separate phase?2 study.

Other companies are working on ALK inhibitors, but they are further behind this one, said Dr. Bunn. "This particular drug inhibits both ALK and MET, and it was the first one developed."

Genetic Testing for Most Adenocarcinomas

Dr. Bunn pointed out that this study demonstrates that research can move quickly, given the right circumstances. "The fusion gene was first reported in lung cancer in 2007 and, in 2009, the benefit in patients was reported," he said. "Sometimes research in cancer is criticized for moving too slowly, but this is an example of something discovered in the laboratory that is benefiting patients 2 years later."

It is clear that most patients with adenocarcinomas of the lung should have genetic testing of their tumors.

David Carbone, MD, PhD, Harold L. Moses chair in cancer research and director of the Specialized Program of Research Excellence in Lung Cancer at Vanderbilt-Ingram Cancer, in Nashville, Tennessee, emphasized the increasing importance of genetic testing. "From a wider perspective, with the knowledge of these inhibitors, we think that it is clear that most patients with adenocarcinomas of the lung should have genetic testing of their tumors done on a routine basis," he said.

"This is an extremely important point; none of these patients can be identified by clinical parameters — it is the mutations that identify these patients, and more and more of these drugs are going to become available," said Dr. Carbone, who was not involved with this study.

American Association for Cancer Research-International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy: Abstract?A24. Presented January?13, 2009.