本帖最後由 lsc0019 於 2009-4-16 00:32 編輯
作者：Zosia Chustecka
出處：WebMD醫學新聞
April 1, 2009 — Cetuximab(Erbitux，Bristol-Myers Squibb藥廠)加入化療，用於大腸直腸癌的大型第三期試驗結果發表，顯示只有KRAS 野生型腫瘤病患可以從標靶治療中獲益。
此試驗名稱為CRYSTAL(Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer)，發表於4月2日的新英格蘭醫學期刊。
該試驗包括了1,198名病患，由比利時Gasthuisberg大學醫院的Eric Van Cutsem博士統籌；結果顯示，將cetuximab加入irinotecan、fluorouracil加leucovorin (FOLFIRI)化療處方中，相較於單用FOLFIRI，減少了轉移大腸直腸癌風險。
不過，cetuximab的好處僅限於KRAS野生型腫瘤病患。研究者指出，KRAS突變的病患無法獲利。
本試驗的KRAS突變結果在去年的美國臨床腫瘤協會(ASCO)年會中發表，當時被ASCO形容為年終報告中的重大進展，由Medscape Oncology 報導。
【已經整合到臨床實務】
研究發現cetuximab僅對於KRAS野生型腫瘤大腸直腸癌病患有效，而KRAS突變者無效，這已經整合到臨床實務。許多其他試驗已經重現此發現，且擴展到類似的標靶製劑，如panitumumab(Vectibix，Amgen藥廠)，此藥也是上皮生長因素受體抑制劑。
國家癌症綜合網絡指引現在建議對大腸直腸癌進行KRAS突變檢測，且由ASCO的Provisional Clinical Opinion進行特別報導，線上發表於2月2日的臨床腫瘤期刊。
華盛頓喬治城大學、Lombardi綜合癌症中心的John Marshall醫師在他的Medscape Oncology專家部落格上提出看法。這進展相當迅速—從研究發現到臨床指引不到一年；但是之後，在大腸癌治療，KRAS 改變了諸多事務。
Marshall醫師表示，KRAS的發現將大腸癌分成兩種疾病。約有40%轉移性大腸癌病患之腫瘤是KRAS基因突變，這些病患對cetuximab或者panitumumab治療比較不可能有反應。
他表示，其他病患是正常的野生型KRAS基因，對這些藥物比較可能有反應。在某些病患中，將cetuximab或者panitumumab加入化療可以產生10%到15%的效果改善，不過不是所有病患都有反應。我們已經排除那些不可能有反應的病患。
Marshall醫師將這和乳癌的狀況相提並論，人類上皮生長因素受體第2型的發現，將乳癌病患分成對單株抗體trastuzumab(Herceptin，Genetech/Roche藥廠)有效或無效的兩類。
Merck (Darmstadt)支持本研究。Van Cutsem醫師報告接受Amgen、Merck (Darmstadt)、Pfizer、Roche以及Sanofi-Aventis藥廠的顧問或諮商費用；Amgen，Merck (Darmstadt)、Roche以及Sanofi-Aventis藥廠的演講費用；Merck (Darmstadt)與Roche的資金支持。許多其他共同作者報告相關的財務關係，兩名共同作者是Merck (Darmstadt)的員工，詳列於報告中。
N Engl J Med. 2009;360:1408-1417.
Cetuximab in Colorectal Cancer Works Only in Wild-Type KRAS Tumors; CRYSTAL Trial Published
By Zosia Chustecka
Medscape Medical News
April 1, 2009 —Results from a large phase?3 trial of cetuximab (Erbitux, Bristol-Myers Squibb) added to chemotherapy in colorectal cancer, which showed that only patients with KRAS wild-type tumors benefited from the targeted therapy, have now been published.
The trial, known as CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer), is reported in the April 2 issue of the New England Journal of Medicine.
The trial, involving 1198 patients, was headed by Eric Van Cutsem, MD, PhD, from University Hospital Gasthuisberg, in Leuven, Belgium. The results show that adding cetuximab to a chemotherapy regimen of irinotecan, fluorouracil, plus leucovorin (FOLFIRI) reduced the risk for progression of metastatic colorectal cancer, compared with FOLFIRI alone.
However, the benefit from cetuximab was limited to patients with KRAS wild-type tumors. Patients who had tumors with KRAS mutations did not benefit, the researchers noted.
The KRAS mutation results from this trial were presented last year at the annual meeting of American Society for Clinical Oncology (ASCO), and were highlighted by ASCO as a "major advance" in its year-end report, as previously reported by Medscape Oncology.
Already Incorporated Into Clinical Practice
The finding that cetuximab is effective in only colorectal cancer patients with tumors that express the wild-type KRAS, and not KRAS mutations, has already been incorporated in clinical practice. This finding was duplicated in several other trials, and extends to a similar targeted agent, panitumumab (Vectibix, Amgen), which also acts an inhibitor of epidermal growth-factor receptor.
Testing for KRAS mutations is now recommended in the National Cancer Comprehensive Network guidelines for colorectal cancer, and was featured in a Provisional Clinical Opinion from ASCO, published online February 2 in the Journal of Clinical Oncology.
This has been a very rapid uptake — from a research finding into clinical guidelines in little more than a year. But then, in the treatment of colon cancer, "KRAS changes everything," John Marshall, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, commented in his Medscape Oncology expert blog.
The KRAS discovery has effectively split colon cancer into 2 separate diseases, Dr. Marshall said. About 40% of patients with metastatic colon cancer have tumors with a mutated form of the KRAS gene, and these patients are unlikely to respond to treatment with cetuximab or panitumumab.
The other patients with the normal, or wild-type, KRAS genes are likely to respond to these drugs, he said. In some patients, the addition of cetuximab or panitumumab to chemotherapy can produce a 10% to 15% improvement in benefit, he noted, although not all patients respond. "But we have weeded out the patients who are not going to respond," he pointed out.
Dr. Marshall likened the situation to that in breast cancer, where the discovery of the human epidermal growth-factor receptor-2 divided patients into those who would and those who would not benefit from the monoclonal antibody trastuzumab (Herceptin, Genetech/Roche).
The study was supported by Merck (Darmstadt). Dr. Van Cutsem reports receiving consulting or advisory fees from Amgen, Merck (Darmstadt), Pfizer, Roche, and Sanofi-Aventis; lecture fees from Amgen, Merck (Darmstadt), Roche, and Sanofi-Aventis; and grant support from Merck (Darmstadt) and Roche. Several other coauthors report relevant financial relationships, and 2 coauthors are employees of Merck (Darmstadt), as detailed in the paper.
N Engl J Med. 2009;360:1408-1417. |
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