( 肺癌 ) 肺癌療法獲得重大突破個性治療成為可能

13-04-2014

對於在過去十年裡最常見的肺癌——非小細胞癌（NSCLC）來說，其化療已經有三種可用的生物藥品和至少十多種已掌握的化合物，這些方法在未來幾年普及到各個醫院。本週發佈在《新英格蘭醫學雜誌（NEJM）》上的一項新研究刊登了這些藥物的首發成果。

治療的革命已經初顯成效，至少兩個目標突變的發現，讓表皮生長因子受體（EGFR）和間變性淋巴瘤激酶（ALK）患者的個性治療成為可能。現如今，任何肺部腫瘤的分析都是為了瞭解這兩種基因病症的狀態，以確定哪些對患者是最合適的治療方法。

對於間變性淋巴瘤激酶（ALK），用克唑替尼（crizotinib）進行治療（幾個月前才被西班牙藥監局批准）是目前化療後的常用選擇。儘管藥物的反應良好，但是患者在使用其七個月之後都開始有了抗藥性，藥物對他們慢慢地失去了作用。

發表在《新英格蘭醫學雜誌》第一期的研究，將ceritinib推向了大眾，這是一種可應對間變性淋巴瘤激酶（ALK）的新型藥物，它似乎對於不論有沒有接受過克唑替尼（crizotinib）治療的患者都有效果。“此藥品的反響非常好。有一個有效的藥物來應對克唑替尼出現的抗藥性問題是非常重要的，因為到現在為止我們並沒有別的選擇。”巴塞羅那瓦爾德希伯倫醫院的腫瘤學家金內布拉·恩裡克塔·菲利普對《世界報》解釋說。

具體來說，巴塞羅那瓦爾德希伯倫醫院為了支持這項工作，由23名患者共組成了130例樣本。在x光片中顯示，有60％的病例其情況已得到了明顯控制，腫瘤復發的時間已經延長至7個月。

近日菲利普博士參加了歐洲肺癌大會，他強調稱這項研究的另一個重要發現，是使用ceritinib後患者的陽性反應十分類似於那些最初使用過克唑替尼crizotinib的患者反應。雖然研究確認該藥物對胃腸具有一定的副作用，菲利普博士表示，這些副作用也可能由腫瘤學家輕鬆操控。（“比如說控制夜間的藥物或減少劑量。”）

非小細胞肺癌占世界上所有確診肺癌的80％以上，而這個類別中大約有5 ％的患者為間變性淋巴瘤激酶ALK陽性（通常為不吸煙者）。大多數情況下這種病症會被院方診斷為不適宜手術，這就使得化療通常會成為第一期治療方法。對於ALK陽性的腫瘤患者，若病情進一步發展，那麼目前改採取的第二期治療方法則是使用克唑替尼crizotinib（雖然已經有一些研究試圖將此方法與第一期的化療進行比較）。

我們現在必須確定的工作是，什麼才是理想的治療順序？什麼時候應該使用新藥——ceritinib：一定要等待患者的crizotinib療法取得進展？還是治療的一開始就可以使用ceritinib？

對抗此類肺癌，ceretinib不是唯一等着臨床使用的藥物。菲利普博士在歐洲肺癌大會上剛剛提出了幾個由其他免疫治療研究的結果。研究中的主角是PD1和PDL1，這兩個分子能使腫瘤細胞從免疫系統的行動中逃脫。

目前為止，數據顯示antiPD1和antiPDL1化合物已被證明是有效果的，特別是在黑色素瘤中效果顯著。儘管如此，但巴黎古斯塔夫•魯西研究（法國）的簡·查爾斯·索里亞的研究數據同時顯示，肺部腫瘤也會從免疫治療中獲益。（實習編譯：石劍）

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Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer

Alice T. Shaw, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., Ranee Mehra, M.D., Daniel S.W. Tan, M.B., B.S., Enriqueta Felip, M.D., Ph.D., Laura Q.M. Chow, M.D., D. Ross Camidge, M.D., Ph.D., Johan Vansteenkiste, M.D., Ph.D., Sunil Sharma, M.D., Tommaso De Pas, M.D., Gregory J. Riely, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Juergen Wolf, M.D., Ph.D., Michael Thomas, M.D., Martin Schuler, M.D., Geoffrey Liu, M.D., Armando Santoro, M.D., Yvonne Y. Lau, Ph.D., Meredith Goldwasser, Sc.D., Anthony L. Boral, M.D., Ph.D., and Jeffrey A. Engelman, M.D., Ph.D.

N Engl J Med 2014; 370:1189-1197March 27, 2014DOI: 10.1056/NEJMoa1311107

BACKGROUND

Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.

METHODS

In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.

RESULTS

A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).

CONCLUSIONS

Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.)

Supported by Novartis Pharmaceuticals, by a grant from the National Cancer Institute (5R01CA164273, to Drs. Shaw and Engelman), by a V Foundation Translational Research Grant (to Drs. Shaw and Engelman), by Be a Piece of the Solution, and by the Evan Spirito Memorial Foundation.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the participating patients, their families, research coordinators, and nurses; and Matthew Naylor (Articulate Science) for providing editorial assistance with an earlier version of the manuscript.

SOURCE INFORMATION

From Massachusetts General Hospital, Boston (A.T.S., J.A.E.); Seoul National University Hospital, Seoul, South Korea (D.-W.K.); Fox Chase Cancer Center, Philadelphia (R.M.); National Cancer Center and Genome Institute of Singapore, Singapore (D.S.W.T.); Vall d'Hebron University, Barcelona (E.F.); University of Washington, Seattle (L.Q.M.C.); University of Colorado, Denver (D.R.C.); University Hospital KU Leuven, Leuven, Belgium (J.V.); Huntsman Cancer Institute, Salt Lake City (S.S.); Istituto Europeo di Oncologia (T.D.P.) and Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas (A.S.) — both in Milan; Memorial Sloan-Kettering Cancer Center, New York (G.J.R.); Peter MacCallum Cancer Center, Melbourne, VIC, Australia (B.J.S.); Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg, German Center for Lung Research (M.T.), and German Cancer Consortium (M.S.), Heidelberg, and University Duisburg-Essen, Essen (M.S.) — all in Germany; Princess Margaret Cancer Center, Toronto (G.L.); and Novartis Institutes for BioMedical Research, Cambridge, MA (Y.Y.L., M.G., A.L.B.).

Address reprint requests to Dr. Shaw at the Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit St., Boston, MA 02114, or at[email protected].

www.nejm.org/doi/full/10.1056/NEJMoa1311107