Lapatinib在肝癌中令人失望


September 14, 2009 — Lapatinib(商品名Tykerb)用於肝癌的第2期試驗結果令人失望,只有其中一小組病患有利,不過,在服藥期間還是發生紅疹。這些結果登載於9月15日的臨床癌症研究期刊。
  
  Lapatinib試驗用於肝細胞癌,是因為其作用之一是抑制上皮細胞生長因子接受體(EGFR),該受體在這個疾病中相當重要。不過,lapatinib也會抑制第2型EGFR(HER2/neu),這對乳癌來說是重要路徑,lapatinib目前獲核准用於已經使用capecitabine (商品名Xeloda)治療的乳癌病患。
  
  目前,肝癌的標準治療是sorafenib(商品名Nexavar),此藥物類似lapatinib,是酪胺酸激酶抑制劑,只不過是抑制不同的路徑,包括了Raf激酶(Raf kinase)、血小板衍生性生長因子、血管內皮生長因子、幹細胞因子的c-kit受體。
  
  【沒有客觀反應,只有一小組病患獲益】
  研究對象為26名惡化不適合手術的肝細胞腫瘤病患。病患每天口服lapatinib 1500 mg、治療28天。療程中位數是兩個療程(範圍1–14)。最常見的副作用是腹瀉(有73%的病患)、噁心(45%)、紅疹(42%),但是研究者指出,藥物耐受良好。
  
  無惡化存活的中位數是1.9個月,研究者稱之為「不令人感興趣的結果」。不過,他們指出,整體存活的中位數為12.6個月,是文獻報告中最高的。但是,他們指出,這有部份是因為其中40%的病患在疾病惡化之後使用sorafenib,而sorafenib已知對於肝細胞腫瘤有存活利益。
  
  沒有病患有客觀反應。不過,有一小組病患顯示一些藥物利益。10名病患(40%)有最佳反應的穩定疾病狀態,6人(23%)的疾病穩定狀態持續超過120天。
  
  發生皮膚紅疹的病患,存活期間比沒有發生紅疹者長一些,略高於統計上的顯著程度(16.2 vs 8.7個月,P= .07)。研究者指出,EGRF抑制劑在其他各種癌症中也有類似效應。
  
  第一作者、俄亥俄州立大學綜合癌症中心胃腸腫瘤內科主任Tanios Bekaii-Saab醫師在新聞稿中表示,我們的發現認為,EGFR抑制可能會有幫助。
  
  Bekaii-Saab醫師表示,整體來說,雖然我們相當希望lapatinib更有效,但結果有點令人失望。
  
  不過,根據臨床癌症研究期刊編輯委員Samuel Ho醫師表示,該研究提供了這些訊息路徑在肝癌中之關聯的重要發現。Ho醫師是VA San Diego健康體系胃腸科主任、加州大學聖地牙哥分校內科教授。
  
  Ho醫師在聲明中表示,這些結果支持肝細胞腫瘤在臨床和生化上有異質性的這個事實,有一些肝細胞腫瘤的反應和其他不同,建議對可能產生反應的病患進行更大型的試驗,以確認明確的存活利益。
  
  Ho醫師指出,該研究未能發現可以找出預測腫瘤之間有無反應的標記。不過,可能不會只有一個標記用於預測;多重標記比較合理,因為牽涉的是整個複雜的生物學。
  
  Bekaii-Saab醫師報告接受Genentech發言獎助金,同時也是Genentech的顧問。其他作者宣告沒有相關財務關係。
  
  

Lapatinib Disappoints in Liver Cancer

By Zosia Chustecka
Medscape Medical News

September 14, 2009 — Results from a phase?2 trial of lapatinib (Tykerb) in liver cancer were disappointing, with benefit seen only in a small subgroup of patients who developed a rash while taking the drug. The results are reported in the September 15 issue of Clinical Cancer Research.

Lapatinib was tested in hepatocellular cancer because one of its actions is to inhibit epidermal growth-factor receptor (EGFR), which is thought to be important in this disease. However, lapatinib also inhibits EGFR type?2 (HER2/neu), a pathway that is important in breast cancer, and lapatinib is currently approved for use in breast cancer patients who are being treated with capecitabine (Xeloda).

Currently, the standard treatment for liver cancer is sorafenib (Nexavar). This drug, like lapatinib, is an inhibitor of tyrosine kinase, but it inhibits a different set of pathways, including Raf kinase, platelet-derived growth factor, vascular endothelial growth factor, and the c-kit receptor for stem-cell factor.

No Objective Responses, But Benefit in Small Subgroup

The study tested lapatinib in 26 patients with advanced inoperable hepatocellular carcinoma. Patients received oral lapatinib 1500?mg each day for 28 days. A median of 2 cycles were administered (range, 1–14). The most common adverse effects were diarrhea (reported by 73% of patients), nausea (45%), and rash (42%), but the researchers report that the drug was well tolerated.

Median progression-free survival was 1.9?months, which the researchers describe as "uninteresting." However, the median overall survival was 12.6?months, which is "one of the highest reported in the literature," they note. But this may be partially explained by the use of sorafenib after disease progression in 40% of the patients, they add, noting that sorafenib has a known survival advantage in hepatocellular carcinoma.

No patient had an objective response. However, a small subgroup of patients showed some benefit from the drug. Ten patients (40%) had stable disease as their best response, and 6 (23%) had stable disease that lasted for more than 120 days.

Patients who developed a skin rash had a borderline statistically significant longer survival than patients who did not have a rash (16.2 vs 8.7?months, P?= .07). This effect has also been seen with EGRF inhibitors in a variety of other cancers, the researchers note.

"Our findings suggest a potential benefit from EGFR inhibition," said lead author Tanios Bekaii-Saab, MD, medical director of gastrointestinal oncology at the Ohio State University Comprehensive Cancer Center in Columbus, in a press release.

"Overall, though, we were certainly hopeful that lapatinib would be more active and were somewhat disappointed by the results," Dr. Bekaii-Saab said.

Nevertheless, the study provides important information about the relevance of these signaling pathways in liver cancer, according to Samuel Ho, MD, an editorial board member of Clinical Cancer Research. Dr. Ho is chief of gastroenterology at the VA San Diego Healthcare System, and professor of medicine at the University of California, San Diego.

"The results support the fact that hepatocellular carcinomas are clinically and biochemically heterogenous, and that certain subsets of hepatocellular carcinoma may respond differently than others, suggesting that larger trials with patients more likely to respond may show a definite survival benefit," Dr. Ho said in a statement.

"However, this study failed to find a marker that could differentiate between tumors that may or may not be expected to respond," Dr. Ho pointed out. But it is unlikely that 1 marker alone would be predictive; multiple markers would make "more sense," given the complexity of the biology involved, he added.

Dr. Bekaii-Saab reports receiving honoraria from the Genentech speakers bureau and is a consultant for Genentech. The other authors have disclosed no relevant financial relationships.

Clin Cancer Res. 2009;18:5895-5901.

    
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