與pemetrexed加cisplatin的標準處方相比,afatinib使多數具有exon 19消失或exon 21 L858R突變這兩種常見之EGFR突變之一病患的無惡化存活率加倍;這兩種突變約佔所有EGFR突變的 90%。
  「LUX-Lung 3」這篇國際性afatinib研究結果發表於美國臨床腫瘤協會2012年會。
  追蹤期中位數8個月,研究者發現,與標準治療相比,afatinib延緩疾病惡化超過4個月(中位數11.1 vs. 6.9個月;風險比[HR]0.58;95%信心區間[CI],0.43-0.78;P= .0004)。308名具有exon 19消失或exon 21 L858R突變者中,使用afatinib者的無惡化存活更加明顯(13.6 vs 6.9個月;HR,0.47;95% CI,0.34- 0.65;P< .0001)。
  國立台灣大學的James Chih-Hsin Yang博士表示,LUX-Lung 3是最完整的EGFR突變陽性肺癌病患第3期試驗。他在發表前的記者會簡報時解釋,符合無惡化存活的初級終點。我們不只測量惡化時間,還測量腫瘤縮小情況。使用afatinib者,咳嗽和呼吸短促等症狀則是比較長時間之後才會惡化。
  Afatinib是一種選擇性口服生體可利用的不可逆ErbB屬EGFR (ErbB1)、HER2 (ErbB2)和ErbB4阻斷劑;可逆的酪胺酸激酶抑制劑可顯著改善EGFR突變陽性非小細胞肺癌病患的結果;Afatinib則是不同,因為不像可逆性EGFR酪胺酸激酶抑制劑,它是不可逆地阻斷整個ErbB屬受體。
  LUX-Lung 3是最大型的EGFR突變陽性肺癌前瞻試驗,這是首度比較afatinib和pemetrexed加cisplatin之效果與安全性的研究。
  LUX-Lung 1第2b/3期試驗的結果發表於歐洲腫瘤醫學協會2010年會。
  該研究中,afatinib之無惡化存活比安慰劑長(3.3 vs 1.1個月),此外,8週時,使用afatinib治療之病患的腫瘤縮減顯著優於安慰劑組(疾病控制率58% vs 19%;P< .0001)。
  檢測EGFR 突變之後,Yang博士等人將345名新接受化療的第IIIB/IV期PS 0 -1肺癌病患隨機分成兩組:230人接受afatinib 40 mg/天,115人接受靜脈注射 pemetrexed 500 mg/m2加 cisplatin 75 mg/m2,每21天1次,最多6個循環。
  這兩組在開始時的各項特徵都相似,年齡中位數為61歲;65%是女性、72%是亞洲人、68%未曾抽菸、49%有exon 19消失、40%有exon 21 L858R突變、11%有其他突變。
  Afatinib的客觀反應率也顯著高於標準治療(56% vs 23%;P< .0001),發生癌症相關咳嗽(HR,0.60;P= .0072)和呼吸困難(HR,0.68;P= .0145)惡化的時間也顯著較久。
  新聞簡報主持人、紐約大學Langone醫學中心醫學系助理教授Sylvia Adams醫師表示,這是篇重要研究,因為它顯示出在這組病患,與第一線化療相比,這項治療有助於無惡化存活與生活品質。另外,這篇研究令人興奮的是,代表了新一代的酪胺酸激酶抑制劑。

Afatinib Doubles Progression-Free Survival in Lung Cancer

By Roxanne Nelson
Medscape Medical News

June 4, 2012 — The investigational drug afatinib (Boehringer Ingelheim) appears to prolong progression-free survival in patients with advanced lung adenocarcinomas that harbor epidermal growth-factor receptor (EGFR) mutations.

Compared with a standard treatment regimen of pemetrexed plus cisplatin, afatinib doubled progression-free survival in most patients who harbored 1 of 2 common EGFR mutations — the exon 19 deletion or the exon 21 L858R mutation. These 2 mutations account for about 90% of all EGFR mutations.

The results of the international LUX-Lung 3 study of afatinib were presented here at the 2012 Annual Meeting of the American Society of Clinical OncologyR.

At a median follow-up of 8 months, the researchers found that afatinib delayed disease progression by more than 4 months, compared with standard therapy (median, 11.1 vs. 6.9 months; hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.43 to 0.78; P = .0004). In the 308 participants with the exon 19 deletion or the exon 21 L858R mutation, progression-free survival was even more pronounced with afatinib (13.6 vs 6.9 months; HR, 0.47; 95% CI, 0.34 to 0.65; P < .0001).

"LUX-Lung 3 is the most robust phase 3 trial in EGFR-mutation-positive lung cancer patients," said lead author James Chih-Hsin Yang, MD, PhD, from the National Taiwan University in Tainan.

The primary end point of progression-free survival was met, he explained during a press briefing held in advance of the presentation. "We not only measured progression time, we also measured tumor shrinkage," said Dr. Yang. "Symptoms such as cough and shortness of breath had a longer time to worsening with afatinib."

Afatinib is a selective, orally bioavailable, irreversible ErbB family blocker of EGFR (ErbB1), HER2 (ErbB2), and ErbB4. Reversible tyrosine kinase inhibitors have significantly improved outcomes for patients with EGFR-mutation-positive nonsmall-cell lung cancer, he said. "Afatinib is different because, unlike reversible EGFR tyrosine kinase inhibitors, it irreversibly blocks the entire ErbB family of receptors."

LUX-Lung 3 is the largest prospective trial of EGFR-mutation-positive lung cancer, and is the first study to compare the efficacy and safety of afatinib with pemetrexed plus cisplatin.

Results from the LUX-Lung 1 phase 2b/3 trial were presented at the 2010 annual meeting of the European Society for Medical Oncology.

In that study, progression-free survival was also longer with afatinib than with placebo (3.3 vs 1.1 months). In addition, at 8 weeks, tumor shrinkage was significantly higher in patients treated with afatinib than in those treated with placebo (disease control rate, 58% vs 19%; P < .0001).

Study Details of LUX-Lung 3

After central testing for EGFR mutations, Dr. Yang and colleagues randomized 345 chemotherapy-naive patients with stage IIIB/IV PS 0 to 1 lung cancer to 1 of 2 study groups; 230 patients received afatinib 40 mg daily, and 115 received intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 every 21 days for up to 6 cycles.

The baseline characteristics in the 2 study groups were similar. Median age in the cohort was 61 years; 65% of the cohort was female, 72% was Asian, 68% had never smoked, 49% had the exon 19 deletion, 40% had the exon 21 L858R mutation, and 11% had other mutations.

The objective response rate was also significantly higher with afatinib than with standard treatment (56% vs 23%; P < .0001). There was a significant delay in the time to deterioration of cancer-related symptoms of cough (HR, 0.60; P = .0072) and dyspnea (HR, 0.68; P = .0145).

Adverse events were as expected on the basis of previous anti-EGFR experience, Dr. Yang noted. "They were manageable and predictable."

The most common drug-related adverse events with afatinib were diarrhea (95%), rash (62%), and paronychia (57%); with standard therapy, the most common adverse events were nausea (66%), decreased appetite (53%), and vomiting (42%).

Overall survival data are expected in about 2 years, Dr. Yang noted.

"This study is important because it shows that in this setting, there is a clear benefit in progression-free survival and quality of life, compared with first-line chemotherapy," said news briefing moderator Sylvia Adams, MD, assistant professor in the Department of Medicine at Langone Medical Center, New York University, in New York City. "The other exciting part about this study is that this represents a new generation of tyrosine kinase inhibitors."

Several studies of afatinib, which is being investigated in other cancers, will be presented at the ASCO meeting. These include phase 3 trials of head and neck squamous cell carcinoma (abstract TPS5598), HER2-overexpressing metastatic breast cancer (abstract TPS649), and lung cancer (abstracts 7557 and 7558).

Dr. Yang reports serving as a consultant or advisor and receiving honoraria from Boehringer Ingelheim. Several of the coauthors report financial relationships with industry, as noted in the abstract

2012 Annual Meeting of the American Society of Clinical OncologyR: Abstract LBA7500. Presented June 4, 2012.

2015/4/15 上午 10:28:31
2012/6/20 下午 01:39:11
2012/4/25 下午 02:23:43

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