LUX-Lung 7: 第一代標靶gefitinib PK第二代標靶afatinib

標靶藥推陳出新 肺腺癌活久活好 發稿時間：2016/04/06 09:12最新更新（中央社記者陳清芳台北6日電）第一、二代肺腺癌標靶藥療效硬碰硬比較，經過一年半到兩年的試驗，最近分出高下。醫學專家認為，肺腺癌將會愈來像慢性病，活過5年很常見。這是首次出現第一代標靶藥(gefitinib)對決第二代標靶藥(afatinib)的2B期試驗，表皮生長因子受體( EGFR)突變基因型為del 19或L858R 的晚期肺腺癌患者319人，有超過半數來自亞洲。日前披露結果，第二代標靶藥能顯著降低27%的癌症疾病惡化及治療失敗。主持這項LUX-Lung 7試驗的韓國成均館大學醫學院教授朴根七說，第一代標靶藥並非弱者，這也是為何試驗進入第18、24個月，第二代標靶藥才拉開領先距離。至於病人存活率的差異，預計在今年底的歐洲腫瘤醫學會(ESMO)上公布。朴七根說，如果從療效反應率來看，第二代標靶藥更顯著，且治療失敗率較低；更值得一提的是，副作用發生率相差無幾，而且都能處理或防範，幾乎沒有病人會因為副作用而打退堂鼓。那麼醫師該怎麼幫病人選擇用哪一種藥呢？中國廣州中山大學腫瘤防治中心主任醫師張力強調，當然先要檢驗病人的EGFR突變基因型，確保對因下藥，病患持續治療，多半能活上5年或更長，如果標靶藥物都有療效，耐受性良好，「剩下的就是錢的問題」。在台灣，第一、二代的肺腺癌標靶藥共有3種上市，健保給付都列為第一線用藥，晚期病人不必忍受化、放療副作用折磨及治療失敗。許多醫院都能找到第一種標靶用到沒效，改吃第二種、第三種，活到現在5到10年或更久的阿公阿嬤。台北慈濟醫院胸腔內科肺癌治療團隊召集人黃俊耀就說，健保的癌症重大傷病卡效期5年，他的肺腺癌病患有的已換發第2張重大傷病卡，肺腺癌之於他們就是像「多了一種慢性病」。有的甚至被拒絕續發重大傷病卡，黃俊耀安慰說「這代表你的癌症已經痊癒」，還有患者死於中風或心肌梗塞，而非癌症 。「有些癌友的生活過得比我還好」，黃俊耀指出，固定出國賞櫻、賞楓的癌友，他提醒按時吃止瀉藥、穿的抹的防曬莫疏忽，控制標靶藥帶來的腹瀉、皮疹等副作用；到目前為止，還沒有病患死於標靶藥造成的間質性肺炎等嚴重副作用。他說，在台灣，肺癌名列十大癌症死因的頭號殺手，每年約1萬個新增肺癌病患，其中8成屬於肺腺癌，國家衛生研究院曾研究，5到6成的肺腺癌患者帶有EGFR基因變異；雖然如此，高危險群的篩檢，推陳出新的標靶藥，以及後起之秀的免疫製劑，扭轉了肺癌絕症的面貌。

Erlotinib Bests Gefitinib in Phase III NSCLC Study, Published Online: Tuesday, March 29, 2016  Treatment with gefitinib (Iressa) failed to show noninferiority compared with erlotinib (Tarceva) for patients with pretreated non–small cell lung cancer (NSCLC), according to findings from a phase III study that were published in the Journal of Clinical Oncology. In patients with EGFR-mutant advanced lung adenocarcinoma (n = 401), the median progression-free survival (PFS) with gefitinib was 8.3 versus 10.0 months with erlotinib (HR, 1.093; 95% CI, 0.879-1.358; P = .424). Grade 3 rash was more common with erlotinib versus gefitinib (18.1% vs 2.2%) and liver enzymes were more frequently elevated with gefitinib versus erlotinib."This was the first phase III study to compare erlotinib with gefitinib in NSCLC," said David Spigel, MD, director, Lung Cancer Research Program, Sarah Cannon Research Institute, who was not involved in the trial. "The aim of the study, PFS, was not met; however, there were issues with the methods of the study. The PFS plots were similar." In the study, which was conducted exclusively in Japan, 553 patients received treatment with gefitinib (n = 277) or erlotinib (n = 276). Gefitinib was administered at 250 mg per day and erlotinib was given at 150 mg per day. The median age of patients was 67 years and the majority had stage IV disease (69.2%). Predefined testing for EGFR revealed a mutation in 66.4% of participants. However, a secondary post-hoc assessment of EGFR revealed that 71.7% of tumors were positive for L858R mutations, exon 19 deletions, double mutations, or uncommon EGFR alterations. Baseline characteristics were well balanced between the two arms, except for performance status (PS). Overall, the PS was higher in the gefitinib arm compared with erlotinib (P = .028). In the erlotinib and gefitinib arms, respectively, the PS was 0 (50% vs 40.1%), 1 (42.5% vs 53.8%), and 2 (7.5% vs 6.1%). The primary endpoint of the study was noninferiority in PFS by investigator assessment. The secondary endpoints focused on overall survival (OS), overall response rate (ORR), disease control rate (DCR), safety, and time to treatment failure (TTF). In those with EGFR alterations, median OS was 26.5 months with gefitinib versus 31.4 months with erlotinib (HR, 1.189; 95% CI, 0.900-1.570; P = .221). The ORR was 58.9% versus 55% and the DCR was 81.7% versus 84.4% for gefitinib and erlotinib, respectively. In patients with exon 19 deletions, the median PFS was 11.1 versus 11.5 months for gefitinib and erlotinib, respectively (HR, 1.120; 95% CI, 0.813-1.544; P = .487). In the L858R mutation group, the median PFS with gefitinib was 8.1 versus 8.5 months with erlotinib (HR, 0.938; 95% CI, 0.675-1.304; P = .704). In those with uncommon EGFR mutations, median PFS was 6.4 months with gefitinib versus 5.3 months with erlotinib (HR, 1.109; 95% CI, 0.464-2.653; P = .815). Across the full study, including those without EGFR mutations, the median PFS was 6.5 months with gefitinib versus 7.5 months with erlotinib (adjusted HR, 1.125; 95% CI, 0.940-1.347). Median OS was 22.8 months with gefitinib versus 24.5 months with erlotinib (HR, 1.038; 95% CI, 0.833-1.294). The TTF was 5.6 versus 5.3 months, in the gefitinib and erlotinib arms, respectively (HR, 1.032; 95% CI, 0.866-1.231). The ORRs were 45.9% versus 44.1% and the DCRs were 70.9% versus 75.3%, for gefitinib and erlotinib, respectively. Overall, toxicity was lower in the gefitinib arm compared with erlotinib (P <.001). Grade 3/4 aspartate aminotransferase increases occurred in 6.1% of patients treated with gefitinib versus 2.2% of those in the erlotinib arm. Grade 3/4 alanine aminotransferase increases were seen in 13% of those in the gefitinib arm versus 3.3% in the erlotinib group. These data add to a phase IIb analysis that compared afatinib (Gilotrif) with gefitinib for patients with untreated EGFR-mutant NSCLC, according to Gregory J. Riely, MD, PhD. In this study, which was labeled LUX-Lung 7, 319 patients were randomized to receive afatinib at 40 mg per day (n = 160) or gefitinib at 250 mg per day (n = 159). Median PFS was 11.0 versus 10.9 months, for afatinib and gefitinib, respectively (HR, 0.73; 95% CI, 0.57-0.95; P = .0165). The 18-month PFS rates were 27% versus 15%, for afatinib and gefitinib, respectively. At 24 months, 18% of those in the afatinib arm remained alive and progression-free compared with 8% in the gefitinib group. After a median follow-up of 27.3 months, median overall survival data were not yet mature. TTF was 13.7 months with afatinib versus 11.5 months with gefitinib (HR, 0.73; 95% CI, 0.58-0.92; P = .0073). The ORR was 70% compared with 56% for afatinib and gefitinib, respectively (P = .0083). "The results of recent randomized studies comparing EGFR tyrosine kinase inhibitors helps inform a decision that we have largely had to make without data," said Riely, vice chair, Clinical Trials Office, Department of Medicine, Memorial Sloan Kettering Cancer Center, who was not involved in the trial. "Unfortunately, these studies have been imperfect, sometimes enrolling patients without EGFR mutations or being too small. They are provocative, but I don't think they are really going to change many people's practice." Urata Y, Katakami N, Morita S, at al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L [published online March 28, 2016]. J Clin Oncol. doi: 10.1200/JCO.2015.63.4154