第三代標靶藥 晚期肺腺癌抗藥性治療有救 iCare愛健康–Apr 18,2016今歐洲肺癌年會發表最新研究指出，晚期肺腺癌抗藥性不再無藥可醫，透過抽血驗癌DNA可更精準選對標靶藥。出席瑞士日內瓦歐洲肺癌年會的中山醫學大學附設醫院副院長陳志毅說，國外研究發現，使用第三代肺腺癌TKI標靶藥物，做為晚期非小細胞肺腺癌第一線治療使用，不僅有將近八成的患者腫瘤獲得控制，疾病無惡化存活期將近二十個月，存活期較其他一線標靶藥物增加將近1倍，如果後續再接上使用其他標靶藥物，推測有可能存活期更長，如果後續的三期大型臨床試驗證實此推測，很有可能會改寫EGFR基因突變的非小細胞肺腺癌標臨床治療標準。此外，陳志毅表示，對於晚期非小細胞肺腺癌患者，針對EGFR和ALK基因突變的標靶治療是目前標準的治療方案，不過，臨床約有九成患者，使用EGFR標靶藥物治療11個月後產生抗藥性，常導致治療失敗。因此，另一項全球大型研究(AURA)也發現，若將第三代肺腺癌TKI標靶藥物拿來治療出現抗藥性的晚期非小細胞肺腺癌，有將近七成的患者腫瘤縮小，疾病無惡化存活期也延長至11月。陳志毅說，第三代肺腺癌TKI標靶藥物適用於T790M基因突變的晚期肺腺癌抗藥性患者，病患只要檢測基因，72小時就可以知道體內基因是否突變，一旦確認基因產生突變，就適合用新標靶藥爭取生機。陳志毅強調，該研究對患者與醫師而言，不止原位腫瘤或轉移到其他器官的腫瘤獲得良好的控制，原本因腫瘤細胞出現抗藥而惡化的症狀，包含咳喘、胸痛、胸水的情況也一併獲得控制，不僅延長存活期，更保有優良的生活品質，而第三代肺腺癌TKI標靶藥物去年已經在美國，歐盟以及日本，以加速批准的方式迅速獲准上市，成為晚期非小細胞肺腺癌患者出現抗藥性無藥可醫時的新延命希望。
AstraZeneca Presents Positive Tagrisso (osimertinib) Follow-up Data in Lung Cancer at ELCC 2016 Phase I first-line Tagrisso data show an objective response rate of 77%, and progression-free survival of 19.3 months in patients with EGFRm NSCLC1 Updated results in pre-treated patients with EGFR T790M mutation-positive NSCLC further support recent approvals in the US, EU and Japan April 14, 2016 08:45 AM Eastern Daylight Time LONDON--(BUSINESS WIRE)--AstraZeneca today reported new Phase I extended follow-up data on osimertinib in both first- and second-line treatment of patients with non-small cell lung cancer (NSCLC), at the European Lung Cancer Conference (ELCC) 2016. Late-breaker presentations reinforced the efficacy and safety profile for osimertinib previously seen in the AURA clinical trials programme. Phase I data from the AURA trial on osimertinib investigated as first-line treatment in 60 patients (pooled 80mg and 160mg dose cohorts) with epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC showed an objective response rate (ORR, a measurement of tumour shrinkage) of 77% (95% confidence interval (CI): 64%-87%) and a progression-free survival (PFS) of 19.3 months, with 55% of patients remaining progression-free at 18 months (95% CI: 41%-67%).1 Median duration of response (DoR) was non-calculable (NC) (95% CI: 12.5 months to NC) at the time of data cut off, with 53% of patients continuing to respond at 18 months (95% CI: 36%-67%).1 Of the 60 first-line patients, five had tumours also harbouring the T790M mutation at diagnosis (known as de novo patients) and all five of these patients showed durable responses.1 The most common adverse events were rash (78% overall; 2% ≥Grade 3), diarrhoea (73% overall; 3% ≥Grade 3), dry skin (58% overall; 0 ≥Grade 3) and paronychia (50% overall; 3% ≥Grade 3). All of the Grade 3 or above events in these categories occurred at the 160mg dose.1 Klaus Edvardsen, Vice President, Clinical Oncology and Interim Head of Oncology, Global Medicines Development at AstraZeneca said: "In a Phase I study with osimertinib as first-line therapy in EGFR-mutation positive NSCLC, we are seeing consistently durable responses. In many cases, responses continue for at least 18 months including in a small group of patients with the T790M mutation detectable at diagnosis. The ongoing Phase III FLAURA trial will further characterise the potential of osimertinib 80mg in the first-line EGFRm setting." Updated pooled results from AURA Phase II studies in 411 pre-treated patients with EGFR T790M mutation-positive NSCLC treated with osimertinib 80mg showed a median PFS of 11 months (95% CI: 9.6-12.4 months), an ORR of 66% (95% CI: 61%-71%) and a median DoR of 12.5 months (95% CI:11.1 months to NC).2 Pooled treatment-related adverse events data from the AURA Phase II studies included rash (41% overall; <1% ≥Grade 3), diarrhoea (38% overall; <1% ≥Grade 3), dry skin (30% overall; 0% ≥Grade 3) and paronychia (29% overall; 0% ≥Grade 3). Interstitial lung disease was seen in 12 patients (3% overall; 2% ≥Grade 3), hyperglycaemia in 1 patient (<1% overall; 0 ≥Grade 3) and QT prolongation in 14 patients (3% overall; 1% ≥Grade 3).2 Osimertinib recently received accelerated approval as the first indicated treatment for patients with EGFR T790M mutation-positive metastatic NSCLC in the US,3 EU4 and Japan.5 The ongoing confirmatory Phase III trial, AURA3, is assessing the efficacy and safety of osimertinib versus platinum-based doublet chemotherapy in patients with EGFR T790M mutation-positive, locally advanced, or metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI.6 AstraZeneca is also continuing studies in the adjuvant and locally-advanced/metastatic first-line EGFRm settings,7,8, in patients with and without brain metastases,9 in leptomeningeal disease, and in combination with other compounds.10,11
About Non-Small Cell Lung Cancer (NSCLC) Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined.12 Patients who have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC patients in Europe13 and 30-40% of NSCLC patients in Asia,14 are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signaling pathways that drive the growth of tumour cells.15 However, tumours almost always develop resistance to treatment, leading to disease progression.16 In approximately two-thirds of patients treated with approved EGFR-TKIs such as gefitinib and erlotinib, this resistance is caused by the secondary mutation, T790M.16
About osimertinib Osimertinib 80mg once-daily tablet is the first medicine indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC.3,4,5 Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFR and T790M mutant NSCLC cell lines with significantly less activity against EGFR in wild-type cell lines.17 Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M mutation-positive, locally advanced or metastatic NSCLC who have progressed after EGFR-TKI therapy.6 It is also being investigated in the adjuvant and metastatic first-line settings,7,8 including in patients with and without brain metastases,9 in leptomeningeal diseases, and in combination with other compounds.10,11
1 Ramalingam SS, et al. Osimertinib (AZD9291) as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. Abstract LBA1_PR [Oral Presentation]. Presented at the European Lung Cancer Conference, 13-16 April 2016, Geneva, Switzerland.
2 Yang JCH, et al. Osimertinib (AZD9291) in pre-treated patients with T790M-positive advanced NSCLC: updated Phase I and pooled Phase II results. Abstract LBA2_PR [Oral Presentation]. Presented at the European Lung Cancer Conference, 13-16 April 2016, Geneva, Switzerland.
3 AstraZeneca PLC. TAGRISSO™ (AZD9291) approved by the US FDA for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on November 13th 2015. Available at: https://www.astrazeneca.com/our-company/media-centre/press-releases/2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-patients-with-EGFR-T790M-mutation-positive-metastatic-non-small-cell-lung-cancer-13112015.html. Accessed April 2016.
4 AstraZeneca PLC. TAGRISSO™ (osimertinib) approved in EU as first-in-class treatment for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on February 3rd 2016.https://www.astrazeneca.com/media-centre/press-releases/2016/tagrisso-osimertinib-approved-in-eu-as-first-in-class-treatment-for-lung-cancer-03022016.html. Accessed April 2016.
5 AstraZeneca PLC. Tagrisso™ (osimertinib) approved in Japan for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer. Issued on March 29th 2016. Available at: https://www.astrazeneca.com/media-centre/press-releases/2016/tagrisso-approved-in-japan-for-patients-with-egfr-t790m-mutation-positive-metastatic-non-small-cell-lung-cancer-29032016.html. Accessed April 2016.
6 National Institutes of Health. AZD9291 Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (AURA3). Available at: https://clinicaltrials.gov/ct2/show/NCT02151981?term=AURA3&rank=1. Accessed April 2016.
7 National Institutes of Health. AZD9291 Versus Placebo in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02511106?term=AZD9291+Versus+Placebo+in+Patients&rank=1. Accessed April 2016.
8 National Institutes of Health. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA). Available at https://clinicaltrials.gov/ct2/show/NCT02296125?term=FLAURA&rank=1. Accessed April 2016.
9 National Institutes of Health. Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have Advanced Non-Small Cell Lung Cancer (BLOOM). Available at: https://clinicaltrials.gov/ct2/show/NCT02228369?term=AZD9291+brain+met&rank=1. Accessed April 2016.
10 National Institutes of Health. Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours (CAURAL). Available at https://clinicaltrials.gov/ct2/show/NCT02454933?term=CAURAL&rank=1. Accessed April 2016.
11 National Institutes of Health. AZD9291 in Combination With Ascending Doses of Novel Therapeutics. Available at: https://clinicaltrials.gov/ct2/show/NCT02143466?term=azd9291&rank=1. Accessed April 2016.
12 GLOBOCAN (2012). Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed April 2016.
13 Szumera-Ciećkiewicz A, et al. EGFR mutation testing on cytological and histological samples in non-small cell lung cancer: a Polish, single institution study and systematic review of European incidence. Int J Clin Exp Pathol. 2013;6:2800-12.
14 Ellison G, et al. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol. 2013;66:79-89.
15 Langer CJ, et al. Epidermal Growth Factor Receptor Inhibition in Mutation-Positive Non-Small-Cell Lung Cancer: Is Afatinib Better or Simply Newer? Journal of Clinical Oncology. 2013;31(27);3303-3305
16 Yu HA, et al. Analysis of Tumour Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancer. Clin Cancer Research:2013:19(8):2240-2246
17 Cross DAE, et al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov. 2014;4:1046-61.
