台大 楊志新 2015WCLC發表AZD9291 AURA extension trial 肺腺癌治療/ 16th World Conference on Lung Cancer (WCLC).

肺腺癌標靶藥物 第三代可抑制腫瘤 2015年09月10日 04:10 魏怡嘉／台北報導 台灣約有1萬多名非小細胞肺癌病例，其中一半為肺腺癌，對於這類患者，經基因檢測符合可用標靶藥物治療，但有9成病患會出現抗藥性，國內腫瘤科醫師昨日在國際會議上，發表第三代肺腺癌標靶藥物第二期臨床試驗，已有抗藥性病患服用後，腫瘤受到抑制的比率為70.9％，疾病控制率則為91.5％，目前已進行第三期臨床研究，最快明年上半年在美國上市、造福肺癌病患。第16屆世界肺癌年會於美國舉行，國內包括台北榮總胸腔部胸腔腫瘤科主任蔡俊明以及台大醫院腫瘤醫學部主任楊志新均受邀出席。蔡俊明表示，肺腺癌病患基因檢測EGFR和ALK呈現陽性，即可以標靶藥物治療，而病患之所以出現抗藥性，是因為癌細胞能夠通過突變及改變生長方式來逃避EGFR或ALK抑制劑的治療活性，約有50％是因為肺腺癌患者體內的T790M基因產生第二次突變所導致。蔡俊明指出，第二期研究晚期非小細胞肺腺癌患者受試者共210位，其中台灣有23位，結果發現，第三代肺腺癌標靶藥物，對EGFR標靶已經有抗藥性和T790M基因突變的非小細胞肺癌患者有較佳的治療效果，且皮疹、腹瀉等副作用比例明顯下降，而疾病無惡化存活期約有70％～75％存活一年。另針對EGFR基因沒有出現突變的晚期非小細胞肺腺癌患者，目前的治療方式為化療或化療合併放療，或是化療搭配抗血管新生藥物，蔡俊明表示，今年的研究發現，建議EGFR基因沒有出現突變的病患，不要加入化療治療，以免產生更多的副作用。而研究發現以標靶藥物Gefitinib合併化療藥物，做為晚期第一線治療使用，無惡化存活期為8.4個月，為比單使用化療藥物治療的3.8個月延長2倍。(中國時報)

晚期肺腺癌抗藥性有救了　七成受試者有效抑制腫瘤NOWnews-2015年09月10日 下午17:34晚期肺腺癌抗藥性有救了　七成受試者有效抑制腫瘤 記者陳宜婷／台北報導  晚期肺腺癌治療又向前邁出一大步，晚期肺腺癌患者使用標靶治療，癌細胞會透過突變逃避標靶藥物的治療活性，造成治療失敗。國內醫師跨國研究，找出第三代肺腺癌標靶藥物AZD9291，有七成受試者有效抑制腫瘤，九成受試者有效控制疾病，存活期超過一年，仍持續增加中，副作用也降低許多。這項研究9號在世界肺癌年會（WCLC）發表，令醫界十分振奮。第16屆世界肺癌年會，今年在美國科羅拉多州舉行，來自一百多個國家七千多名代表，齊聚討論肺癌研究最新進展。代表台灣出席的台北榮總胸腔部胸腔腫瘤科主任蔡俊明表示，為了解決晚期肺腺癌患者出現基因二次突變，第三代肺腺癌標靶藥物，成為臨床研究的重點。蔡俊明指出，晚期非小細胞肺腺癌患者的標準治療，是使用EGFR和ALK標靶藥物，但約使用9個月到11個月後，肺腺癌細胞會透過基因突變和改變生長方式，產生抗藥性，使療效變差，導致治療失敗。台灣參與跨國研究發現，第三代肺腺癌標靶藥物，對於EGFR基因突變已產生抗藥性的患者來說，有較佳的治療效果，210名受試的非小細胞肺腺癌患者中，腫瘤受到抑制的比率為70.9%，疾病控制率為91.5%，皮疹、腹瀉等副作用比例下降。蔡俊明強調，在第二期研究測試者中，患者年齡為35到88歲，女性占七成，台北榮總在兩個月內就招收23個試驗者，收案速度令國外十分訝異，美國FDA還特地在上個月來北榮稽核臨床試驗，最後以無瑕疵通過，顯示台灣臨床研究的執行效率。至於EGFR基因沒有出現突變的晚期非小細胞肺腺癌患者，目前治療方式為化療、化療合併放療或化療搭配抗血管新生藥物，但化療的副作用常使病患難以忍受，而且存活期約三個月。蔡俊明說，最新研究是以標靶藥物Gefitinib合併化療藥物，研究發現受試的55名患者中，無惡化存活期為8.4個月，比單使用化療藥物治療3.8個月，延長2倍存活時間，皮疹、腹瀉、肝毒性等副作用程度較輕，可望成為EGFR基因未突變患者更好的治療方式。蔡俊明表示，研究結果是今年WCLC年會的兩大重點，讓晚期肺腺癌患者治療多了不同的新選擇，尤其是第三代肺腺癌標靶藥物，在今年大會上，不少國度學者均強烈要求美國FDA能儘快上市，目前已知正在進行第三期臨床研究，預期第三代肺腺癌標靶藥物可能在明年上半年於美國核可通過，未來可望成為抗藥性患者的接續治療方式，甚至可能做為第一線治療方法。

AZD9291 Produces Strong Responses in EGFR-Mutated NSCLC Roxanne Nelson September 14, 2015 DENVER -- An investigational third-generation tyrosine kinase inhibitor (TKI) showed strong and consistent response rates across three studies in both treatment-naïve and pretreated patients with advanced non–small cell lung cancer (NSCLC) that harbored specific mutations.

Confirmed objective response rates ranged from 61% to 75%. These data were presented here at the 16th World Conference on Lung Cancer (WCLC) and are from the AURA phase 1 trial first-line cohort and two AURA phase 2 studies conducted in pretreated patients. AZD9291 (AstraZeneca Pharmaceuticals LP) is an oral, potent, irreversible EGFR TKI that is selective for EGFR tyrosine kinase inhibitor–sensitizing mutations and the T790M resistance mutation. The EGFR T790M mutation confers resistance to treatment with first-generation EGFR inhibitors, such as erlotinib (Tarceva, Osi Pharmaceuticals, Inc) and gefitinib (Iressa, AstraZeneca Pharmaceuticals LP) or the second-generation EGFR inhibitor afatinib (Gilotrif, Boehringer Ingelheim Pharmaceuticals, Inc), making the disease difficult to treat. Studies are assessing this agent as both a first-line agent and for use in patients who have developed or have shown resistance to other treatments. "Conceptually, what we all struggle with is, should we develop the sequential model -- start with one inhibitor, develop resistance, and move on to another," said Pasi Jänne, MD, PhD, director of the Lower Center for Thoracic Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts, and an investigator in several AZD929 studies being presented at the meeting. "Or should we put our best weapon first," he told Medscape Medical News, "take the one that can overcome all resistance mechanisms first and use it up front." Another important issue is that agents such as AZD9291 are better tolerated than erlotinib and afatinib in terms of dermatologic side effects. "That means it will be easier to use it as a building block for combination regimens," said Dr Jänne. "It's harder to do that with erlotinib and afatinib because of their toxicities, but it will be easier with this agent. There are already ongoing phase 1 trials looking at that." "For advanced cancers, I don't think we are going to get cures with single agents, but maybe we will with combinations or series of combinations," he added. "And early data suggest that there are agents that can be combined together."

High Response in the First-Line Setting In the AURA phase 1 trial, updated data were presented for the use of AZD9291 as a first-line therapy for patients with EGFRm-positive advanced NSCLC. In this treatment-naïve group, AZD9291 "demonstrated encouraging clinical activity and a manageable tolerability profile," according to Dr. Jänne, who presented the study on behalf of study author Suresh S. Ramalingam, MD, chief of thoracic oncology and director of medical oncology, Emory University School of Medicine, Atlanta, who wasn't able to attend. The confirmed objective response rate was 75% (95% confidence interval [CI], 62% to 85%), and the longest duration of response at the time of data cutoff was ongoing at 18 months. "Seventy-two percent of patients remain alive and progression-free at 12 months," he told attendees, "and this has prompted the initiation of the phase 3 FLAURA study, comparing AZD9291 at the 80-mg dose vs current standard of care EGFR TKIs for treatment-naïve patients, and the study is currently enrolling."

In this expansion cohort, 60 patients received AZD9291 at 80 or 160 mg/day in sequential dose groups. Central testing revealed several EGFR mutation subtypes, including L858R (40%), exon 19 deletion (37%), other EGFR-sensitizing mutations (3%), and T790M (8%). At data cutoff, 52 patients in the cohort remained on treatment. The disease control rate was 97% for both cohorts. Two patients experienced a complete response (both were in the 160-mg dose group). In addition, 43 patients had a partial response, 13 had stable disease, and only two experienced disease progression (both in the 80-mg group). For duration of response and progression-free survival, Dr Jänne noted that the data are still relatively immature. "For progression-free survival, it is only at 35% maturity, and in the total population of patients, the lower limit of the 95% confidence interval is 13.7 months," he said. "The maximum for the two different dose levels is 19.2 months." Although the median progression-free survival has not yet been reached, "if you look at the curves, the lower limit of the 95% confidence interval for progression-free survival was about 12 to 13 months, which is higher than we normally see the medians for EGFR inhibitors," Dr Jänne said. "That part is incredibly exciting because, as you move an effective therapy that works in patients that have developed resistance and give it early on the treatment, it may in fact work even better." "And I think we are getting hints of that," he said. "But this is an exciting area in this field, because they are better tolerated than erlotinib or afatinib, so it would be great to able to start with this, but we'll see how the data evolve."

Continuing Efficacy and Tolerability The AURA clinical program also included two phase 2 studies, AURA 2 and AURA extension cohort, that evaluated the efficacy and safety of the compound in patients with EGFRm advanced NSCLC and with positive T790M status, who had progressed after treatment with EGFR tyrosine kinase inhibitors. Although still preliminary, in both of these studies, AZD9291 also showed an efficacy and tolerability profile that is consistent with previously reported data, Dr Janne pointed out. The AURA extension trial, which is a continuation of a phase 1 dose-escalation study, included 201 patients who received the 80-mg once-daily dose of AZD9291. The overall response rate was 61% (95% CI, 54% to 68%), but the median duration of response and median progression-free survival have not yet reached maturity. There were no complete responses, 122 (61%) partial responses, 58 patients with stable disease (29%), and 19 (10%) with progressive disease. "The disease control rate was 91%," said lead author James Chih-Hsin Yang, MD, director, Department of Oncology and Department of Medical Research, National Taiwan University Hospital, Taipei City, who presented the findings. "Only a few patients had progressive disease as their best response." But although progression-free survival has not reached maturity, "the curve shows there is a very long progression-free survival, up to 12 months of follow-up," he said. Consistent results were observed in the third study, the AURA2, a global, open-label, single-arm phase 2 study. As in the AURA extension trial, all participants tested positive for T790M, as well as other EGFR mutations, including Ex19del (65%), L858R (32%), others (3%). In this study, AZD9291 showed a 71% objective response rate. There were two complete responses and 139 partial responses. The stable disease rate at 6 weeks or longer was 21%, for a disease control rate of 92%. The 71% response rate is "somewhat higher than you saw in the AURA extension trial," said lead investigator Tetsuya Mitsudomi, MD, PhD, chief of thoracic surgery at Aichi Cancer Center Hospital, in Nagoya, Japan. The median progression-free survival was 8.6 months (38% maturity), and the median duration of response was 7.8 months (27% maturity)."AZD9291 has demonstrated a positive clinical benefit across two phase 2 studies with encouraging duration of response and progression-free survival data," he noted. "A longer follow-up is needed to fully characterize these efficacy outcomes." The AURA3 trial, which is currently ongoing, features AZD9291 vs platinum-based doublet chemotherapy in patients with EGFRm- and T790M-positive advanced NSCLC who have disease progression after prior tyrosine kinase therapy, added Dr Mitusdomi. The planned enrollment is 410 patients. In all three studies, there was predominance of female and Asian patients, and in the phase 2 trials, the majority were also never-smokers (67% and 76%, respectively). The safety profile of AZD9291 in these studies was in line with that already reported for this agent. In the AURA first-line cohort, the most common all-cause adverse events of any grade across different dose groups included rash (grouped terms) (77% all grades, 2% grade ≥3) and diarrhea (73% all grades, 3% grade ≥3). These events were also reported as the most common in the two AURA phase 2 studies: for the AURA extension -- rash, 40% all grades, 1% grade ≥3; diarrhea, 45% all grades, 1% grade ≥3; and for AURA2 -- rash, 42% all grades, 1% grade ≥3; and diarrhea, 39% all grades, 1% grade ≥3. In a discussion of all three papers, Martin Reck, MD, PhD, from the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf, Germany, noted that there are several interesting points that were seen in the presentations. "We have seen confirmed efficacy in pretreated patients," he said. "As far as tolerability, due to the mechanism of these drugs, these compounds seem to be very well tolerated, so we typically do not the side effects of the first-generation TKIs," he said. As for using this agent as first-line therapy, it is still unclear how effective it is in untreated patients. "But that question will be answered by the first-line FLAURA trial," he said. Dr Reck added that "impressive efficacy" has been observed in pretreated patients. "But there are questions about efficacy in T790M-negative patients, and we do see responses in about 20% to 30% of these patients." But in the end, he summarized, "I would say that these drugs should become available as soon as possible." According to the manufacturer, marketing authorization applications for AZD9291 for the treatment of EGFRm T790M mutation-positive NSCLC have been submitted to the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and other regulatory authorities. The FDA has already granted priority review to AZD9291, and the drug has also been granted accelerated assessment by the EMA. All three trials were sponsored by AstraZeneca. Dr Yang, Dr Mitsudomi, Dr Ramalingam, and Dr Reck have disclosed relationships with industry, including AstraZeneca, the manufacturer of AZD9291. 16th World Conference on Lung Cancer (WCLC). Presented September 8, 2015. Abstract Mini 16.06, 16.07, 16.08 presented September 9, 2015.