Poziotinib ( for EGFR exon 20–mutant) 治療肺癌73% objective response rate !!!! (other TKI: < 10%)

到底是啥藥，治療肺癌控制率刷新歷史接近100%！ 2018-05-01 可依 肺癌康復圈肺癌新藥Poziotinib，針對EGFR20號外顯子突變，已經進入臨床二期試驗。小型的試驗中，有效率接近100%。小編最近在美國臨床試驗官網上面看到個肺癌新藥物，Poziotinib，是個雙靶點的藥物哦。不但可以針對HER家族受體，也可以用於治療有EGFR20號外顯子突變非小細胞肺癌患者。

1EGFR突變，肺癌患者很常見 肺癌的覓友們都知道，EGFR突變是非小細胞肺癌主要的突變位點，尤其是亞裔不抽煙的女性肺癌患者。但是之前常見的突變位點有19號外顯子、21號外顯子T790M、L858R和。現在上市的藥物，像是大家熟知的泰瑞沙、吉非替尼這些1~3代的靶向藥物都可以不同地治療這些常見位點的突變。

2不但治療原發，還可對抗耐藥 除了這些突變，非小細胞肺癌還可以原發EGFR 20號外顯子的插入突變，占肺癌患者的10%。不僅如此，EGFR 20號外顯子的突變也是一種耐藥突變。也就是說，很多患者本來沒有是其他EGFR位點突變，沒有20號的突變；在經過靶向藥物治療後，可能會出現新的突變位點，從而產生耐藥。20號就是一個耐藥位點，會讓患者的腫瘤對之前的靶向藥物免疫而失效。

3新藥新希望—精准抗擊腫瘤 那麼我們來看看這個新藥-波奇替尼：這個藥物是針對HER1-3號基因和EGFR 20號外顯子突變的靶向藥物。在非小細胞肺癌患者中，這類突變的患者占4%左右。在2017年10月，日本橫濱舉辦的18屆世界肺癌大會（WCLC）上，藥品研發公司也介紹了；波奇替尼在EGFR外顯子插入突變的NSCLC患者中表現出來非常好的抗腫瘤活性，臨時資料顯示73%的客觀緩解率。動物實驗中，poziotinib治療EGFR外顯子20插入突變的NSCLC效果是阿法替尼的40倍、奧希替尼的100倍。而且，波奇替尼治療EGFR外顯子20插入突變的效果是治療EGFR T790M突變的65倍。首例使用波奇替尼的患者的腫瘤成功縮小了，這給研究者非常大的信心。馬上開始了小樣本的臨床二期試驗。現在試驗還在進行中，但首期入組的11名患者，有7個患者的腫瘤得到了縮小，其中1位腫瘤明顯縮小，剩下的三個患者腫瘤也得到了控制。客觀有效率達到了64%。在試驗中，最常見的副作用是腹瀉和皮疹。在這些研究資料中，我們的EGFR突變非小細胞肺癌患者又有了新的希望，特別是對於耐藥的患者。這麼好資料的二期臨床試驗結果，應該在不久的將來，Poziotinib就會進入三期臨床試驗並且上市。不論如何，這個研究的短期結果已經給了我們很多新希望和信心！

參考資料：1.Costa, D. 2015. EGFR Exon 20 Insertion in Non-Small Cell Lung Cancer. My Cancer Genome.2.Y. Elamin, J. Robichaux, V. Lam, et al. 2017. THE PRECLINICAL AND CLINICAL ACTIVITY OF POZIOTINIB, A POTENT, SELECTIVE INHIBITOR OF EGFR EXON 20 MUTANT NSCLC.Presented at: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; Yokohama, Japan. Abstract OA 12.01

 

Poziotinib Data in EGFR Exon 20-Mutant NSCLC  Insights From: John Heymach, MD, PhD, MD Anderson Cancer CenterPublished: Wednesday, Apr 25, 2018  Transcript: John Heymach, MD, PhD: One thing that's important to highlight for exon 20 mutations is that it's not a single mutation. Exon 20 refers to an entire region. Most of the mutations in EGFR occur between amino acid 763 and amino acid 780. That's really the region where these mutations occur. Depending on where those mutations occur, they have different sensitivities. We just had the first FDA approval for a single mutation: the S768I mutation. Afatinib received FDA approval for that single point mutation. But that's a pretty small minority of exon 20 mutants overall. Given this unmet need, we did a lot of drug screening. The first was to actually make all of these individual mutants occur. And so, we've got many, many mutations that have been made in the lab. This work's been led by Jacqulyne Robichaux, who's a postdoctoral Fellow in the laboratory. Dozens and dozens of different drugs were screened to see which was the most active against of all of these different mutations. Across the board, we saw that poziotinib was the most potent, in vitro. We compared it, in clinical testing, to all of the different EGFR inhibitors that were available. This applied for all of the differentiation mutations, although some of the mutations are more sensitive than others. In fact, that S768I mutation that afatinib has been approved for is one that poziotinib is also highly active against. We then took these results and went into mouse models. This included genetically engineered mouse models that had a particular exon 20 mutation as well as human tumors that were grown in mouse xenograft models. Poziotinib was really the best of all of the ones that we tested in mouse models. So, all of this prompted the clinical trial that we recently reported on at the World Conference on Lung Cancer, in Japan, this past October. Based on the preclinical results that we described, we initiated a phase II study of poziotinib. It had already been through phase I testing, so the maximum tolerated dose was already identified. This study had 2 major cohorts. It had an EGFR exon 20 cohort and a HER2 exon 20 cohort. The eligibility criteria were really pretty wide open. It allowed for people who had treatment with prior EGFR tyrosine kinase inhibitors. On the EGFR side, we allowed for both previously untreated and treated patients. On the HER2 side, only people who had received prior chemotherapy were included. This was a single-arm study, starting at a dose of 16 mg. Now, as I mentioned before, first-generation inhibitors have an objective response rate of less than 10%, consistently, for this group of patients. We were hoping to get above 20% or 30%. In Japan, at the World Conference on Lung Cancer, we reported on the initial scan results. Instead of reporting on durable results with progression-free survival and so forth, these were really just the initial scan results because that's the data that were available at that point. In the first 11 patients who we reported on, 8 of them had partial responses. This was based on more than a 30% shrinkage of their tumors by what we call RECIST criteria. That level of activity, that 73% objective response rate, was certainly very encouraging compared to the standard response rates that have been seen for other tyrosine kinase inhibitors—less than 10%. The drug did have toxicities that were consistent with EGFR inhibitors. In particular, there was acne, which is particularly seen with first- and second-generation inhibitors. Diarrhea was also seen in many of the patients. About 55% of that initial group had dose reductions from the 16-mg dose down to lower doses. The therapy did need to be reduced in a significant number of patients, but we're certainly very encouraged by that activity level that was seen there. Shortly, longer-term follow-up for those patients will be published in Nature Medicine. The confirmed objective response rate, meaning that the response was maintained for at least 4 months in our study, ended up being about 64% in that overall group. The median progression-free survival had not yet been reached, and the median follow up for the group was about 6.5 months. So, we don't know the progression-free survival yet, but we know that it's longer than 6.5 months. This was really encouraging. For the first time, there was a drug that had a high response rate for EGFR exon 20–mutant disease. And the responses were reasonably durable. We'll have to see what the ultimate progression-free survival is, but we know it's longer than 6 months. Keeping in mind that the standard drugs had a median progression-free survival of about 2 months in this exact same population in the study. So, this is certainly an encouraging initial result.