RET特異性癌癥的選擇性抑制劑療法
本文于2018年4月15日發(fā)表于AACR網(wǎng)站，翻譯僅供參考！
芝加哥--- BLU-667，可選擇性靶向酪氨酸激酶 RET的下一代抑制劑。其耐受良好且對晚期癌癥病人有廣泛的臨床受益，這些晚期病人通常之前已被證實對包括多激酶抑制劑療法在內(nèi)的療法無效。4月14-18日在芝加哥召開的2018 AACR 年會上將介紹一項正在進(jìn)行中的一期臨床試驗，其中會公布概念驗證數(shù)據(jù)。
Vivek Subbiah, 醫(yī)學(xué)博士，來自休斯頓德州大學(xué)MD安德森癌癥中心靶向療法臨床中心癌癥醫(yī)學(xué)分部調(diào)查型癌癥療法部門，任職助理教授和助理醫(yī)學(xué)主任，他告訴我們：“眾多癌癥類型中，RET特異性癌癥尤其受到關(guān)注，因為目前尚未有批準(zhǔn)藥劑可以用來針對性地靶向這一致癌基因，目前RET特異性癌癥的治療方式僅限于多激酶抑制劑和化療，但這些是非特異性治療并且有很大的脫靶毒性。為了能在這方面獲得突破，科學(xué)家們研制了BLU-667抑制劑，專門靶向致癌RET融合和基因突變?！?/span>
Subbiah博士表示，之前的臨床前工作發(fā)現(xiàn)BLU-667可有效抑制致癌RET，且在諸多RET有關(guān)癌癥病例中表現(xiàn)出明顯的抗腫瘤活性。不僅如此，他還解釋道，在測試了350多種人體激酶后，這一抑制劑對RET激酶的選擇性高出100倍，其能強有力地抑制看門突變，而后者被認(rèn)為是抵抗多重激酶療法的原因。
Subbiah博士和同事進(jìn)行的BLU-667測試是非盲、首次人體試驗。截止2018年2月13日，研究小組已記錄43名無法進(jìn)行切除手術(shù)的晚期實體瘤病人的數(shù)據(jù)，其中26名病人患的是RET突變型甲狀腺髓樣癌（MTC），15名病人患的是RET融合非小細(xì)胞肺癌（NSCLC），兩名病人是非RET癌癥。所有病人此前接受過的抗腫瘤治療次數(shù)中位數(shù)為一次；此前治療次數(shù)為0次到8次不等。
BLU-667的劑量是每天口服30到400 mg，并進(jìn)行監(jiān)管。目前未達(dá)到較大耐受劑量。
在30位RET改變的病人中，給藥≥60mg的BLU-667，在進(jìn)行至少一次的基礎(chǔ)值之后的響應(yīng)評估后，可發(fā)現(xiàn)該抑制劑有著顯著而廣泛的抗癌活性，整體響應(yīng)率為37%，令人滿意。
BLU-667耐受良好；一級便秘是目前已知較大副作用（23%）。記錄在案有三種劑量限制性毒性，沒有4-5級副作用事件。試驗的劑量遞增數(shù)據(jù)仍在確認(rèn)之中。
2018 AACR年會上有望給出更多數(shù)據(jù)。
Subbiah博士表示：“這一進(jìn)行中的一期研究已獲得這一選擇性RET抑制劑的概念性驗證。盡管試驗仍處于早期階段，我們已發(fā)現(xiàn)了NSCLC和MTC的抗腫瘤潛力?！?。
Subbiah 博士告訴我們：“RET抑制劑的精準(zhǔn)靶向療法對于那些由致癌驅(qū)動引起的癌癥病人有明顯的作用，即使是在早期臨床試驗測試階段，也有此效果。我們鼓勵所有的癌癥病人做基因組檢測，因為罕見染色體畸變的腫瘤可能適合一些臨床試驗階段的藥物，那么他們就可以及早受益?！?/span>
這項研究由Blueprint Medicines贊助并執(zhí)行。Subbiah獲得了臨床試驗研究基金，出資方為Blueprint Medicines、Novartis、Bayer、GSK、Nanocarrier、Vegenics、Northwest Biotherapeutics、Boston Biomedical、Berghealth、Incyte, Fujifilm、PharmaMar、D3、Pfizer、Multivir、Amgen、AbbVie、LOXO, Roche/Genentech、NCCN、和NCI-CTEP。
English Version
Selective Inhibitor Shows Early Promise in Patients With RET-altered Cancers
CHICAGO — BLU-667, a next-generation inhibitor that selectively targets the oncogenic receptor tyrosine kinase RET, was well tolerated and had broad clinical benefit in patients with advanced cancer that had progressed on previous therapies including multikinase inhibitor therapy. Proof-of-concept data will be presented from an ongoing phase I clinical trial at the AACR Annual Meeting 2018, April 14-18, in Chicago.
This study is being published simultaneously in The New England Journal of Medicine.
“Patients with stage 3 melanoma have metastatic disease in one or more regional lymph nodes,” said Alexander M. M. Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France. “A patient’s risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis. In the case of a single positive node, the diameter must be greater than 1 millimeter.
"RET-altered cancers across multiple tumor types represent a high medical need, as there are no approved agents that selectively target this oncogene,” said Vivek Subbiah, MD, assistant professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, and Associate Medical Director, The Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, Houston. “Current therapies for RET-altered cancers are restricted to multikinase inhibitors and chemotherapy, which are nonspecific and display significant off-target toxicity. In an effort to revolutionize treatment for these cancers, BLU-667 was designed to specifically."
Prior preclinical work found that BLU-667 potently inhibits oncogenic RET and displays anti-tumor activity in a variety of RET-driven cancers, Subbiah noted. In addition, the inhibitor was 100 times more selective for the RET kinase relative to more than 350 human kinases tested, and it potently inhibited gatekeeper mutations shown to confer resistance to multikinase therapies, he explained.
Subbiah and colleagues tested BLU-667 in an open-label, first-in-human study. As of Feb. 13, 2018, they had enrolled 43 patients with unresectable, advanced solid tumors, with 26 patients having RET-mutant medullary thyroid cancer (MTC), 15 patients having non-small cell lung cancer (NSCLC) with RET fusion, and two patients with non-RET cancers. Patients had a median of one prior anti-neoplastic therapy; prior therapies ranged from zero to eight treatments.
BLU-667 doses ranging from 30 to 400 mg were administered orally every day. The maximum tolerated dose (MTD) was not reached.
BLU-667 demonstrated broad antitumor activity with a best overall response rate of 37 percent in the 30 patients with RET alterations who received doses ≥60mg and had at least one post-baseline response assessment. Patients with NSCLC and MTC had a best overall response rate of 45 and 32 percent, respectively. As of the data cutoff, 33 of 43 enrolled patients remained on study.
BLU-667 was well-tolerated; grade 1 constipation was the most commonly reported adverse event (23 percent). Three dose-limiting toxicities (DLTs) were documented, and there were no grade 4-5 adverse events. The dose escalation portion of the trial is still underway.
Additional data are expected to be presented at the AACR Annual Meeting 2018.
"This ongoing phase I study has shown proof-of-concept of this selective RET inhibitor," said Subbiah. "Although it’s very early in clinical testing, we observed promising antitumor activity in NSCLC and MTC."
"Precision targeted therapy with RET inhibition can have a powerful impact in patients whose cancer is induced by these oncogenic drivers, even in early clinical trial testing,” noted Subbiah. “I encourage all cancer patients to undergo genomic testing, as tumors with rare genomic aberrations may have effective drugs that are in clinical trials that could be beneficial to them."
This study is sponsored and managed by Blueprint Medicines. Subbiah receives research funding for clinical trials from Blueprint Medicines, Novartis, Bayer, GSK, Nanocarrier, Vegenics, Northwest Biotherapeutics, Boston Biomedical, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, LOXO, Roche/Genentech, NCCN, and NCI-CTEP.
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