RET特异性癌症的选择性抑制剂疗法_选择性抑制剂疗法

本文于2018年4月15日发表于AACR网站，翻译仅供参考！

芝加哥--- BLU-667，可选择性靶向酪氨酸激酶 RET的下一代抑制剂。其耐受良好且对晚期癌症病人有广泛的临床受益，这些晚期病人通常之前已被证实对包括多激酶抑制剂疗法在内的疗法无效。4月14-18日在芝加哥召开的2018 AACR 年会上将介绍一项正在进行中的一期临床试验，其中会公布概念验证数据。

Vivek Subbiah, 医学博士，来自休斯顿德州大学MD安德森癌症中心靶向疗法临床中心癌症医学分部调查型癌症疗法部门，任职助理教授和助理医学主任，他告诉我们：“众多癌症类型中，RET特异性癌症尤其受到关注，因为目前尚未有批准药剂可以用来针对性地靶向这一致癌基因，目前RET特异性癌症的治疗方式仅限于多激酶抑制剂和化疗，但这些是非特异性治疗并且有很大的脱靶毒性。为了能在这方面获得突破，科学家们研制了BLU-667抑制剂，专门靶向致癌RET融合和基因突变。”

Subbiah博士表示，之前的临床前工作发现BLU-667可有效抑制致癌RET，且在诸多RET有关癌症病例中表现出明显的抗肿瘤活性。不仅如此，他还解释道，在测试了350多种人体激酶后，这一抑制剂对RET激酶的选择性高出100倍，其能强有力地抑制看门突变，而后者被认为是抵抗多重激酶疗法的原因。

Subbiah博士和同事进行的BLU-667测试是非盲、首次人体试验。截止2018年2月13日，研究小组已记录43名无法进行切除手术的晚期实体瘤病人的数据，其中26名病人患的是RET突变型甲状腺髓样癌（MTC），15名病人患的是RET融合非小细胞肺癌（NSCLC），两名病人是非RET癌症。所有病人此前接受过的抗肿瘤治疗次数中位数为一次；此前治疗次数为0次到8次不等。

BLU-667的剂量是每天口服30到400 mg，并进行监管。目前未达到较大耐受剂量。

在30位RET改变的病人中，给药≥60mg的BLU-667，在进行至少一次的基础值之后的响应评估后，可发现该抑制剂有着显著而广泛的抗癌活性，整体响应率为37%，令人满意。

BLU-667耐受良好；一级便秘是目前已知较大副作用（23%）。记录在案有三种剂量限制性毒性，没有4-5级副作用事件。试验的剂量递增数据仍在确认之中。

2018 AACR年会上有望给出更多数据。

Subbiah博士表示：“这一进行中的一期研究已获得这一选择性RET抑制剂的概念性验证。尽管试验仍处于早期阶段，我们已发现了NSCLC和MTC的抗肿瘤潜力。”。

Subbiah 博士告诉我们：“RET抑制剂的精准靶向疗法对于那些由致癌驱动引起的癌症病人有明显的作用，即使是在早期临床试验测试阶段，也有此效果。我们鼓励所有的癌症病人做基因组检测，因为罕见染色体畸变的肿瘤可能适合一些临床试验阶段的药物，那么他们就可以及早受益。”

这项研究由Blueprint Medicines赞助并执行。Subbiah获得了临床试验研究基金，出资方为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.