靶向AKT的抗肿瘤药物研究曙光已见

A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors.
Background: The PI3K-Akt and RAF/MEK/ERK pathways represent two of the most frequently activated growth factor signaling pathways in human cancer. Inhibition of both pathways could yield greater benefits than inhibiting either pathway alone. The objectives of this phase I study were to examine the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the novel combination of MK-2206 with selumetinib. This investigational study represents a new approach to early-stage drug development with the collaboration of two pharmaceutical companies co-developing early stage targeted agent combinations (NCT01021748). Methods: Eligible patients with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered continuously either once daily (QD) or twice daily (BID). Results: To date, 33 patients have been treated on five dose levels. In the MK-2206 QOD dosing schedule, dose-limiting Grade 3 macular skin rash was reported in 2/3 evaluable patients at MK-2206 45 mg QOD with selumetinib 75mg BID; the tolerable dose was MK-2206 45 mg QOD with selumetinib 75 mg QD. For QW MK-2206, dose-limiting acneiform rash (n=1), stomatitis (n=1) and detached retinal pigment epithelium (n=1) were observed in 3/7 evaluable patients treated at MK-2206 90 mg QW with selumetinib 75mg BID; dose reduction to MK-2206 90mg QW/ selumetinib 50 mg BID was not tolerated due to dose-limiting acneiform rash in 2/ 4 evaluable patients. An intermediate dose of MK-2206 90mg once weekly with selumetinib 75mg QD was tolerable. Preliminary assessment of PK/PD data suggest no apparent drug-drug interactions with the PK profile of each drug administered in this combination. Conclusions: MK2206 at 45 mg QOD, or 90 mg QW is well tolerated in combination with selumetinib 75 mg QD in patients with advanced cancer.

A phase I dose escalation study of oral MK-2206 (allosteric Akt inhibitor) with oral selumetinib (AZD6244; ARRY-142866) (MEK 1/2 inhibitor) in patients with advanced or metastatic solid tumors.
Background: Simultaneous inhibition of both the PI3K-Akt and RAF/MEK/ERK pathways may yield greater benefits than inhibiting either pathway alone. This phase I study (NCT01021748) examined the safety, pharmacokinetics (PK), pharmacodynamics (PD), maximal tolerated dose (MTD), and preliminary antitumor activity of the combination of a MEKi (selumetinib) and AKTi (MK-2206). Methods: Eligible patients (pts) with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered either once daily (QD) or twice daily (BID). Results: 51 pts with advanced solid tumors (15 colon, 8 NSCLC, 6 ovarian, 5 pancreatic, 3 breast and 14 others) were treated across 9 dose levels. There were 2 confirmed partial response (PR) (1 NSCLC, ongoing > 52 wks; 1 ovarian, on treatment for 47 weeks; both KRAS mutation positive), 1 unconfirmed PR (pancreatic, on treatment 20 wks), and 24 pts with stable disease (ranged from 6 to 47 wks). Preliminary assessment of PK data suggested no apparent drug-drug interactions with unaltered PK profiles of each drug when administered in combination. Conclusions: In combination the maximum tolerated doses of MK-2206 and selumetinib are 135 mg QW and 100 mg QD, respectively. This combination of investigational agents demonstrated preliminary antitumor activity in pts with advanced cancer.

http://abstract.asco.org/AbstView_114_99901.html

AKT抑制剂MK-2206、MEK抑制剂AZD6244，小分子靶向药，关注。现在完成临床Ⅰ期了，一般要Ⅳ期吗？吗？

AKT抑制剂GSK2141795与MEK抑制剂GSK1120212联合正在进行Ⅰ期临床试验。
这个临床试验在国内进行吗？

老马幸苦了、、、

AKT是过程中的一个现象而非肿瘤发生的病因，我觉得不能对它抱有太高现象。即便是解决问题的一个过渡办法，但也避免不了因肿瘤干细胞高度灵活的变异性而最终耐药的结果，况且更多的靶向研究都在临床2期或3期研究中陷入尴尬的阴性结果（国内阳性研究结果可靠性让人不放心）。最好的可能是它为靶向药物i的轮换、延长无进展期或生存期。

AKT 貌似有进入临床III期的了，是perfosine，一个小公司做的，做了好久，目前还不确定能不能最终获批，但专利已经快到期了。适应症是MM和结肠癌，这个是进展最快的一个，但好像结肠癌III期失败了。去年和他们的人谈过

顶一个！谢谢老马。

老马V5..

研究的新成果将惠及很多病人的，但国外的一些前沿成果，一般人不了解，谢谢老马！！！