达沙替尼与奥希替尼用于初治的晚期EGFR突变非小细胞肺癌患者的I期试验

A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer.

作者信息

Kim Chul, Liu Stephen V, Crawford Jennifer, Torres Tisdrey, Chen Vincent, Thompson Jillian, Tan Ming, Esposito Giuseppe, Subramaniam Deepa S, Giaccone Giuseppe

机构信息

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, United States.

Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University, Washington, DC, United States.

出版信息

Front Oncol. 2021 Sep 8;11:728155. doi: 10.3389/fonc.2021.728155. eCollection 2021.

BACKGROUND

Osimertinib is an effective first-line therapy option for -mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.

METHOD

This is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced -mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).

RESULTS

Ten patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.

CONCLUSIONS

The combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.

CLINICAL TRIAL REGISTRATION

https://clinicaltrials.gov/ct2/show/NCT02954523.

背景

奥希替尼是治疗EGFR突变型非小细胞肺癌（NSCLC）的一种有效的一线治疗选择，但几乎所有患者都会产生耐药性。CRIPTO通过激活Src，与对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗的耐药性有关。达沙替尼是一种Src抑制剂，已显示出与EGFR-TKI治疗具有临床前协同作用。

方法

这是一项在未接受过TKI治疗的晚期EGFR突变型NSCLC患者中开展的奥希替尼联合达沙替尼的单臂I/II期试验（NCT02954523）。I期采用3+3设计来确定II期推荐剂量（RP2D）。奥希替尼80mg每日一次与达沙替尼70mg每日两次（剂量水平2，DL2）、50mg每日两次（剂量水平1，DL1）、70mg每日一次（剂量水平-1，DL-1）和50mg每日一次（剂量水平-2，DL-2）联合使用。

结果

共入组10例患者（DL2：3例，DL1：6例，DL-1：1例）。DL1组的6例患者中有3例（50%）发生了剂量限制性毒性（DLT，3级头痛/身体疼痛、中性粒细胞减少、皮疹，各1例）。常见的治疗相关不良事件包括胸腔积液（n=10）、腹泻（n=8）、皮疹（n=7）、转氨酶升高（n=7）、血小板减少（n=7）和中性粒细胞减少（n=7）。虽然根据方案定义的DLT标准未确定最大耐受剂量（MTD），但考虑到总体耐受性，选择DL-2作为RP2D。9例（90%）患者获得部分缓解（PR），其中1例PR未经确认。中位无进展生存期（PFS）为19.4个月，中位总生存期（OS）为36.1个月。由于奥希替尼被批准作为一线治疗后入组缓慢，该试验提前停止入组。