新药讨论：ARQ197
本帖最后由 成长的烦恼 于 2012-6-27 19:11 编辑Phase I results of the randomized, placebo controlled, phase I/II study of the novel oral c-MET inhibitor, ARQ 197, irinotecan (CPT-11), and cetuximab (C) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) who have received front-line systemic therapy.
Background: ARQ 197 selectively inhibits the c-MET receptor tyrosine kinase (RTK) which has been implicated in tumor cell migration, invasion, proliferation, and angiogenesis. CPT-11 plus C is a standard of care for CPT-11-refractory mCRC pts with WT KRAS tumors. Resistance to C has been associated with activation of alternative RTK pathways including c-MET. We hypothesize that adding ARQ 197 to CPT-11 plus C may decrease resistance to C therapy and improve pt outcomes. Methods: The primary objectives of the phase I study were to evaluate safety and tolerability of ARQ 197 administered in combination with CPT-11 plus C, and to define a recommended phase II dose (RPTD). Pts with locally advanced or mCRC, who received > 1 prior line of chemotherapy, were KRAS WT and ECOG performance status < 2 were eligible. Cohorts of 3 pts each were treated with CPT-11 (180 mg/m2) and C (500 mg/m2) every 2 weeks along with escalating doses of ARQ 197 (120, 240, 360 mg) PO BID. Blood and tissue specimens were collected for PK, biomarker, and other analyses. If no DLTs were observed during the first 28-day cycle for all 3 cohorts, 360 mg BID would be defined as the RPTD. Radiographic responses were assessed every 8 weeks per RECIST v1.1. Results: Nine pts were treated. Median age: 53 yr (range 30-77); ECOG PS 0/1: 4/5; median prior therapies: 2 (range 1-4). No DLTs were observed. To date, 4 pts have discontinued (2 disease progression, 2 withdrew consent), and 5 pts remain on study for median duration of 5.5 months (4.1-9.2). Reported grade 3/4 adverse events included: neutropenia (3/4: 0/1), fatigue (3/4: 2/0), and one case each of grade 3 leucopenia, acneiform rash, vomiting, diarrhea, anemia and syncope. Preliminary efficacy data in 9 evaluable pts include 1 CR (after 4 cycles), 2 PR (after 2 cycles), 5 SD, and 1 PD as best response. Conclusions: The combination of ARQ 197 and CPT-11 plus C was well tolerated with encouraging preliminary antitumor activity in previously treated mCRC patients. The RPTD for ARQ 197 was 360 mg BID. The randomized phase II portion of the study continues accrual.
ARQ197是c-MET单靶点小分子口服靶向药。上述临床的联合用药是ARQ197+西妥昔单抗+伊立替康，这个组合堪称奢华，但一期的实验结果也是让人眼前一亮。虽然国内用上这个方案的可能性几乎为零，但这种联合治疗的模式给我们的提供了很好的思路。看来c-MET靶点的药物在晚期肠癌治疗方面亦有其用武之地。
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