适合索拉非尼治疗或者在索拉非尼治疗时进展的患者纳入本研究，入组的都是AFP升高的患者，以便于使用AFP监测抗肿瘤疗效。患者随机接受160mg/天 的低剂量或者360mg/天的高剂量治疗。106名患者纳入了本研究，接受过索拉非尼治疗的患者比例分别为78%和83%。中位肿瘤进展时间（TTP）为 12周，其中低、高剂量组分别为12.6周、10.9周；其中未接受过索拉非尼治疗的患者，中位TTP是18.3周。按照肝癌发病的危险因素分层，未饮酒 者的TTP显著长于饮酒者（12.1周 vs 6.1周）。20%的患者AFP的下降幅度超过25%。根据这些结果，作者拟选取高剂量的 LY2157299进行下一步研究。
摘要详情：
Abstract:
Background: TGF-? signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety and antitumor activity of LY in HCC patients with elevated AFP in this ongoing study.
Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days =1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-? and E-cadherin) for each dose. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK).
Results: 106 patients were enrolled (Arm A=37; B=69), including 92% non-Asians. Baseline characteristics were (Arm A/B): median age 61/66 years; PS=0 60/51%; Child-Pugh A 97/86%; etiology: hepatitis C 30/33%, hepatitis B 24/25%, alcohol 22/22%. Overall, 78/83% of patients had received prior SF; 64/58% of patients had AFP ≥400 ng/mL. Median TTP was 12.0 weeks (90% CI: 7.1, 12.6) in the overall population (Arm A, 12.6 weeks; Arm B, 10.9 weeks). In SF-na?ve patients, TTP was 18.3 weeks (90% CI: 6.3-non-estimable). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-?1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >25% occurred in 21/106 patients (20%). Four patients discontinued treatment due to a drug-related AE. Most common grade 3/4 related AEs in patients were: neutropenia (n=3), GI bleeding (n=2), fatigue (n=2), and anemia (n=2). Preliminary PK analysis (51 patients) demonstrated moderate interpatient exposure variability (42%).
Conclusions: Based on the manageable toxicity profile, the evidence for biomarker/TTP responses, and an analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC.
Clinical trial information: NCT01246986.
