BackgroundLEN is a multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT. In a Phase III trial (REFLECT), LEN demonstrated a treatment effect on overall survival (OS) by statistical confirmation of noninferiority vs sorafenib for first-line treatment of uHCC. PEMBRO is an anti-PD-1 monoclonal antibody. LEN and PEMBRO monotherapies are approved for unresectable first- and second-line treatment of HCC, respectively. We report updated results from a Phase Ib trial of LEN + PEMBRO in uHCC.

Methods In this open-label, multicenter phase 1b study of tolerability and safety of LEN + PEMBRO, patients (pts) with uHCC, BCLC stage C or B (not amenable for transarterial chemoembolization), Child-Pugh class A, and ECOG PS ≤ 1 received LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day, QD) and PEMBRO (200 mg IV Q3W). No dose-limiting toxicities were reported in Part 1 (n=6); thus, pts with no prior systemic therapy for uHCC (n=24) were enrolled in Part 2 (Expansion). Primary endpoint was safety. Tumor assessments were by investigators per modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC, and independent imaging review (IIR) per mRECIST and RECIST 1.1.

Results 30 pts were enrolled and received LEN + PEMBRO (Part 1, n=6; Part 2, n=24). Pts had BCLC stage B (n=9) or C (n=21), Child-Pugh scores of 5 (n=26) or 6 (n=4). At data cutoff (Aug 23, 2018), 18 (60%) pts were still on study treatment; median duration of follow-up was 9.7 months (95% CI 7.6-12.2). Any-grade treatment-emergent adverse events (TEAEs) occurred in 28 pts (93%); the most common any-grade TEAEs were decreased appetite (63%) and hypertension (60%). 7 (23%) pts discontinued treatment due to TEAEs, and no new safety signals were identified. Efficacy outcomes reported in the Table.

Conclusions The LEN + PEMBRO combination showed promising antitumor activity and an acceptable safety profile in pts with uHCC. The trial protocol has been amended to enroll up to a total of 100 pts to part 2 of the study.

LEN + PEMBRO (N=30) 
 mRECIST per investigator mRECIST per IIR RECIST 1.1 per IIR 
Objective Response Rate, n (%)* 11 (36.7) 15 (50.0) 11 (36.7) 
Best Overall Response, n (%)    
Complete Response* 1 (3.3) 3 (10.0) 
Partial Response* 10 (33.3) 12 (40.0) 11 (36.7) 
Stable Disease 18 (60.0) 13 (43.3) 16 (53.3) 
Progressive Disease 1 (3.3) 2 (6.7) 
Unknown/Not Evaluable 1 (3.3) 1 (3.3) 1 (3.3) 
LEN + PEMBRO (N=30) 
 mRECIST per investigator mRECIST per IIR RECIST 1.1 per IIR 
Objective Response Rate, n (%)* 11 (36.7) 15 (50.0) 11 (36.7) 
Best Overall Response, n (%)    
Complete Response* 1 (3.3) 3 (10.0) 
Partial Response* 10 (33.3) 12 (40.0) 11 (36.7) 
Stable Disease 18 (60.0) 13 (43.3) 16 (53.3) 
Progressive Disease 1 (3.3) 2 (6.7) 
Unknown/Not Evaluable 1 (3.3) 1 (3.3) 1 (3.3) 

IIR, independent imaging review; (m)RECIST, (modified) Response Evaluation Criteria in Solid Tumors (Lencioni et al. Semin Liver Dis. 2010 Feb;30(1):52-60). *Confirmed responses only

Citation Format: Masafumi Ikeda, Max W. Sung, Masatoshi Kudo, Masahiro Kobayashi, Ari D. Baron, Richard S. Finn, Shuichi Kaneko, Andrew X. Zhu, Tomoki Kubota, Silvija Kralijevic, Hiroki Ikezawa, Abby B. Siegel, Hiromitsu Kumada, Takuji Okusaka. A Phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT061.