Safety and Efficacy of Sintilimab and Anlotinib as First Line Treatment for Advanced Hepatocellular Carcinoma (KEEP-G04): A Single-Arm Phase 2 Study

Abstract

Purpose: Immune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors may offer a first-line treatment for advanced hepatocellular carcinoma (HCC). In this phase 2 trial [registered with clinicaltrials.gov (NCT04052152)], we investigated the safety and efficacy of first-line anti-PD-1 antibody sintilimab plus antiangiogenic TKI anlotinib for advanced HCC.

Methods and materials: Pathologically-proven advanced HCC patients received sintilimab (200 mg) on day 1 and anlotinib (12 mg) once daily on days 1 to 14 every 3 weeks, with a safety run-in for the first six participants to assess dose-limiting toxicities (DLTs). The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1.

Results: Twenty advanced HCC patients were enrolled. No DLTs occurred in the safety run-in. All patients had treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 8 (40.0%) patients, the most common being decreased platelet count (10.0%) and increased γ-glutamyl transferase (10.0%). No grade 4/5 TRAEs occurred. Five (25%) patients developed immune-related AEs. The ORR was 35.0% (95%CI 15.4%-59.2%) per RECIST v1.1 and 55.0% (95%CI 31.5%-76.9%) per modified RECIST. At data cutoff (March 31, 2021), the median progression-free survival was 12.2 months (95%CI, 3.8 to not reached). The median PFS was significantly longer in patients with lower LDH levels (not reached [NR], 95% CI, 8.7 to NR vs. higher LDH levels 5.2 months, 95% CI 3.4 to NR; P=0.020) and a CONUT score ≤2 (NR, 95% CI 5.1 to NR vs. CONUT score >2 6.2 months, 95% CI 1.8 to NR; P=0.020). Furthermore, patients showing tumor response had a significantly higher median proportion of CD16+CD56+ NK cells than patients who had stable or progressive disease (21.6% vs. 14.6%; P=0.026).

Conclusion: Sintilimab plus anlotinib showed promising clinical activities with manageable toxicity as first-line treatment of advanced HCC.

Keywords: advanced hepatocellular carcinoma; anlotinib; anti-PD1; receptor tyrosine kinase; sintilimab.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Chen, Li, Wu, Zhao, Wang, Wu, Gu, Li, Qian, Hu, Li, Xia, Rao, Dai, Shao, Tang, Li and Shu.

Figures

Figure 1

The study flowchart.

Figure 2

Waterfall plots of the best percentage changes for the sum of target lesion diameters after treatment are shown for individual patients with best objective response per RECIST v1.1 (A) and modified RECIST (B) as indicated by the color codes. Both investigator-confirmed and unconfirmed responses are included. The dotted line indicates a 30% reduction in the target lesion size. Swimmer plots of time to tumor response (months) of individual unresectable or metastatic hepatocellular carcinoma patients. Responses were evaluated by RECIST v1.1 (C) and modified RECIST (D). Each bar represents one patient in the efficacy-evaluable population. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. (E) The spider plot presents individual changes in tumor measurements over time relative to baseline tumor burden in the study patients. Patients are coded in different colors.

Figure 3

The Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS) of unresectable or metastatic hepatocellular carcinoma patients in the efficacy-evaluable population.

Figure 4

The Kaplan-Meier curves of PFS of unresectable or metastatic hepatocellular carcinoma patients in the efficacy-evaluable population stratified by the presence or absence of immune related-adverse events (irAEs) (A), grade 3 treatment-related adverse events (TRAEs) (B), and baseline controlling nutritional status (CONUT) score (> 2 vs. ≤2) (C).