Abstract CT210: Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in patients (pts) with advanced hepatocellular carcinoma (HCC)
Authors: Iyer Renuka , Sonti Sahithi , Mahalingam Devalingam , Mukherjee Sarbajit , Chakraborty Sayan , Attwood Kristopher , George Anthony , Maguire Orla , Minderman Hans , Fountzilas Christos 
Published: April 2024

Abstract
Background: SOR is an active agent and has favorable immunomodulatory effects in HCC. Combinations of immune checkpoint inhibitors with SOR may enhance effector T-cell function and lead to improved clinical outcomes for patients with HCC. We tested this hypothesis in an open-label, multicenter study of SOR and PEM in patients with advanced HCC.
Methods: Pts with advanced or metastatic HCC, CP Class A, ECOG PS of 0/1 were included. One prior therapy was allowed. Pts were treated with SOR alone for 4 weeks (lead-in) at a stable dose (minimum 200 BID), followed by SOR plus PEM 200mg IV q3 weeks. The phase Ib part included the first 6 pts who completed the SOR lead-in and began SOR+PEM. Treatment continued until disease progression or unacceptable toxicity. Disease assessment was performed q6 weeks using the RECIST 1.1 criteria. The primary endpoint was overall response rate (ORR). The study used an exact one-stage design. With 27 evaluable pts, the study had 80% power to detect an ORR ≥20% with SOR/PEM vs. 5% with SOR alone (a=0.05). Peripheral blood mononuclear cells were collected at baseline and on-treatment for correlative analyses (flow cytometry).
Results: Of the 37 total pts enrolled, 27 were evaluable (9 female). Median age was 68 years. Forty-four percent of the pts had viral hepatitis. Four pts were pre-treated with atezolizumab/bevacizumab (n=3) or tivozanib/durvalumab (n=1). The ORR was 33% (95% CI: 18 - 52%) p= 0.08. Best response was PR in 9 patients (33%), 12 patients SD (44%), and 6 (22%) had PD. One patient had a near CR. Median progression-free (PFS) and overall survival (OS) were 4.8 (95% CI: 3.4 - 16.3) and 28.5 (95% CI: 15.2 - 57.7) months respectively. Fifty-two percent of patients had a decrease in AFP &gt;50%. One atezolizumab/bevacizumab pretreated pt with progressive disease as best response had a near-complete response to SOR+PEM. The most common grade ≥3 treatment-related adverse events (AEs) in the safety population (n=37) were hypertension (16%), immune-related AEs (11%), fatigue (8%) and diarrhea (8%). CD8+ T-cells increased by 5.5% (-35.6 - 36.9%; p=0.035) and Tregs decreased by 14.73% (-378.6 - 61%, p=0.049) from baseline to C1D1. The increase in activated Tregs prior to PEM initiation was associated with worse OS (HR: 1.8, p=0.03) while a higher Teff/Treg at C1D1 (prior to PEM initiation) was associated with improved PFS (HR: 0.4, p=0.036). An increase in the percentage of Tregs between baseline and C4D1 was associated with worse PFS (HR: 2; p=0.03).
Conclusions: SOR+PEM is a safe and active treatment for pts with advanced HCC. The results of our study confirm the favorable immunomodulatory effects of SOR and support further exploration of this regimen for patients with advanced HCC. Further tissue and blood correlative analyses are ongoing. NCT03211416.
Citation Format: Renuka Iyer, Sahithi Sonti, Devalingam Mahalingam, Sarbajit Mukherjee, Sayan Chakraborty, Kristopher Attwood, Anthony George, Orla Maguire, Hans Minderman, Christos Fountzilas. Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in patients (pts) with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT210.