GPC3 Offers Highly Specific Target in HCC

Aiming to expand treatment options for patients with hard-to-treat malignancies such as hepatocellular carcinoma (HCC), investigators have turned their focus to GPC3, which has the potential to be targeted with reduced off-target toxicities compared with currently available targeted agents such as sorafenib (Nexavar) or lenvatinib (Lenvima).

“GPC3 is a cell surface antigen [that] interacts with various signaling pathways,” Khaldoun Almhanna, MD, a gastrointestinal oncologist at Brown University Health Cancer Institute in Providence, Rhode Island, explained in an interview with OncologyLive. “It’s involved in cell development and proliferation in cancer, especially in HCC. It’s also expressed in other malignancies such as breast, lung, gastric, and pancreatic cancer. GPC3 is an attractive target because it’s expressed only in cancer cells and not normal cells, which lessens the toxicity [of treatment].”

GPC3 is expressed in over 60% of HCC tumors, and the presence of the antigen is associated with a poor prognosis.1 Expression of GPC3 is restricted to the tumor cell surface, making it a potential target for T-cell engagers and other agent classes. Additionally, preclinical data have shown that chimeric antigen receptor (CAR) T-cell agents have preliminary efficacy in GPC3-positive tumors, including HCC.]

SAR444200 Demonstrates Feasibility of GPC3 Targeting in HCC

One anti-GPC3 agent, SAR444200, generated excitement among investigators by showing that targeting the antigen is feasible. The agent was examined for the treatment of adult patients with metastatic and/or unresectable HCC and other solid tumors in a phase 1/2 trial (NCT05450562).2 “SAR444200 is a bispecific T-cell engager that binds with T cells and tumor cells that express GPC3. It stimulates the immune system to attack GPC3-positive cells directly,” Almhanna said.

The phase 1/2 trial enrolled patients for whom available standard-of-care therapies were not suitable. These patients had tumors positive for GPC3 expression with an H-score of at least 1 and an ECOG performance status of 2 or less. During part 1A of the study, patients received SAR444200 monotherapy at escalating doses ranging from 3 mg every 2 weeks to 70 mg every 3 weeks following lead-in dosing.

The primary end points were the incidence of dose-limiting toxicities (DLTs) and adverse effects (AEs); key secondary end points included overall response rate (ORR), duration of response (DOR), pharmacokinetics, and the incidence of antidrug antibodies.

The median number of treatment cycles was 23 (range, 1-32), and most patients had HCC (n = 22 of 33). Most patients were heavily pretreated; the median number of prior lines of therapy was 4 (range, 2-8).

Updated findings presented during the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that patients treated across all dose levels achieved a best overall response of stable disease (30.3%), had disease progression (54.5%), or were not evaluable (NE; 15.2%). The disease control and clinical benefit rates were 30.3% and 9.1%, respectively.

Among patients with baseline α-fetoprotein (AFP) levels of at least 20 ng/mL (n = 18), 27% experienced an AFP decrease of at least 50% from baseline during treatment. Three patients experienced a sustained decrease in AFP levels exceeding 39 weeks, including 2 heavily pretreated patients with a shrinkage of tumor burden.

Regarding safety, any-grade AEs were reported in 97.0% of the overall population. Any-grade treatment-related AEs (TRAEs) occurred in 93.9% of patients; grade 3 or greater TRAEs were reported in 15.2% (Figure).2 DLTs comprised 2 instances of grade 3 or higher cytokine release syndrome (CRS), which occurred during lead-in dosing. Grade 3 or higher TRAEs reported in at least 5% of patients comprised CRS (9.1%), anemia (9.1%), disease progression (9.1%), and pneumonitis (6.1%).

Although the phase 1/2 study was terminated early due to sponsor portfolio reprioritization, the study authors emphasized that this was not due to safety or efficacy concerns. In addition to SAR444200, other GPC3-targeted agents are being pursued in HCC.

Additional GPC3-Targeted Agents Move Through the Development Pipeline

The GPC3-specific TGFβRIIDN armored autologous CAR-T cell therapy C-CAR031 is being examined for the treatment of patients with advanced HCC in a Chinese phase 1 study (NCT05155189).3 The trial enrolled patients aged 18 to 75 years old with GPC3-positive disease who experienced disease relapse or progression or who were intolerant to at least 1 line of systemic HCC therapy. The primary end point was safety and tolerability. Secondary end points included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival, and overall survival (OS).

Patients who received C-CAR031 across all dose levels (n = 24) achieved an ORR of 56.5%, including 75.0% among those treated at dose level 4 (n = 8). The DCR was 91.3% and the median target lesion reduction rate was 42.2% (range, –28.1%-94.4%). The median DOR was 7.36 months (range, 2.9-NE), and the median OS was not reached; the estimated median OS was 11.14 months (95% CI, 7.4-NE).

Regarding safety, all patients experienced TRAEs. The grade 3 or 4 TRAEs rate was 37.5% and there were no grade 5 TRAEs. Any-grade CRS was reported in 91.7% of patients, including grade 3 CRS in 4.2%. The median times to CRS onset and resolution were 3 days (range, 1-7) and 4 days (range, 2-8). Notably, there were no instances of immune effector cell–associated neurotoxicity syndrome.

“We’re getting better at treating the AEs [of GPC3-targeted therapy], especially CRS,” Almhanna said. “We need more data on the precise function and mechanism of GPC3, [but] it’s a big field that is moving forward and hopefully in the [coming] years we will see GPC3 used [more often] as a target.”

Moreover, plans to evaluate the trispecific T-cell engager AZD9793, which engages CD8+ T cells and GPC3-positive tumor cells, in the first-in-human phase 1/2 RHEA-1 study (NCT06795022) were presented during the 2025 ASCO Annual Meeting.1 The study is enrolling adult patients with locally advanced or metastatic GPC3-positive solid tumors. To be eligible for modules 1 and 2, patients must have received a diagnosis of HCC with at least 1 measurable lesion per RECIST 1.1 criteria. Other key eligibility criteria include an ECOG performance status of 0 or 1, Child-Pugh score class A disease, and Barcelona Clinic Liver Cancer stage B or C disease.

In the dose-escalation portion, patients in the second line or beyond will receive AZD9793 intravenously or subcutaneously via fixed-dosing in part A1 and step-up dosing, if necessary, in part A2. In part B, the dose expansion/optimization portion, patients will receive the agent via intravenous or subcutaneous administration using fixed or step-up dosing depending on the results of part A. In part B, patients will be randomly assigned to at least 2 recommended doses for expansion arms.

The primary objectives in parts A and B are safety and tolerability; preliminary efficacy by ORR will also be a primary end point in part B. Secondary end points include other preliminary efficacy measures, pharmacokinetics, immunogenicity, and CD8+ T-cell infiltration.

“We’ve come a long way in HCC [in recent years], but we can always use more treatments,” Almhanna said. “The current treatments are [largely] effective, but there are still patients who do not respond. We still don’t have a clear treatment for adjuvant therapy after resection or locoregional therapy. Given that [GPC3] is a target…expressed only on cancer cells, we expect [therapies directed toward it] to decrease toxicities and off-target AEs. It’s very specific, so there is a lot of potential.”

References

1. Champiat S, Grierson P, Hsieh JCH, et al. RHEA-1: first-in-human (FIH) study of AZD9793, a first-in-class CD8-guided T cell-engager (TCE) for glypican-3-positive (GPC3+) advanced or metastatic hepatocellular carcinoma (HCC). J Clin Oncol. 2025;43(suppl 16):TPS4215. doi:10.1200/JCO.2025.43.16_ suppl.TPS4215
2. Dumbrava EE, El-Khoueiry A, Samol J, et al. Phase 1/2, open-label, first-in-human study of the anti-GPC3 T-cell engager SAR444200 in patients with advanced solid tumors: updated efficacy and biomarker analysis. J Clin Oncol. 2025;43(suppl 16):2521. doi:10.1200/JCO.2025.43.16_suppl.2521 
3. Zhang Q, Fu Q, Cao W, et al. Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2024;42(suppl 16):4019. doi:10.1200/JCO.2024.42.16_suppl.4019