Results from a phase 2 study of triplet blockade of the IL-27, PD-(L)1, and VEGF pathways with casdozokitug (casdozo, CHS-388) in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).
Authors: Li Daneng , Rau Kun-Ming , Yu Ming-Lung , Chon Hong Jae , Pelster Meredith , Roberts Stuart K. , Crysler Oxana V. , Vaccaro Gina M. , Kim Hyung-Don , Iizuka Koho , Tang Hong , Kapoor Varun N , Chin Daniel J , Hsu Chih-Hung , Kang Yoon-Koo 
Published: January 2025

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Background:
Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which induces increased serum IFN-γ and NK cell gene activation, leading to reversal of IL-27-mediated immune suppression. A phase (Ph) 1 study demonstrated a favorable safety profile and antitumor activity of casdozo alone and in combination with PD-1 blockade in indications with known high levels of IL-27 pathway activation, including HCC (NCT04374877). This open-label Ph 2 trial examined the potential antitumor activity and safety of casdozo with PD-L1 and VEGF blockade in uHCC (NCT05359861). Updated clinical and biomarker data are presented.
Methods:
Patients (Pts) with untreated uHCC received casdozo 10 mg/kg, atezolizumab (atezo) 1200 mg, and bevacizumab (bev) 15 mg/kg IV Q3W. Primary endpoints were safety and tolerability, with key secondary endpoints of investigator-assessed ORR by RECIST1.1 and mRECIST, PFS, and OS.
Results:
As of Sept 4, 2024, 30 pts received casdozo/atezo/bev. Most pts were male (77%), Asian (67%), had viral etiology (53% HBV, 17% HCV), and poor-prognosis disease assessed by metastatic spread (67%) and/or macrovascular invasion (13%). Median follow-up was 15 months (mo). Median time on therapy was 8 mo. The most common (>20%) adverse events related to any study drug were proteinuria (43%), hypertension (27%), fatigue (23%), and diarrhea (20%); Grade ≥3 events occurred in 67%, with only hypertension (20%), arising in >10% of pts. Treatment-emergent adverse events (TEAEs) resulting in any study drug discontinuation occurred in 30% of pts. No treatment-related deaths were reported. In the 29 RECIST1.1 response-evaluable pts, ORR was 38% with 17% of pts achieving a CR (5 CRs, 6 PRs); mPFS (95% CI) was 8.1 mo (1.9, 13.6); landmark PFS rates at 6, 12 and 18 mo were 58.6%, 36.1% and 27.1%, respectively; mDoR (95% CI) was NR (6.1, -). In the 28 pts evaluable for mRECIST, ORR was 43% (5 CRs, 7 PRs); mPFS (95% CI) was 8.4 mo (2.0, 14.5); mDoR was NR (12.7, -). mOS (95% CI) was 19.9 mo (14.2, -); the 12-mo survival rate (95% CI) was 85% (65, 94). More than 40% of pts remain on study, and 16.7% remain on study treatment. Available archival tissue of responders expressed IL-27+ TAMs by IHC, including tumors of viral and nonviral etiologies.
Conclusions:
Triplet blockade of IL-27, PD-(L)1, and VEGF pathways with casdozo/atezo/bev continues to show a manageable safety profile with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing. Additional clinical studies of casdozo in combination with toripalimab are planned.
Clinical trial information: NCT05359861
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