A Randomized Phase 2 Study of Casdozokitug in Combination With Toripalimab Plus Bevacizumab in Participants With Unresectable and/or Locally Advanced or Metastatic Hepatocellular Carcinoma

Overview

CHS-388 (also known as SRF388; INN: casdozokitug, short name “casdozo”) is a first‑in‑class, clinical‑stage monoclonal antibody that targets the immunoregulatory cytokine interleukin‑27 (IL‑27). Early clinical experience includes a completed/ongoing first‑in‑human phase 1 study across solid tumors and a phase 2 open‑label cohort testing casdozokitug in combination with atezolizumab plus bevacizumab in previously untreated unresectable/metastatic hepatocellular carcinoma (HCC).(ascopubs.org)

Mechanism of action

IL‑27 is a heterodimeric cytokine (p28/EBI3) that signals via IL‑27Rα and gp130 to promote inhibitory checkpoint pathways and dampen pro‑inflammatory responses in the tumor microenvironment. Structural studies show SRF388 binds human IL‑27 at an epitope that overlaps the IL‑27Rα interface, antagonizing receptor engagement and downstream signaling; blockade has been associated with increased IFN‑γ/NK‑cell gene activation in clinical biomarker analyses.(pubmed.ncbi.nlm.nih.gov)

Efficacy

• HCC (first‑line), triplet combination (casdozokitug + atezolizumab + bevacizumab), phase 2 open‑label cohort (NCT05359861):
• Among 29 response‑evaluable patients (data cutoff August 9, 2023), investigator‑assessed ORR was 38% by RECIST v1.1 (including 3 CRs, 5 confirmed PRs, 3 unconfirmed PRs); by mRECIST, ORR was 43% (12/28 evaluable). Sixty‑seven percent of patients had any tumor shrinkage.(ascopubs.org)

• An updated ASCO GI 2025 abstract reports continued “promising antitumor activity” with the same regimen in 30 patients (data cutoff September 4, 2024); detailed efficacy numbers are consistent with prior reporting but not fully enumerated in the abstract text.(ascopubs.org)

• Phase 1 first‑in‑human study (NCT04374877):

• Monotherapy dose‑escalation (n=29 across tumor types) observed a confirmed PR in a heavily pretreated NSCLC patient and disease stabilization in multiple patients; these data supported selecting 10 mg/kg as the recommended phase 2 dose. Combination cohorts with pembrolizumab were also explored.(ascopubs.org)

Note: Additional signals in other tumor types have been described in meeting communications and company updates, but peer‑reviewed full manuscripts are not yet available. Priority is given here to scientific abstracts.(ascopubs.org)

Safety

• In the HCC triplet cohort (casdozokitug + atezolizumab + bevacizumab; n=30 treated), most treatment‑related adverse events (TRAEs) were low grade. The most common TRAEs were proteinuria (33%), fatigue (20%), decreased appetite (20%), and hypertension (20%). Grade 3/4 TRAEs occurred in 33% (hypertension ≥10%); 20% discontinued any study drug due to TRAEs; no treatment‑related deaths were reported. Safety was consistent with known profiles of atezolizumab/bevacizumab without new signals.(ascopubs.org)

• In phase 1 dose‑escalation (monotherapy, up to 20 mg/kg), SRF388 was well tolerated with no dose‑limiting toxicities or grade ≥3 treatment‑related events observed; pharmacokinetics supported dosing every 3–4 weeks, and pharmacodynamic assays showed pathway inhibition.(ascopubs.org)

Development status and ongoing studies

• Phase 1/1b first‑in‑human trial in advanced solid tumors (NCT04374877) continues with monotherapy and combination expansions (ccRCC, HCC, NSCLC).(kidneycancer.org)
• Phase 2 program in HCC includes a triplet with atezolizumab/bevacizumab (NCT05359861); abstracts note plans to evaluate casdozokitug with toripalimab plus bevacizumab in a randomized study.(ascopubs.org)

Further reading

• ASCO GI 2024 abstract: Triplet blockade with casdozokitug + atezolizumab + bevacizumab in first‑line unresectable/metastatic HCC (efficacy and safety details).(ascopubs.org)
• ASCO GI 2025 abstract: Updated phase 2 triplet data in HCC (clinical and biomarker updates).(ascopubs.org)
• ASCO 2022 abstract: First‑in‑human study of SRF388 monotherapy and with pembrolizumab in advanced solid tumors (dose selection, early activity, PK/PD).(ascopubs.org)
• Structural biology: Mechanistic insights into IL‑27 signaling and antagonism by SRF388.(pubmed.ncbi.nlm.nih.gov)

Notes on interpretation: The most detailed numerical efficacy and safety results currently come from meeting abstracts rather than peer‑reviewed full papers. As with all early‑phase data, findings should be considered preliminary and subject to confirmation in randomized trials.(ascopubs.org)

Last updated: Oct 2025

Key Inclusion Criteria:

* Unresectable locally advanced or metastatic HCC with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases criteria in cirrhotic participants.

* Disease that is not amenable to curative surgical and/or locoregional therapies or progressive disease (PD) after surgical and/or locoregional therapies.

* ≥ 1 measurable lesion (per RECIST v1.1) that is untreated.

Exclusion Criteria:

* Has received prior systemic therapy for HCC.

* Has previously received an anti-IL-27 antibody (Ab) or anti-IL-27-targeted therapy.

* Has known fibrolamellar HCC histology, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

* Has moderate or severe ascites.

* Has uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).

Additional protocol-defined inclusion/exclusion criteria apply.