Preliminary Casdozokitug Activity in HCC Supports Further Exploration of IL-27 as a Treatment Target

Daneng Li, MD

IL-27 pathway blockade is gaining traction in early-phase clinical trials as a mechanism for reducing IL-27–mediated antitumor immune system suppression in solid tumors, most notably hepatocellular carcinoma (HCC) and non–small cell lung cancer (NSCLC), in which this immunoregulatory cytokine is highly expressed on tumor-associated macrophages.1,2

“IL-27 is an immune-modulatory cytokine that’s expressed on myeloid cells, including macrophages and dendritic cells, and it plays a role in terms of dampening T-cell and natural killer [NK] effector cell function,” Daneng Li, MD, noted in an interview with OncologyLive during the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI).

“Casdozokitug [CHS-388; formerly SRF388] is a first-in-class, high-infinity human IL-27 antagonistic antibody that promotes immune activation, thereby helping with antitumor response.” Li is an associate professor in the Department of Medical Oncology and Therapeutics Research and codirector of the neuroendocrine tumor program at City of Hope in Duarte, California.

Casdozokitug has been shown to boost immune system activation and drive T and NK cell–driven antitumor responses in the tumor microenvironment that IL-27 is known to inhibit. In the NSCLC cohorts of parts A and B of a phase 1 trial (NCT04374877), casdozokitug monotherapy was associated with a tolerable safety profile and demonstrated antitumor activity and immune activation in heavily pretreated, PD-(L)1 inhibitor–exposed patients with squamous NSCLC.1 Among response-evaluable patients (n = 42), the objective response rate (ORR) was 5%; all responses were confirmed partial responses (PRs), and the rate of stable disease (SD) was 26%. Notably, the ORR was 22% among patients with RECIST-evaluable squamous disease (n = 9). This trial also showed favorable preliminary safety profiles and antitumor activity when casdozokitug was combined with the PD-1 inhibitors pembrolizumab (Keytruda) and toripalimab-tpzi (Loqtorzi) in patients with NSCLC, renal cell carcinoma, or HCC, which are known to have high levels of IL-27 pathway activation.

Translational analyses from this phase 1 trial showed that IL-27 expression levels were upregulated following PD-(L)1 treatment in tumor biopsies from patients with squamous NSCLC and those with NSCLC adenocarcinoma. Moreover, IL-27 expression levels from biopsies from patients with squamous disease were significantly higher than those from patients with adenocarcinoma, suggesting that IL-27 may be a resistance factor for anti–PD-(L)1 inhibitor mediated antitumor immunity.

Expanding on these findings, an open-label phase 2 trial (NCT05359861), for which Li was the lead author, investigated the combination of casdozokitug plus the PD-L1 inhibitor atezolizumab (Tecentriq) and the VEGF inhibitor bevacizumab (Avastin) in patients with previously untreated advanced, unresectable, or metastatic HCC.1,2 This trial enrolled 30 patients with Barcelona Clinic Liver Cancer B or C and Child-Pugh A disease and an ECOG performance status of 0 or 1.2 Patients with controlled hepatitis B virus or cured hepatitis C virus were permitted to enroll.

In this single-arm trial, patients received atezolizumab at 1200 mg, bevacizumab at 15 mg/kg, and casdozokitug at 10 mg/kg all intravenously every 3 weeks. Safety was the primary end point. Key secondary end points included progression-free survival (PFS), ORR, and disease control rate (DCR).

Spotlighting the Clinical Activity of IL-27/PD-(L)1/VEGF Pathway Blockade

Data presented at ASCO GI showed that the median time on treatment was 36 weeks (range, 3-122). At data cutoff, 40% of patients remained on the study, and 16.7% of patients were still receiving study treatment.

Among RECIST 1.1–evaluable patients (n = 29), the ORR was 37.9%, the complete response (CR) rate was 17.2%, and the confirmed PR rate was 20.7%. Additionally, 27.6% and 31.0% of patients had best responses of SD and progressive disease (PD), respectively; 1 patient was not evaluable (NE) for response. The antitumor activity of the triplet was seen across patients with viral and nonviral HCC subtypes.

Among modified RECIST (mRECIST)– evaluable patients (n = 28), the ORR was 42.9%; the rates of CR and confirmed PR were 17.9% and 25.0%, respectively. In total, 25.0% and 28.6% of patients had best responses of SD and PD, respectively; 1 patient was NE for response.

In the RECIST 1.1–evaluable population, the median PFS was 8.1 months (95% CI, 1.9-13.6). The 6-, 12-, and 18-month PFS rates were 58.6% (95% CI, 38.8%-74.0%), 36.1% (95% CI, 19.0%-53.6%), and 27.1% (95% CI, 11.9%-44.9%), respectively. The median overall survival (OS) was 19.9 months (95% CI, 14.2-NE). The 6-, 12-, and 18-month OS rates were 88.7% (95% CI, 68.9%-96.2%), 84.9% (95% CI, 64.5%-94.0%), and 56.6% (95% CI, 34.0%-74.0%), respectively.

Furthermore, the DCR per RECIST 1.1 criteria was 58.6%, and the median duration of response (DOR) was not reached (NR; 95% CI, 6.1 months-NR). Among mRECIST-evaluable patients (n = 28), the DCR was 60.7%, and the median DOR was NR (95% CI, 12.7 months-NR; Table).2

“These are patients who are having all their tumors…disappeared on imaging per RECIST criteria, which is promising,” Li emphasized. “If you compare these [outcomes] with [those with] historical first-line treatments for HCC, the CR rate in these patients with the current standard-of-care treatments is only [approximately] 8%, so an over 17% CR rate for these patients is remarkable. [Additionally, for] many of these patients, [these responses have] been durable, lasting for multiple years now. This begs the question: Are these patients potentially in ongoing remission from their cancer, an aggressive tumor like HCC? [That] is incredibly promising for the future.”

Breaking Down the Triplet's Safety Profile and Pharmacodynamics

All patients experienced treatment-emergent adverse effects (TEAEs), and 90.0% of patients had treatment-related AEs (TRAEs). Grade 3 or higher TEAEs and TRAEs were reported in 66.7% and 40.0% of patients, respectively. In total, 46.7% and 26.7% of patients had serious TEAEs and serious TRAEs, respectively. TEAEs led to discontinuation of any study drug; discontinuation of casdozokitug; and death in 30.0%, 20.0%, and 10.0% of patients, respectively. TRAEs led to discontinuation of any study drug and discontinuation of casdozokitug in 23.3% and 13.3% of patients, respectively; no patients died due to TRAEs.

The toxicities reported with the triplet were consistent with the known AE profiles of each of the study drugs. The most common TEAEs/ TRAEs were proteinuria, decreased appetite, diarrhea, hypertension, fatigue, rash, hyponatremia, headache, decreased platelet counts, pruritus, pyrexia, increased alanine aminotransferase levels, arthralgia, and increased aspartate aminotransferase levels.

The trial investigators used an independently validated assay to perform immunohistochemistry staining for IL-27 on archival resection and biopsy tissue samples. This analysis revealed a preliminary association between higher levels of IL-27–positive tumor-associated macrophages and clinical CR or PR with the triplet. Additionally, the triplet was shown to promote NK- and T-cell activation, as well as inhibit IL-27 signaling.

Reframing the Future of Targeted Therapy for HCC

Building on positive findings from the single-arm phase 2 research, an ongoing randomized phase 2 trial (NCT06679985) is investigating the efficacy of casdozokitug plus toripalimab and bevacizumab vs toripalimab plus bevacizumab alone in patients with unresectable and/ or locally advanced or metastatic HCC.3 Notably, the phase 3 HEPATORCH trial (NCT04723004), which evaluated first-line bevacizumab plus toripalimab vs sorafenib (Nexavar) in patients with advanced HCC, met its dual primary end points of PFS per independent radiographic review and OS.4

“One of the key differentiators with targeting IL-27 is that this is a novel pathway that has not been previously explored,” Li explained. “These [phase 2 trial data provide] preliminary evidence and the beginning of potentially [treating] patients who have aggressive HCC in a targeted fashion. We have never been able to achieve that with HCC previously. [However, if we determine that] IL-27 is a predictive biomarker that we can [use to] see [which patients] are likely to respond [to IL-27–targeted therapy], then we can start to target HCC as a targetable tumor, which so far has been a challenge for the field and something we haven’t established. I look at this as an opening of a targeted therapy era for HCC moving forward.”

References

1. Naing A, Mantia C, Pennell N, et al. Casdozokitug (casdozo, CHS-388), a first-in-class IL-27 antagonistic antibody, as monotherapy in treatment-refractory non-small cell lung cancer (NSCLC). Immunooncol Technol. 2024;24:100783. doi:10.1016/j.iotech.2024.100783
2. Li D, Rau KM, Yu ML, et al. 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). J Clin Oncol. 2025;43(suppl 4):605. doi:10.1200/ JCO.2025.43.4_suppl.605
3. A trial of casdozokitug in combination with toripalimab plus bevacizumab in participants with unresectable and/or locally advanced or metastatic hepatocellular carcinoma. ClinicalTrials. gov. Updated April 6, 2025. Accessed April 14, 2025. https:// clinicaltrials.gov/study/NCT06679985
4. Junshi Biosciences announces phase 3 study of toripalimab combined with bevacizumab for the first-line treatment of advanced hepatocellular carcinoma meets primary endpoint. News release. Shanghai Junshi Biosciences, Co, Ltd. June 11, 2024. Accessed April 14, 2025. https://www.biospace.com/ junshi-biosciences-announces-phase-3-study-of-toripalimabcombined-with-bevacizumab-for-the-first-line-treatment-ofadvanced-hepatocellular-carcinoma-meets-primary-endpoint