Commentary
Article
Daneng Li, MD, discusses the efficacy and safety findings of a casdozokitug-based regimen in unresectable, advanced HCC.
Hepatocellular Carcinoma |
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A triplet regimen comprised of casdozokitug (CHS-388), atezolizumab (Tecentriq), and bevacizumab (Avastin) demonstrated antitumor activity with a manageable safety profile in the treatment of patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma (uHCC), according to Daneng Li, MD.
Data from a phase 2 trial (NCT05359861) revealed that in response-evaluable patients (n = 29), the overall response rate (ORR) was 37.9% per RECIST 1.1 criteria. Of note, 17.2% of patients achieved a complete response (CR); confirmed partial response, stable disease, and disease progression were observed in 20.7%, 27.6%, and 31.0% of patients, respectively. Additionally, the median progression-free survival (PFS) was 8.1 months (95% CI, 1.9-13.6), and the median overall survival was 19.9 months (95% CI, 14.2-not reached). The disease control rate (DCR) per RECIST 1.1 criteria was 58.6%, and the modified DCR per RECIST 1.1 criteria was 60.7%.
“The landscape of HCC continues to rapidly evolve, and we're doing everything possible to achieve good control of the tumor, like in this study, in terms of having a very impressive complete response rate of 17.2%, which is certainly encouraging for our patients,” Li said in an interview with OncLive®.
During the interview, Li discussed the rationale for evaluating the triplet regimen in uHCC, the efficacy and safety data from the phase 2 study, and future research directions evaluating casdozokitug.
Li is an associate professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Neuroendocrine Tumor Program at City of Hope in Duarte, California.
Li: IL-27 is an immune modulatory cytokine that's expressed on myeloid cells, including macrophages, dendritic cells, and plays a role in terms of dampening T cells, as well as natural killed effector cell function. One of the things that's particularly interesting about IL-27 is that it's highly expressed on tumor-associated macrophages in several cancers, including HCC.
Casdozokitug is a first-in-class, high-infinity human IL-27 antagonist antibody, which promotes immune activation, thereby helping with antitumor response. We previously performed a phase 1 study of casdozokitug as a single agent, and it demonstrated favorable safety as well as antitumor activity. That was also looked at in combination with a PD-1 blockade in various types of indications, including HCC, renal cell carcinoma, and non–small cell lung cancer. Based on the preliminary phase 1 study, we therefore performed this open-label phase 2 trial of this triplet blockade with casdozokitug for patients with uHCC.
This is an open-label, phase 2 trial that looked at the combination of casdozokitug with standard-of-care [SOC] treatment of the combination of atezolizumab and bevacizumab for the treatment of patients with advanced or metastatic HCC. As part of this initial open-label lead-in and safety analysis, we accrued a total of 30 patients. All patients receive the triplet combination of atezolizumab/bevacizumab plus casdozokitug intravenously every 3 weeks, and the primary end point was initial safety, along with key secondary end points of ORR, PFS, and DCR.
In this study, we saw very promising efficacy data. Specifically, we saw an ORR of 37.9% per RECIST 1.1 criteria, which is historically higher compared with our current SOC, as well as the ORR of 43% per modified RECIST 1.1 criteria, which is also higher compared with our SOC treatment.
What was particularly interesting about this study is the fact that we saw a CR rate of 17.2%, which is actually quite remarkable. These are patients having all their tumors essentially disappear on imaging per RECIST 1.1 criteria, which is very promising. Compared with our historical first-line treatments that we have for HCC, the CR rate in these patients is only anywhere between 2% to 8%. Therefore, having a 17.2% CR rate for these patients is very remarkable. This now begs the question of whether these patients are potentially in ongoing remission from their cancer, for aggressive tumors like HCC, which is incredibly promising for the future.
The overall safety profile of the triplet combination was also very encouraging, and this is important as well. Whenever we're trying to build on this current SOC and add additional agents, the concern for our patients is whether those treatments will be well tolerated. What you can see from our study is that when we add in casdozokitug, there weren't necessarily any additional adverse effects [AEs] that we saw compared with our SOC of just atezolizumab/bevacizumab. Most of the grade 3 or higher toxicities were often already associated with bevacizumab, such as hypertension and proteinuria. We had very minimal—if any—grade 4 AEs, and no grade 5 treatment-related toxicities.
From my experience with treating patients with casdozokitug, some of the AEs that we've noticed is that some patients express that they might have some grade 1 chills or experience a colder sensation. One of the key areas to also highlight is that the addition of casdozokitug so far is very tolerable, with minimal additional AEs that impact our patients receiving treatment in the first-line setting for uHCC.
The next steps are to go to a randomized, phase 2 study. Most recently, we were able to launch a randomized phase 2 study [NCT04723004] of casdozokitug now in combination with toripalimab-tpzi [Loqtorzi] plus bevacizumab. The rationale for using toripalimab is that, most recently, the phase 3 HEPATORCH study [NCT04723004] showed that toripalimab plus bevacizumab was superior to the older SOC in terms of sorafenib [Nexavar] in the first-line setting. This establishes that toripalimab/bevacizumab is equivalent as a potential first-line SOC treatment. Therefore, for our future with the triplet combination, we're combining it in a randomized phase 2 fashion with casdozokitug plus toripalimab with bevacizumab vs toripalimab plus bevacizumab, and that will establish whether the triplet combination has superior efficacy, along with tolerable safety compared with our SOC doublet regimens.
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