On January 22, 2025 Coherus BioSciences, Inc. (Coherus, NASDAQ: CHRS), reported final data from its Phase 2 open label clinical trial evaluating casdozokitug (casdozo), a selective and potent Interleukin (IL)-27-targeting antibody, in combination with atezolizumab (atezo) and bevacizumab (bev) in treatment naïve patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) (Press release, Coherus Biosciences, JAN 22, 2025, View Source [SID1234649822]). These data are being presented at the 2025 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium taking place January 23-25, 2025, in San Francisco, California.
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These data showed an overall response rate of 38% compared to initially announced 27%1, and complete responses (CR) per RECIST v1.1 increased to 17.2% compared to previously announced 10.3%2 and initial assessment of 0%1, demonstrating both an increase in ORR and a deepening of responses compared to previous datasets. Importantly, responses were seen in viral and nonviral disease, and toxicity was consistent with the known safety profiles of atezolizumab and bevacizumab, with no new safety signals identified.
These data support continued evaluation of casdozo with other therapies, including a trial of casdozo/toripalimab (tori)/bev in HCC, which Coherus has now opened for enrollment. Casdozo is a first-in-class antibody, and the only clinical-stage immunomodulatory cytokine antagonist targeting IL-27, an immunoregulatory cytokine involved in suppressing anti-tumor immune responses and an important new target for cancer treatment.
"The casdozo data in HCC demonstrate translation of the preclinical data in liver cancer to first-line HCC cancer patients with efficacy and a favorable safety profile. These data support the ongoing development of IL-27 as a promising novel target for advanced solid tumors," said Rosh Dias, M.D., Coherus’ Chief Medical Officer. "We recently opened enrollment for our randomized, controlled, multinational Phase 2 trial of casdozo in combination with toripalimab, our anti-PD-1 antibody, plus bev. The combination of tori plus bev has demonstrated promising Phase 3 results in HCC3, and we believe the addition of casdozo may further enhance anti-tumor effects and advance our next-generation immuno-oncology combinations focused on overcoming immune suppression in the tumor microenvironment."
"The treatment landscape for liver cancer, particularly for patients who are not eligible for surgery or who are metastatic, has improved in recent years thanks to immunotherapy combinations. However, there is still a clear unmet need for novel treatment options that can further improve survival without added toxicity," said Daneng Li, M.D., Associate Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director, Liver Cancer Collaborative Program, City of Hope Comprehensive Cancer Center. "These final casdozo data continue to be encouraging and compare very favorably in the current treatment landscape, and speak to the potential for its novel anti-IL-27 mechanism to address these substantial unmet needs."
Results from Phase 2 trial evaluating casdozo/atezo/bev combination in HCC
This open-label Phase 2 clinical trial evaluated casdozo in combination with atezo and bev in 30 treatment-naïve patients with unresectable locally advanced or metastatic HCC. Patients received casdozokitug 10 mg/kg IV q3w in combination with atezolizumab (1200 mg) and bevacizumab (15 mg/kg). The primary endpoint was safety and tolerability. Key secondary endpoints included PFS and ORR based on investigator review per RECIST v1.1 (primary) and mRECIST (secondary), as well as disease control rate (DCR).
As of the data cutoff date of September 4, 2024:
Triplet blockade of the IL-27, PD-(L)1 and VEGF inhibitors with casdozo/atezo/bev demonstrated an acceptable safety profile with promising antitumor activity in immunotherapy naïve HCC.
Triplet combination treatment was well tolerated with a side effect profile consistent with known adverse event (AE) profiles of atezo/bev.
Encouraging early activity with casdozo/atezo/bev:
RECIST v1.1: ORR of 38% (n=29) with 11 objective responses, including 5 complete responses and 6 confirmed partial responses; median progression-free survival (PFS) of 8.1 months and disease control rate of 58.6%.
mRECIST: ORR of 43% (n=28) with 12 objective responses, including 5 complete responses and 7 confirmed partial responses; median PFS of 8.4 months and disease control rate of 60.7%.
Biomarker data show peripheral inhibition of IL-27 signaling and immune activation in NK and T cells following treatment, consistent with the casdozo preclinical data and mechanism of action.
These results support continued evaluation of casdozo with VEGF and PD-(L)1 blockade in HCC.
Recent Launch of New Phase 2 trial evaluating casdozo in combination with bev and toripalimab
Coherus has initiated a new randomized Phase 2 study (NCT06679985) evaluating casdozo, in combination with bev and tori, Coherus’ next-generation anti-PD-1 monoclonal antibody, in participants with unresectable locally advanced or metastatic HCC. This randomized, parallel, open-label Phase 2 study is designed to evaluate the safety, efficacy, and Project Optimus4 dosing of the triplet combination. The study is expected to enroll up to 72 patients, who will be randomized to receive one of two biologically active doses of casdozo with tori plus bev or tori plus bev without casdozo.
ASCO-GI 2025 Presentation Details
Title: 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)
Lead Author: Daneng Li, City of Hope National Comprehensive Cancer Center
Abstract 605: Poster Board #D6
Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Date and Time: Friday, January 24, 2025; 11:30am – 1:00pm PT
About Hepatocellular Carcinoma
Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma; HCC), gall bladder, and bile ducts (collectively called biliary tract cancers). The most common type of primary liver cancer in adults is HCC (accounting for ~90%), which is the third leading cause of cancer-related deaths worldwide. According to the NCI Surveillance, Epidemiology and End Results Program (SEER), there will be an estimated 41,630 new cases and 29,840 deaths from liver and intrahepatic bile duct cancer in the US in 2024.5 The U.S. 5-year relative survival rate for liver and intrahepatic bile duct cancer is 21.7%.5 The liver cancer treatment pattern has changed in recent years with the emergence of immunotherapy combinations and will continue to evolve as more treatment options become available for these highly lethal cancers.
About Casdozokitug
Casdozokitug is a first-in-class human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine. Particular tumor types have been identified where IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors. Blocking IL-27 with casdozokitug in clinical trials has led to monotherapy tumor growth inhibition and partial responses in patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) (NCT04374877). An ongoing trial is studying combinations with PD-(L)1 pathway blockade in NSCLC, and a planned clinical trial will study the triplet combination of IL-27, PD-(L)1, and VEGF pathway blockade in HCC. Casdozokitug has been granted Orphan Drug designation and Fast Track designation for the treatment of refractory hepatocellular carcinoma from the FDA. It is the first IL-27 antibody to enter the clinic.