Trial of Atezolizumab and Bevacizumab With CHS-388 or Placebo in Patients With Hepatocellular Carcinoma

This is a Phase 2 trial designed to evaluate the efficacy and safety of SRF388 in combination with atezolizumab plus bevacizumab (Arm A) compared to placebo in combination with atezolizumab plus bevacizumab (Arm B) in patients with first-line advanced or metastatic HCC.

After a Lead-In Phase of up to 30 patients who will receive open-label SRF388 + atezolizumab + bevacizumab, the blinded Randomized Phase will randomize approximately 104 patients with a 1:1 allocation to Arm A or Arm B and stratified by geographic region (Asia excluding Japan vs. rest of world) and Barcelona Clinic Liver Cancer (BCLC) stage (B or C).

• Casdozokitug (Drug), also known as CHS-388, SRF388: Casdozokitug will be administered by intravenous injection (IV)
• Atezolizumab (Drug), also known as Tecentriq: Atezolizumab will be administered by IV
• Bevacizumab (Drug), also known as Avastin: Bevacizumab will be administered by IV
• Placebo (Drug): Placebo will be administered by IV

Primary outcomes

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Up to approximately 37 months]: A TEAE was defined as an AE that emerged or worsened in the period from the first dose of study drug to 30 days after the last dose of study drug. A summary of other non-serious AEs and all serious AEs, regardless of causality, is located in the Reported AE section.

Secondary outcomes

• Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) [Up to approximately 38 months]: PFS was defined as the time from the date of randomization to the first documented evidence of disease progression as assessed according to RECIST v1.1 or death due to any cause, whichever occured first. Disease progression was defined according to RECIST v1.1 criteria, including at least a 20% increase in the sum of diameters of target lesions relative to the smallest sum recorded during the study, with an absolute increase in the sum of diameters of at least 5 millimeters (mm), or the appearance of one or more new lesions.
• PFS According to Hepatocellular Carcinoma Modified RECIST (HCC mRECIST) (mPFS) [Up to approximately 38 months]: mPFS was defined as the time from the date of randomization to the first documented evidence of disease progression as assessed according to HCC mRECIST or death due to any cause, whichever occured first. Disease progression was defined per HCC mRECIST criteria, including at least a 20% increase in the sum of diameters of target lesions (including viable tumor diameters for typical intrahepatic target lesions and short axis diameters for nodal lesions) relative to the smallest sum recorded during the study, with an absolute increase in the sum of diameters of at least 5 mm.
• Objective Response Rate (ORR) According to RECIST v1.1 [Up to approximately 38 months]: ORR was defined as the percentage of participants achieving complete response (CR) and partial response (PR) per RECIST v1.1. * CR: Disappearance of all extranodal target lesions. All pathological lymph nodes must have decreased to < 10 mm in short axis. * PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
• ORR According to HCC mRECIST (mORR) [Up to approximately 38 months]: mORR was defined as the percentage of participants achieving complete response CR and PR per HCC mRECIST. * CR: Disappearance of any intratumoral arterial enhancement in all target lesions.. All pathological lymph nodes must have decreased to < 10 mm in short axis. * PR: At least a 30% decrease in the sum of the diameters of viable (enhancement in the arterial phase) target lesions. target lesions, taking as reference the baseline sum diameters.
• Duration of Response (DoR) According to RECIST 1.1 [Up to approximately 38 months]: DoR was defined as the time from first documentation of CR or PR until the time of the first documentation of PD evaluated using RECIST v1.1 or death due to any cause.
• DoR According to HCC mRECIST (mDoR) [Up to approximately 38 months]: mDoR was defined as the time from first documentation of CR or PR until the time of the first documentation of PD evaluated using HCC mRECIST or death due to any cause.
• Disease Control Rate (DCR) According to RECIST v1.1 [Up to approximately 38 months]: DCR was defined as the percentage of participants who achieved CR, PR, or SD according to RECIST v1.1 for at least 12 weeks.
• DCR According to HCC mRECIST (mDCR) [Up to approximately 38 months]: mDCR was defined as the percentage of participants who achieved CR, PR, or SD according to HCC mRECIST for at least 12 weeks.
• Time to Progression (TTP) According to RECIST v1.1 [Up to approximately 38 months]: TTP was defined as time from study drug initiation to the occurrence of disease progression per RECIST v1.1.
• TTP According to HCC mRECIST (mTTP) [Up to approximately 38 months]: mTTP was defined as time from study drug initiation to the occurrence of disease progression per HCC mRECIST.
• Overall Survival (OS) [Up to approximately 38 months]: OS was defined as the time from study drug initiation to death from any cause.
• Time to Response (TTR) According to RECIST v1.1 [Up to approximately 38 months]: TTR was defined as the time from study drug initiation to initial documented objective response per RECIST v1.1.
• TTR According to HCC mRECIST (mTTR) [Up to approximately 38 months]: mTTR was defined as the time from study drug initiation to initial documented objective response per HCC mRECIST.
• Time on Therapy [Up to approximately 38 months]: Time on therapy was defined as the time from study drug initiation to last treatment.
• Mean Serum Epstein-Barr Virus Induced Gene 3 (EBI3) Concentration by Best Overall Response (BOR) According to RECIST v1.1 [Baseline up to approximately 38 months]: Baseline Serum EBI3 was collected and is reported by BOR status per RECIST v1.1. * CR: Disappearance of all target lesions. Any pathological lymph nodes must have reduction in the short axis to <10 mm. * PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of 1 or more new lesions is also considered progression.) * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• PFS According to RECIST v1.1 by Baseline Serum EBI3 Status [Up to approximately 38 months]: PFS was defined as the time from the date of randomization to the first documented evidence of disease progression as assessed according to RECIST v1.1 or death due to any cause, whichever occured first. Disease progression was defined according to RECIST v1.1 criteria, including at least a 20% increase in the sum of diameters of target lesions relative to the smallest sum recorded during the study, with an absolute increase in the sum of diameters of at least 5 millimeters (mm), or the appearance of one or more new lesions.
• TTP According to RECIST v1.1 by Baseline Serum EBI3 Status [Up to approximately 38 months]: TTP was defined as time from study drug initiation to the occurrence of disease progression per RECIST v1.1.
• OS by Baseline Serum EBI3 Status [Up to approximately 38 months]: OS was defined as the time from study drug initiation to death from any cause.

Sex: All, ages: 18 Years to any

Abbreviated Inclusion Criteria:

* ≥ 18 years of age on day of signing informed consent
* Unresectable locally advanced or metastatic HCC
* No prior systemic treatment for unresectable locally advanced or metastatic HCC
* BCLC Stage B or Stage C disease
* Child-Pugh Class A disease
* ≥ 1 measurable lesion per RECIST v1.1
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Laboratory values indicative of adequate organ function as defined in the protocol
* Women of childbearing potential must have a negative pregnancy test within 1 week prior to first dose of study drug
* Women of childbearing potential or men with a heterosexual partner of childbearing potential or pregnant must agree to refrain from sexual intercourse or be willing to use effective methods of contraception as defined in the protocol while receiving study drug and for 6 months after the last dose of any study drug

Abbreviated Exclusion Criteria:

* Currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
* Previously received an anti-interleukin (IL)-27 antibody (Ab) or anti-IL-27-targeted therapy.
* Received prior systemic therapy for unresectable or metastatic disease. (Note: Prior systemic therapies administered for neoadjuvant, adjuvant, or curative intent (localized disease) are permitted if they were given > 1 year prior to the development of recurrent or metastatic disease)
* Known fibrolamellar HCC histology, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
* Moderate or severe ascites
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* History of or current hepatic encephalopathy
* Unable to undergo disease evaluation with a triphasic CT or MRI because of contrast allergy or other contraindication
* Untreated or incompletely treated varices with bleeding or high risk for bleeding.
* Symptomatic or untreated brain metastases or leptomeningeal carcinomatosis.
* Active or history of autoimmune disease or immune deficiency with some exceptions such as controlled thyroid disease, Type 1 diabetes, eczema and other minor skin disorders.
* Medical conditions requiring chronic steroid therapy (ie, > 10 mg/day of prednisone or its equivalent) or anticipates the need for systemic immunosuppressive medications during treatment with study drug
* Known active infection with HIV
* Known infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), except for controlled active HBV or fully treated HCV infection as defined by the protocol
* Inadequately controlled arterial hypertension

Participant flow

Outcome results

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Casdozokitug + Atezolizumab + Bevacizumab 30
• Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab 8.3 (2.0 to 14.5)
• PFS According to Hepatocellular Carcinoma Modified RECIST (HCC mRECIST) (mPFS) (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab 10.3 (2.0 to 20.0)
• Objective Response Rate (ORR) According to RECIST v1.1 (Secondary), Number, percentage of participants: Casdozokitug + Atezolizumab + Bevacizumab 39.3 (21.5 to 59.4)
• ORR According to HCC mRECIST (mORR) (Secondary), Number, percentage of participants: Casdozokitug + Atezolizumab + Bevacizumab 44.4 (25.5 to 64.7)
• Duration of Response (DoR) According to RECIST 1.1 (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab NA (12.7 to NA)
• DoR According to HCC mRECIST (mDoR) (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab NA (12.7 to NA)
• Disease Control Rate (DCR) According to RECIST v1.1 (Secondary), Number, percentage of participants: Casdozokitug + Atezolizumab + Bevacizumab 60.7 (40.6 to 78.5)
• DCR According to HCC mRECIST (mDCR) (Secondary), Number, percentage of participants: Casdozokitug + Atezolizumab + Bevacizumab 63.0 (42.4 to 80.6)
• Time to Progression (TTP) According to RECIST v1.1 (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab 8.1 (2.0 to 13.6)
• TTP According to HCC mRECIST (mTTP) (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab 8.4 (2.0 to 24.6)
• Overall Survival (OS) (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab NA (14.5 to NA)
• Time to Response (TTR) According to RECIST v1.1 (Secondary), Mean, months: Casdozokitug + Atezolizumab + Bevacizumab 3.28 +/- 1.433
• TTR According to HCC mRECIST (mTTR) (Secondary), Mean, months: Casdozokitug + Atezolizumab + Bevacizumab 2.90 +/- 1.457
• Time on Therapy (Secondary), Mean, weeks: Casdozokitug + Atezolizumab + Bevacizumab 46.7 +/- 43.34
• Mean Serum Epstein-Barr Virus Induced Gene 3 (EBI3) Concentration by Best Overall Response (BOR) According to RECIST v1.1 (Secondary), Mean, ng/mL: Casdozokitug + Atezolizumab + Bevacizumab: Participants With CR 2.117 +/- 1.4513; Casdozokitug + Atezolizumab + Bevacizumab: Participants With PR 2.347 +/- 1.0920; Casdozokitug + Atezolizumab + Bevacizumab: Participants With SD 1.572 +/- 1.0121; Casdozokitug + Atezolizumab + Bevacizumab: Participants With PD 2.194 +/- 1.1775; Casdozokitug + Atezolizumab + Bevacizumab: Participants With BOR Not Evaluable 3.203 +/- 2.9529
• PFS According to RECIST v1.1 by Baseline Serum EBI3 Status (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab: Participants With <= Median Baseline EBI3 Concentration 8.1 (1.9 to 24.6); Casdozokitug + Atezolizumab + Bevacizumab: Participants With > Median Baseline EBI3 Concentration 8.4 (1.9 to 20.0)
• TTP According to RECIST v1.1 by Baseline Serum EBI3 Status (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab: Participants With <= Median Baseline EBI3 Concentration 8.1 (1.9 to 24.6); Casdozokitug + Atezolizumab + Bevacizumab: Participants With > Median Baseline EBI3 Concentration 8.4 (1.9 to NA)
• OS by Baseline Serum EBI3 Status (Secondary), Median, months: Casdozokitug + Atezolizumab + Bevacizumab: Participants With <= Median Baseline EBI3 Concentration NA (9.5 to NA); Casdozokitug + Atezolizumab + Bevacizumab: Participants With > Median Baseline EBI3 Concentration 19.9 (14.0 to NA)

Adverse events

Time frame: Up to approximately 39 months

Serious adverse events by term

Other adverse events by term

106 more terms not shown.

Limitations and caveats: Only the Lead-In Phase of the study was completed prior to study termination.

• Study Protocol (PDF, 2024-09-19)
• Statistical Analysis Plan (PDF, 2025-08-11)

• Study Director, Study director, Coherus Oncology