Phase III Randomized Open‑Label Study of Atezolizumab + Lenvatinib or Sorafenib vs Lenvatinib/Sorafenib Alone in Previously Treated Unresectable HCC

The primary objective is to assess the effect of atezolizumab combined with lenvatinib or sorafenib versus lenvatinib or sorafenib alone on overall survival in patients with unresectable hepatocellular carcinoma who have previously received atezolizumab‑bevacizumab, providing a direct measure of clinical benefit in this setting.

Secondary objectives include:

• Evaluation of efficacy endpoints such as progression‑free survival, objective response rate, time to progression, duration of response, time to confirmed deterioration and health‑related quality of life for the combination versus monotherapy.
• Assessment of patient‑reported outcomes covering general health status/quality of life for the combination versus monotherapy arms.
• Characterisation of safety by monitoring incidence and severity of adverse events, vital signs, and clinical laboratory parameters.
• Characterisation of the pharmacokinetic profile of atezolizumab when administered with lenvatinib or sorafenib.
• Evaluation of the immune response to atezolizumab.

284 participants were enrolled, comprising both male and female patients classified as vulnerable. Eligible individuals were adults (age categories corresponding to codes 3 and 4) with unresectable hepatocellular carcinoma that was locally advanced, metastatic, or not amenable to curative surgery or locoregional therapy, confirmed by histology, cytology, or American Association for the Study of Liver Diseases criteria. Selection required an Eastern Cooperative Oncology Group Performance Status of 0 or 1 and Child-Pugh class A liver function within 7 days prior to randomization, as well as a minimum life expectancy of 12 weeks. Patients with active hepatitis B virus infection needed HBV DNA <500 IU/mL and at least 14 days of antiviral therapy before enrollment. The cohort excluded individuals lacking the specified performance status, liver function class, or adequate hepatitis B control.

The study is a phase III, open‑label, randomized trial evaluating atezolizumab combined with lenvatinib or sorafenib versus lenvatinib or sorafenib monotherapy in patients with unresectable hepatocellular carcinoma previously treated with atezolizumab and bevacizumab. Eligible participants undergo a screening visit to confirm inclusion criteria, followed by a baseline visit for randomization and initiation of the assigned treatment. Subsequent follow‑up visits are scheduled at regular intervals (e.g., every 6 weeks) to assess safety, conduct laboratory tests, perform imaging for tumor response, and obtain pharmacokinetic samples. An end‑of‑study visit is performed after the final follow‑up or earlier if discontinuation criteria are met. The primary endpoint is overall survival; secondary endpoints include progression‑free survival, objective response rate, time to progression, duration of response, health‑related quality‑of‑life deterioration, and safety outcomes according to NCI CTCAE v5.0. Participants remain in the trial until disease progression, unacceptable toxicity, withdrawal of consent, death, or the scheduled end‑of‑study visit. The trial period extends from the estimated recruitment start on 26 August 2021 to the projected completion on 30 June 2026.

The investigational product is atezolizumab supplied as Tecentriq 1,200 mg concentrate for solution for infusion. It is administered intravenously as a 1,200 mg dose in a solution for infusion. The infusion is given according to the study‑specified schedule and is performed under clinical supervision.

Two non‑experimental comparator regimens are utilized. The first comparator is sorafenib provided as Nexavar 200 mg film‑coated tablets, administered orally at a total daily dose of 800 mg. The second comparator is lenvatinib supplied as LENVIMA 4 mg hard capsules, administered orally at a total daily dose of 12 mg. Each oral agent is taken in accordance with the dosing schedule defined in the protocol.

Drug administration is recorded in the study case‑report forms, and compliance is monitored by pill count for oral agents and infusion records for the intravenous product. Dosing adjustments, interruptions, or discontinuations are documented per protocol‑defined criteria to ensure accurate assessment of exposure.

Efficacy will be evaluated using time‑to‑event and response endpoints defined in the protocol. The primary parameter is overall survival, measured as the interval from randomization to death from any cause. Secondary efficacy parameters include progression‑free survival (time from randomization to first documented disease progression or death), objective response rate (proportion of participants achieving a confirmed complete or partial response), time to progression (interval from randomization to first disease progression), duration of response (time from documented response to subsequent progression or death), and time to confirmed deterioration of health‑related quality of life (interval from randomization to the first confirmed worsening in HRQoL scores). Incidence and severity of adverse events, vital sign and laboratory abnormalities, serum atezolizumab concentrations, and anti‑drug antibody status are also captured as secondary outcomes.

These endpoints will be assessed according to predefined schedule of study visits, with survival status collected continuously, radiographic evaluations performed at protocol‑specified intervals to determine disease progression and response, and patient‑reported outcome instruments administered to evaluate HRQoL. All adverse events will be graded using NCI CTCAE v5.0. Data will be analyzed using standard time‑to‑event methods (e.g., Kaplan‑Meier estimates and Cox proportional hazards models) for survival‑type endpoints and appropriate categorical analyses for response rates.