This multicenter, prospective, randomized, controlled, open-label, two-arm Phase III clinical trial is designed to evaluate whether adding radiotherapy to oligoprogressive lesions while continuing first-line systemic therapy at the time of oligoprogression can effectively prolong progression-free survival compared to early switching to second-line systemic therapy in oligoprogressive hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage due to its aggressive nature and lack of early symptoms, making most patients ineligible for curative treatment. In recent years, novel therapeutic approaches, including targeted therapy, immunotherapy and combination regimens, have improved systemic treatment outcomes for advanced HCC, thereby increasing patient survival. However, the objective response rate of first-line systemic treatments remains limited at approximately 20-35%, and most patients inevitably develop resistance and disease progression during treatment. For patients undergoing first-line systemic therapy (FLST) who develop oligoprogression - defined as the progression of a limited number of lesions during systemic treatment - the standard approach is typically to move to second-line systemic therapy (SLST). However, available SLST options remain limited, with median progression-free survival (PFS) of only 2.6-3.1 months, underscoring the urgent need for optimized treatment strategies. The investigators hypothesize that administering local radiotherapy to oligoprogressive lesions while continuing current FLST - provided it remains effective for non-progressing disease - could delay the need for SLST and potentially improve both PFS and OS. This treatment approach has been validated in prospective studies in other malignancies. In addition, our recent multicenter retrospective study published in the Red Journal demonstrated that maintaining FLST in combination with radiotherapy for oligoprogressive lesions significantly prolonged PFS in patients with HCC. Based on these findings, this study aims to conduct a prospective, randomized, controlled Phase III clinical trial in patients with oligoprogressive HCC following FLST. The trial will evaluate whether adding radiotherapy to oligoprogressive lesions while continuing current FLST provides clinical benefit compared to early transition to SLST. The primary endpoint of this trial is PFS. The secondary endpoints include OS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety (assessed according to CTCAE 5.0). This trial will enroll patients with HCC who experience oligoprogression while receiving FLST, provided they have received at least three months of FLST prior to oligoprogression. Patients will be randomized 1:1 to one of two cohorts: Cohort 1: Radiotherapy targeting oligoprogressive lesions while continuing current FLST. Cohort 2: Early transition to SLST. In addition, exploratory objectives include the collection and analysis of circulating tumor DNA (ctDNA) to assess dynamic changes at baseline (time of oligoprogression), at first follow-up after radiotherapy, and at subsequent disease progression. A subset of participants will also undergo biopsies of both primary tumors and progressive lesions at baseline (oligoprogression) and at subsequent progression to further investigate molecular and genomic changes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
132
Radiotherapy (Biologically Equivalent Dose \[BED\]≥60Gy)
Continuation of current first-line systemic therapy, which may include, but is not limited to, combinations such as atezolizumab plus bevacizumab, tremelimumab plus durvalumab, or monotherapies such as lenvatinib, sorafenib, tislelizumab, durvalumab, or pembrolizumab, at the discretion of the treating physician.
For patients who received sorafenib as FLST, regorafenib will be the preferred second-line option. For patients who received other FLST regimens, the SLST selection will be determined through an MDT discussion led by the treating physician based on the patient's overall condition, prior therapies, drug indications, and potential adverse effects, ensuring an individualized treatment approach. The specific dosing regimen, administration frequency, and dose adjustments will strictly follow the same prescribing information for each drug.
Jinan, Shandong 0531
Jinan, Shandong, China
RECRUITINGProgression-free survival (PFS)
The time between enrollment and disease progression or death for patients in the intent-to-treat population, whichever occurred first; for those who did not progress at the time of withdrawal from the study or whose time to disease progression was not recorded, the date of the last visit was used as the endpoint date.
Time frame: 2 years
Overall survival (OS)
Defined as the time from initiation of treatment to death from any cause.
Time frame: 5 years
Adverse event incidence (Safety)
Treatment-related adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE 5.0).
Time frame: 2 years
Objective response rate (ORR)
Defined as the proportion of patients whose tumor size decreases (partial response) or disappears (complete response) after radiation based on RECIST 1.1.
Time frame: 2 years
Disease control rate (DCR)
Defined as the proportion of patients whose tumor size decreases (partial response), disappears (complete response), or is stable after radiation based on RECIST 1.1.
Time frame: 2 years
Duration of response (DOR)
Defined as the time in patients whose tumor size decreases (partial response), disappears (complete response), or is stable after radiation based on RECIST 1.1.
Time frame: 2 years
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