Continuation of First-line Therapy With Radiotherapy Versus Early Switch to Second-line Therapy in Oligoprogressive HCC

Continuation of First-line Therapy With Radiotherapy for Oligoprogression Versus Early Switch to Second-line Therapy in Oligoprogressive Hepatocellular Carcinoma (CROSS): a Multi-center, Randomized, Controlled, Open-label, Phase Ⅲ Trial

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.

Inclusion Criteria:

• 1. Histological or cytological confirmation of primary hepatocellular carcinoma (HCC), or diagnosis based on the Clinical Diagnosis and Treatment Guidelines for Primary Liver Cancer (2024 edition) issued by the National Health Commission of the People's Republic of China.
• 2. BCLC stage C at the time of first-line systemic treatment.
• 3. Oligoprogression must be confirmed by imaging or histopathology during first-line systemic therapy (FLST). The number of oligoprogressive lesions is limited to 1-5, involving no more than 1-3 organs or systems. These lesions may represent either new metastatic sites or progression of pre-existing lesions. In addition, they must fit one of the two classifications defined in the ESTRO-EORTC consensus on oligometastases: repeat oligoprogression or induced oligoprogression. Oligoprogression may occur within intrahepatic lesions. In the case of lymph node progression, each lymphatic drainage region is considered a separate lesion. For example, the para-aortic lymph nodes (number 16a and number 16b) are each counted as separate lymph node regions.
• 4. Patients must have experienced oligoprogression while receiving their current FLST and must not have previously received any other FLST that resulted in disease progression. Additionally, the current FLST must have maintained disease stability (SD) for at least three months prior to the occurrence of oligoprogression. Furthermore, the expected survival time must be ≥6 months.
• 5. Oligoprogressive lesions must be eligible for radiotherapy and should have at least one measurable lesion that meets RECIST v1.1 criteria; Bone metastases without soft tissue formation are eligible but are considered non-measurable lesions; Bone metastases with soft tissue formation that meet RECIST v1.1 measurable criteria are considered measurable lesions.
• 6. Liver function must be assessed as Child-Pugh score ≤7 points.
• 7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0-1.
• 8. Participants must be able to understand and voluntarily sign a written informed consent prior to the initiation of any study-specific procedures and must agree to comply with the treatment and follow-up requirements of the study.
• 9. Male or female patients between 18 and 75 years of age.
• 10. Availability of tumor and blood samples for biomarker assessment.

Exclusion Criteria:

• 1. Patients who received FLST as adjuvant treatment after curative surgery for HCC.
• 2. Tumor progression occurring within 3 months after initiation of FLST.
• 3. Patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC)
• 4. History of grade ≥3 serious adverse events due to FLST.
• 5. Presence of brain, peritoneal or omental metastases with bleeding after FLST.
• 6. Previous radiation therapy to the site of the oligoprogressive lesion.
• 7. Active untreated hepatitis B, defined as HBsAg positive with HBV DNA levels above the upper limit of normal in the participating center's laboratory.
• 8. Oligoprogressive lesions not amenable to radiotherapy.
• 9. Alpha-fetoprotein (AFP) level ≥10,000 ng/mL at the time of oligoprogression.
• 10. Diagnosis of malignancy other than liver cancer within 3 years prior to enrollment (excluding curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, and/or carcinoma in situ).
• 11. Currently participating in any interventional clinical research treatment or having received any other investigational drug or investigational device therapy within the last 4 weeks prior to enrollment.
• 12. Presence of autoimmune disease or other conditions requiring long-term steroid use.
• 13. Severe impairment of the heart, lungs, kidneys, or other vital organs, active infections (other than viral hepatitis), or other serious comorbidities that render the patient unable to tolerate treatment.
• 14. known or suspected allergy to any study drug or to any drug related to this study.
• 15. History of organ transplantation
• 16. Pregnant or breastfeeding women
• 17. Any other factor that the investigator believes may affect the enrollment of patients or the evaluation of study results.