To explore the efficacy and safety of cryoablation combined with hepatic arterial infusion of iparomlimab and tuvonralimab, intravenous dacarbazine, and oral lenvatinib in patients with liver metastases from malignant melanoma.
Age 18-70 years;
Patients with pathologically confirmed metastatic malignant melanoma after failure of standard treatment;
Presence of liver metastases, with at least one lesion assessed as suitable for cryoablation;
The largest diameter of each intrahepatic metastatic lesion < 5 cm;
Liver metastases previously treated with radiotherapy, microwave ablation, radiofrequency ablation, or irreversible electroporation;
ECOG performance status score >= 2;
Child-Pugh score >= 7; decompensated liver function, such as massive ascites, gastric fundal or esophageal varices with upper gastrointestinal bleeding within the previous year, hepatic encephalopathy, or bilirubin encephalopathy;
Known central nervous system metastases that are clinically unstable, or acute meningitis (except patients with central nervous system metastases who have received treatment and are clinically stable).
Single group
Cryoablation
Procedure/SurgeryCryoablation is performed using the Hygea Co-ablation System (Hygea Medical Technology Co. Ltd, Beijing, China), a combined cryoablation and hyperthermic ablation device. Under CT guidance and local anesthesia with 2% lidocaine, one to five intrahepatic lesions with a maximum diameter \<5 cm are ablated per session. Each ablation consists of two 10-minute freeze cycles, with a passive thaw between cycles. Technical success is defined as ice-ball extension of at least 0.5 cm beyond the tumor margin. Cryoablation is mandatory in the first cycle and may be repeated in subsequent cycles at the discretion of the investigator, for a maximum of four sessions within 3 months.
Iparomlimab and Tuvonralimab
DrugIparomlimab and tuvonralimab (QL1706; Qilu Pharmaceutical Co., Ltd., Jinan, China) is a dual PD-1/CTLA-4 combination antibody. During the combination phase, QL1706 is administered by hepatic arterial infusion. The catheter tip is positioned in the tumor-feeding artery, proper hepatic artery, or left/right hepatic artery based on intra-hepatic tumor location, and correct positioning is confirmed by repeat angiography. QL1706 7.5 mg/kg diluted in 100 mL of 0.9% normal saline is then infused at a constant rate over 2 hours. Hepatic arterial infusion is given every 3 weeks for a maximum of 4 cycles within 3 months, and if combined with cryoablation, it is administered 7-14 days after ablation. During the maintenance phase, QL1706 is administered intravenously at the same dose every 3 weeks until disease progression or intolerable toxicity. Dose reduction of QL1706 is not permitted.
Dacarbazine
DrugDacarbazine is administered intravenously as a 2-day regimen at a total dose of 850-1000 mg/m², divided over 2 consecutive days, every 3-4 weeks. During the combination phase, dacarbazine is administered intravenously on the day immediately following hepatic arterial infusion of QL1706 (i.e., day 1 after infusion). During the maintenance phase, dacarbazine is continued intravenously at the same dose and schedule until disease progression, intolerable toxicity, or discontinuation after 2 years of maintenance in patients without disease progression.
Lenvatinib
DrugLenvatinib is administered orally at a starting dose of 8 mg once daily. During the combination phase, lenvatinib is started on day 3 after hepatic arterial infusion of QL1706 and catheter removal. During the maintenance phase, lenvatinib is continued orally at the same dose until disease progression or intolerable toxicity, and is continued beyond 2 years after discontinuation of immunotherapy and chemotherapy in patients without disease progression.
Objective Response Rate (ORR)
ORR is defined as the proportion of patients whose best overall response is complete response (CR) or partial response (PR) according to RECIST v1.1, assessed by the investigator. Response evaluation is performed exclusively on pre-specified target lesions that are not subjected to cryoablation. For patients with both intrahepatic and extrahepatic metastases, extrahepatic target lesions are preferentially selected whenever feasible; for patients with intrahepatic lesions only, at least one measurable intrahepatic lesion is deliberately spared from ablation and serves as the target lesion for response assessment. Patients with a first documented CR or PR must have the response confirmed by repeat assessment at least 4 weeks later or at the next scheduled time point.
Progression-Free Survival (PFS)
PFS is defined as the time from initiation of study treatment to the first documented disease progression on non-ablated target lesions per RECIST v1.1, as assessed by the investigator, or death from any cause, whichever occurs first.
Overall Survival (OS)
OS is defined as the time from initiation of study treatment to death from any cause. Patients still alive at the time of analysis are censored at the date of last follow-up. Patients lost to follow-up are censored at the date of last confirmed survival.
6-Month Progression-Free Survival Rate
The 6-month PFS rate is defined as the proportion of patients who are alive and free of disease progression on non-ablated target lesions per RECIST v1.1 at 6 months after initiation of study treatment, as assessed by the investigator.
Treatment-Related Adverse Events (TRAEs)
TRAEs are defined as adverse events judged by the investigator to be related to any component of the study treatment (cryoablation, hepatic arterial infusion of QL1706, intravenous dacarbazine, or oral lenvatinib). Adverse events are graded according to NCI-CTCAE v5.0, and the incidence, severity, and type of TRAEs and serious adverse events (SAEs) are recorded.
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