A novel combination therapy involving toripalimab, lenvatinib, and GEMOX chemotherapy has shown promising results in patients with locally advanced and metastatic intrahepatic cholangiocarcinoma (ICC). The phase 2 trial, conducted at a single center, demonstrated a high objective response rate (ORR) of 80% and a median overall survival (OS) of 22.5 months in 30 subjects. These findings suggest a potential new treatment option for this aggressive cancer, where effective therapies are limited.
Efficacy of Triple Combination Therapy
The study's primary endpoint was ORR, which reached 80% (95% CI: 62.7-91.9%). The median OS was 22.5 months, indicating a substantial improvement compared to historical data with chemotherapy alone. The combination's efficacy is particularly noteworthy given that all patients had stage IIIA or higher disease at baseline. Specifically, 16.7% had stage IIIA, 43.3% had stage IIIB, and 40% had stage IV disease.
Researchers observed that patients with positive staining for PD-L1 in tumor cells tended to have a good response to this triple combination therapy. More importantly, patients presented with DDR-related gene mutations had a better response to this regimen than those without mutations.
Safety and Tolerability
The adverse events (AEs) associated with the triple therapy were generally manageable. Common AEs included increased AST or ALT levels, thrombocytopenia, anemia, neutropenia, leukocytopenia, abnormal ECG, vomiting, nausea, and fatigue. Grade 3 or higher AEs were observed in 17 subjects, with hematologic toxicity being the main concern. Dose modification was required in six subjects, and medication delay in ten subjects due to AEs. Importantly, there were no discontinuations or deaths due to treatment-related AEs.
Comparison with Existing Treatments
Previous studies have explored the use of anti-PD-1/PD-L1 antibodies in combination with chemotherapy for biliary tract cancers (BTCs). The TOPAZ-1 trial, a phase 3 study, reported that GEMCIS chemotherapy plus durvalumab extended median OS by 1.3 months (12.8 vs. 11.5 months) compared to GEMCIS chemotherapy alone. The ORR in the durvalumab arm was 26.7%, compared to 18.7% in the chemotherapy arm. While these data support the combination of immunotherapy with chemotherapy, the ORR and OS benefits were moderate.
The LEAP-005 study showed that lenvatinib with an anti-PD-1 antibody yields an ORR of 10% as second-line treatment of advanced BTC. A phase 2 study with 14 advanced ICC patients showed that combining lenvatinib with an anti-PD-1 antibody (pembrolizumab or nivolumab) yielded an ORR of 21.4% and a DCR of 92.9%. The median PFS was 5.9 months. These findings suggest that the triple combination of toripalimab, lenvatinib, and GEMOX may offer a synergistic effect, leading to improved outcomes compared to pairwise combinations.
Ongoing Research and Future Directions
While the results of this phase 2 study are promising, the authors acknowledge several limitations, including the single-center design, small sample size, and lack of a control arm. To address these limitations, a multicenter, double-blinded, randomized, phase 3 study (NCT05342194) has been initiated to confirm the efficacy of this combination therapy in patients with advanced ICC. This trial has received approval from the National Medical Products Administration (NMPA) in China and is expected to begin enrolling patients soon. The ongoing phase 3 trial should provide more definitive evidence regarding the efficacy and safety of this triple combination therapy for advanced ICC.
