In the initial treatment of advanced biliary tract cancer (BTC), the combination of immune checkpoint inhibitor (ICI) with cytotoxic chemotherapy has become the established standard of care, as demonstrated by the TOPAZ-1 and KEYNOTE-966 studies. Despite the achievements of ICI combination therapies, there continues to be a significant unmet medical need, particularly regarding second-line treatment options following exposure to ICIs. Antiangiogenic agents have shown to enhance antitumor immune responses by increasing tumor antigen presentation and facilitating lymphocyte infiltration and migration.
A phase 2, open-label trial (NCT04727996) aimed to investigate the effectiveness of combining sitravatinib and tislelizumab (PD-1 inhibitor) as a second-line treatment for patients with advanced BTC. Patients who have previously received 1 prior palliative chemotherapy were included in the trial. All patients were administered sitravatinib 120 mg orally once daily in combination with tislelizumab 200 mg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the disease control rate (DCR), with key secondary end points including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Tissue biopsies were performed at 3 different times: screening, the first response evaluation, and disease progression. Blood samples were collected at every cycle.
The study enrolled a total of 43 patients. The median follow-up period was 10.5 months (95% confidence interval [CI], 7.03-15.6), and 9 patients had previously received ICIs. The primary end point was met with a DCR of 69.2% in the per-protocol population (n=39). The ORR was 20.5% in the unselected per-protocol population, and the PFS in the intent-to-treat population was 4.93 months (95% CI, 3.10-8.87). The OS was 10.3 months (95% CI, 6.67-18.2), and similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events were related to sitravatinib, including hand-foot syndrome (any grade, 60.5%; grade 3/4, 0%) and hypertension (any grade, 34.9%; grade 3/4, 11.6%). Immune-related adverse events (irAEs) occurred in 46.5% of cases, with the majority of irAEs being grade 1-2. An exploratory analysis revealed that patients with homologous recombination deficiency (HRD) detected by baseline tissue next-generation sequencing (frequency [5/27]18.5%) had a longer OS (21.1 vs 8.57 months) compared with patients without HRD. PFS was not reached for patients with HRD, and a higher percentage of patients who were HRD deficient were also responders. RNA sequencing indicated that responders displayed higher inflammatory signaling in both baseline and on-treatment tumor tissue compared with nonresponders.
The combination of sitravatinib and tislelizumab as a second-line therapy for patients with advanced BTC has shown significant effectiveness and a favorable safety profile. Utilizing the HRD biomarker for patient selection could be a promising approach in this context.
Yoon J, Lee CK, Kim JW, et al. Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment. Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; abstract 4018.
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