Editor's Note: Cholangiocarcinoma (BTC), often called the "silent killer," constitutes less than 1% of adult cancers and has a poor prognosis with limited patient survival. Current treatments primarily involve surgery and chemotherapy, but their efficacy is limited. Recently, various targeted drugs and immune checkpoint inhibitors (ICIs) have provided new therapeutic options for BTC patients. The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting presented several new drug research updates on BTC. Here, we summarize three oral presentation studies.Phase II Randomized Study of Atezolizumab and Varlilumab (CDX-1127) with or without Cobimetinib in Previously Treated Unresectable Cholangiocarcinoma[1]
Background: In patients with advanced BTC who have received first-line chemotherapy, combining a MEK inhibitor (MEKi) with a PD-L1 blocker significantly extends progression-free survival (PFS) compared to using a PD-L1 blocker alone (NCT03201458). Further research indicates that MEKi can enhance tumor immunogenicity but may impair host T-cell activation/priming. Adding immune agonists like the CD27 agonist to MEKi could activate T-cell function and potentially optimize the immunomodulatory potential when combined with checkpoint blockade.
Methods: This randomized Phase II clinical trial (NCT04941287) evaluated the efficacy of combining atezolizumab with the CD27 immune agonist [CDX-1127 (Varlilumab)], with or without MEKi (Cobimetinib), in previously treated unresectable BTC patients. The study included adults with pathologically confirmed BTC who had received at least one (but no more than two) systemic treatments, had measurable disease, and an ECOG performance status (PS) ≤1. Patients previously treated with PD-(L)1 inhibitors were also included. The study planned to enroll 64 evaluable patients, randomized 1:1 and stratified by BTC location, to receive AV [atezolizumab (840 mg IV on days 1 and 15) + Varlilumab (3 mg/kg IV on days 1 and 15)] or CAV [Cobimetinib (60 mg orally on days 1-21, off on days 22-28) + atezolizumab + Varlilumab]. Primary endpoints included objective response rate (ORR) and PFS, with key related outcomes being changes in CD8+ infiltrating T cells with treatment.
Results: The pre-specified interim analysis based on ORR showed that neither treatment group met the threshold to continue, leading to early termination due to futility. Fifty-seven patients were enrolled [n=29 (CAV), n=28 (AV)], with 67% having intrahepatic cholangiocarcinoma and 33% previously treated with PD-(L)1 inhibitors. Both the CAV and AV regimens were well-tolerated, with no new safety signals. The ORR was 0% (CAV) and 3.8% (AV). At a median follow-up of 6.2 months, the median PFS was 2.40 (CAV) and 1.84 (AV) months (HR 0.67, P=0.169). In patients previously treated with PD-(L)1 inhibitors, the median PFS was 3.62 (CAV) and 1.84 (AV) months (HR 0.54, P=0.269). The median overall survival (OS) was 7.96 (CAV) and 6.08 (AV) months (HR 0.96, P=0.908). In previously treated patients, the median OS was 6.36 (CAV) and 4.44 (AV) months (HR 0.56, P=0.378).
Conclusion: Atezolizumab and Varlilumab, with or without Cobimetinib, were safe but did not improve clinical outcomes in second-line treatment of advanced BTC patients. Despite the lack of statistical significance, CAV showed numerically better PFS/OS in patients previously treated with immunotherapy.
Phase II Study of Sitravatinib Combined with Tislelizumab in Advanced Cholangiocarcinoma Patients Who Failed at Least One Systemic Therapy[2]
Background: In first-line treatment for advanced BTC, combining ICIs with cytotoxic chemotherapy has become the standard, supported by the TOPAZ-1 and KN-966 studies. There is an urgent unmet need to develop new ICIs for second-line or later-line treatment. Anti-angiogenic drugs improve antitumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration.
Methods: This open-label, Phase II clinical trial investigated the efficacy of the small molecule tyrosine kinase inhibitor Sitravatinib combined with the PD1 inhibitor Tislelizumab as a second-line treatment for advanced BTC. Patients who had received prior ICI therapy were included. All patients took Sitravatinib 120 mg orally daily and received intravenous Tislelizumab 200 mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including ORR, PFS, OS, and safety. Three tissue biopsies were performed: at screening, the first response evaluation, and disease progression, with blood samples collected every cycle.
Results: Forty-three patients were enrolled, with data cutoff on July 31, 2023. The median follow-up was 10.5 months (95% CI: 7.03-15.6). Nine patients had received prior ICI therapy. The primary endpoint was met, with a DCR of 65.1%. The ITT population had an ORR of 20.5%, a PFS of 4.93 months (95% CI: 3.10-8.87), and an OS of 10.3 months (95% CI: 6.67-18.2). Similar efficacy was observed regardless of prior ICI therapy.
The most common treatment-related adverse events (AEs) were associated with Sitravatinib, including hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) occurred in 46.5% of patients, most of which were grade 1-2.
Exploratory analysis found that patients with homologous recombination deficiency (HRD) detected in baseline biopsy tissue by next-generation sequencing (NGS) had higher ORR (60% vs. 13.6%), longer PFS (not reached vs. 4.87 months), and OS (21.1 vs. 8.57 months) compared to those without HRD. ctDNA-detected HRD also complemented patient selection. RNA sequencing showed upregulation of inflammatory signals and downregulation of angiogenesis signals in tumor tissues during treatment, with responders exhibiting higher inflammatory signals compared to non-responders.
Conclusion: Sitravatinib combined with Tislelizumab showed meaningful efficacy and acceptable safety as a second-line therapy in advanced BTC patients. Using HRD biomarkers for patient selection may be a promising strategy in this treatment context.
Adding Stereotactic Body Radiotherapy to Systemic Therapy for Locally Advanced Cholangiocarcinoma: Results from a Randomized Phase II Trial[3]
Background: Local regional treatment for unresectable, non-metastatic cholangiocarcinoma (CC) is not well-defined. Single-arm Phase II data suggest that stereotactic body radiotherapy (SBRT) may improve clinical outcomes. This study aimed to explore the efficacy and safety of combining SBRT with gemcitabine plus cisplatin (CisGem) in locally advanced unresectable CC.
Methods: ABC-07 (ISRCTN:10639376) is a Phase II multicenter randomized trial for patients with histologically confirmed unresectable locally advanced CC and a WHO performance status of 0-1. After registration, patients receiving four cycles of CisGem without disease progression were randomized 2:1 to receive either SBRT (50 Gy in 5 fractions or 67.5 Gy in 15 fractions depending on tumor size) or two additional cycles of CisGem (CG). The primary endpoint was PFS, with the study planned to randomize 65 patients to detect an increase in median PFS from 10.4 to 17.4 months with 80% power and a 15% one-sided α. Secondary endpoints included OS, toxicity, and failure patterns, with radiotherapy quality assurance.
Results: From March 2016 to August 2022, 69 patients were randomized across 16 UK centers (SBRT group, n=45; CG group, n=24). The median age was 66 (range 38-83), with 58 (84.1%) having hilar tumors and 48 (69.6%) having stents. The median tumor size was 3.5 cm (range 0.6-10.5 cm). The median follow-up was 20.7 months. In the SBRT group, 43 (96%) completed 6 cycles of CisGem, and 41 (91%) received SBRT. In the CG group, 18 (75%) completed 8 cycles of treatment.
From randomization, the median PFS was 8.6 months for the SBRT group and 9.0 months for the CG group (HR 1.00; 95% CI: 0.58-1.70; P=0.989). For the first PFS event, 7 (16%) in the SBRT group had local recurrence and 24 (53%) had metastatic recurrence, compared to 7 (29%) and 7 (29%) in the CG group, respectively. From registration, the median OS was 23.4 months (95% CI: 14.6, 27.7) for the SBRT group and 17.2 months (95% CI: 10.2, NR) for the CG group. From randomization, the median OS was 19.4 months (11.2, 24.6) for the SBRT group and 14.2 months (7.0, NR) for the CG group (HR 0.79; 95% CI: 0.41-1.51; P=0.47).
Grade ≥3 AEs occurred in 73% of the SBRT group and 88% of the CG group. Before cycle 6, infection cases like cholangitis were 19 (42%) in the SBRT group and 7 (29%) in the CG group; after cycle 6, there were 17 (38%) in the SBRT group and 6 (25%) in the CG group. The SBRT group had 1 case of grade 3 duodenal bleeding and 1 death from sepsis. The primary causes of death were disease (44% SBRT vs. 46% CG), sepsis (11% SBRT vs. 13% CG), and liver failure (0% SBRT vs. 13% CG).
Conclusion: SBRT did not show superiority in PFS over CG alone but did show longer median OS and better primary tumor control without safety concerns. More mature survival data are needed.
