The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.

Background: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic options. To explore phosphatase and tension homology deleted on chromosome ten (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second line efficacy of bortezomib in PTEN-deficient advanced ICC patients. Methods: Between July 1, 2017, and June 30, 2021, a total of 130 patients with advanced ICC were screened by PTEN immunohistochemical staining and 16 patients were enrolled. Patients with PTEN deficiency who had progressed after gemcitabine combined cisplatin received single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Results: The median time of follow up was 4.63 months (95% CI: 0.7~17.2 months). Among the 16 enrolled patients, 13 of them had completed treatment with bortezomib at least 2 cycles and been evaluated. The ORR was 23% (3/13) and disease control rate was 54% (7/13). The median progress-free survival (mPFS) was 2.95 months (95% CI: 2.1~5.1 months) and the median overall survival (mOS) was 7.2 (95% CI: 0.7~21.6 months) months in the intent-to-treat patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining score of 0 were more likely to benefit from bortezomib than those with staining score > 0. Conclusions: Bortezomib yielded encouraging objective response and a favorable overall survival as a second-line therapy in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising treatment option in selected ICC patients with PTEN deficiency. Trial Registration: ClinicalTrials.gov (NCT03345303).

4086 Background: The prognosis of biliary tract cancer (BTC) remains unsatisfactory. Thus, this study aimed to determine the efficacy, safety, and predictive biomarkers of the immune checkpoint inhibitor sintilimab in combination with gemcitabine and cisplatin (GemCis) in advanced BTCs. Methods: In this single-arm, phase II study (Trial registration number: ChiCTR2000036652), gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) were administered on days 1 and 8, respectively, while 200 mg sintilimab was administered on day 1 of each 21-day cycle for 6–8 weeks, followed by sintilimab alone up to 2 years. The primary endpoint was overall survival (OS). The second endpoints were objective response rate (ORR), progression-free survival (PFS), and disease control rate, assessed using RECIST V.1.1. Multiomics biomarkers associated with clinical response were assessed as exploratory objectives. Results: Thirty patients were enrolled between August 2020 and May 2022. The median follow-up duration, OS, and PFS were 12.3 months (95% confidence interval [CI]: 9.1–16.0), 15.9 months (95% CI: 8.6–not reached), and 5.1 months (95% CI: 4.3–8.7), respectively. Here, 36.7% of patients were found to achieve an objective response. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations (median, PFS: 9.8 vs. 4.5 months, p = 0.023; OS: NR vs. 9.0 months, p = 0.014; ORR: 77.8% vs. 19%, p = 0.004) or loss-of-function mutations in chromatin remodeling genes (median, PFS: 8.7 vs. 4.2 months, p = 0.021; ORR: 63.6% vs. 21.1%, p = 0.046) presented better tumor response and survival outcomes. Furthermore, transcriptome analysis of the tumor immune microenvironment revealed a markedly longer PFS, and tumor response were associated with higher expression of 3-gene effector T cell signature (median, PFS: 7.8 vs. 4.3 months, p = 0.02; ORR: 64.2% vs. 7.1%, p = 0.004) and 18-gene inflamed T cell signature (median, PFS: 8.6 vs. 4.3 months, p = 0.01; ORR: 64.2% vs. 7.1%, p = 0.004). Moreover, our findings highlighted the adverse predictive value of mast cells in immuno-chemotherapy for BTCs for the first time. Conclusions: Sintilimab plus GemCis displayed a promising antitumor activity and acceptable safety profile as a first-line treatment in patients with advanced BTC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000036652 .

Background The most part of primary liver cancer is hepatocellular carcinoma having a poor prognosis. The treatment strategies including multitarget inhibitors, ICIs, and new options are being explored. Recently studies demonstrated the synergistic effect of anti-angiogenesis-targeted drugs combined with immunotherapy. In this study, we explored toripalimab combined with anlotinib as second-line therapy to evaluate the safety and efficacy in advanced hepatocellular carcinoma (HCC). Patients and methods: Twenty-six patients diagnosed with HCC and experienced disease progression or drug intolerance after first-line targeted therapy were included in this study. All enrolled patients received toripalimab combined with anlotinib. The primary endpoint of this study was the objective response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and disease control rates (DCR). Results Finally 22 patients met the protocol were included in the data analysis. The ORR was 7.69%, the mPFS was 3.12 months, mOS was 10.89 months, and DCR was 42.31%, among which 1 patient achieved CR, 1 patient achieved PR, and 9 patients achieved SD. By the last follow-up, the duration of CR in patients had been more than 2 years. No treatment-related deaths occurred, generally this combination therapy is well tolerated. Conclusion In patients who experience disease progression with first-line sorafenib or lenvatinib, toripalimab combined with anlotinib may be a good choice for second-line treatment and is well tolerated. TP53 mutations may serve as biomarkers for this treatment and larger sample size is required for further confirmation.