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Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

ABSTRACT: BACKGROUND:Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS:Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS:The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS:Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.

SUBMITTER: Sun D

PROVIDER: S-EPMC6768892 | biostudies-other | 2019 Sep

REPOSITORIES: biostudies-other

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Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

Sun Danyang D Ma Junxun J Wang Jinliang J Han Chun C Qian Yuanyu Y Chen Guangying G Li Xiaoyan X Zhang Juan J Cui Pengfei P Du Wushuang W Wu Zhaozhen Z Chen Shixue S Zheng Xuan X Yue Zhichao Z Song Jia J Gao Chan C Zhao Xiaochen X Cai Shangli S Hu Yi Y Hu Yi Y

Cancer immunology, immunotherapy : CII 20190918 9

<h4>Background</h4>Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory.<h4>Methods</h4>Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoi ...[more]

PMID: 31535160

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Project description:BackgroundMalignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs).MethodsAn umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools.ResultsA total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13-63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2-5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43-36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59-19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39-4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04-10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27-4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7-0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3-10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18-8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients' OS (HR = 0.91, 95% CI 0.74-1.12, GRADE: Moderate) when compared with best supportive care.ConclusionsThis study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with "Moderate" or "High" levels; however, most of the outcomes were still at "low" or "very low" levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

Project description:BackgroundBiliary tract cancers (BTCs) are heterogenous, highly aggressive tumors that harbor a dismal prognosis for which more effective treatments are needed. The role of cancer immunotherapy in BTC remains to be characterized. The tumor microenvironment (TME) of BTC is highly immunosuppressed and combination treatments are needed to promote effective anticancer immunity. Vascular endothelial growth factor (VEGF) drives immunosuppression in the TME by disrupting antigen presentation, limiting T-cell infiltration, or potentiating immune-suppressive cells. Many VEGF-regulated mechanisms are thought to be relevant to repressed antitumor immunity in BTC, making dual targeting of VEGF and programmed cell death protein 1 (PD-1)/PD-L1 pathways a rational approach. Gemcitabine and Cisplatin (Gem/Cis) can also modulate anticancer immunity through overlapping and complementary mechanisms to those regulated by VEGF. Anti-PD-L1/VEGF inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit.MethodsIMbrave 151 is a randomized, double-blind, placebo-controlled, multicenter, international phase II study to evaluate atezolizumab (a PD-L1 inhibitor) in combination with chemotherapy (gemcitabine and cisplatin) and bevacizumab (an anti-VEGF monoclonal antibody) as a first-line treatment for advanced BTC. Approximately 150 patients with previously untreated, advanced BTC will be randomized to either Arm A (atezolizumab + bevacizumab + Gem/Cis) or Arm B (atezolizumab + placebo + Gem/Cis). Randomization is stratified by the presence of metastatic disease, primary tumor location, and geographic region. The primary efficacy endpoint is investigator-assessed progression-free survival (PFS) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response (DoR), disease control rate (DCR), overall survival (OS), and safety and patient reported outcomes (PROs). Tissue, blood, and stool samples will be collected at baseline and on-treatment in order to perform correlative biomarker analyses.DiscussionIMbrave 151 represents the first randomized study to evaluate combined PD-L1/VEGF blockade on a chemotherapy backbone in BTC.Trial registrationNCT identifier: NCT04677504; EUDRACT number: 2020-003759-14.

Project description:BackgroundTargeted therapy (TT) has resulted in controversial efficacy as first-line treatment for biliary tract cancer (BTC). More efficacy comparisons are required to clarify the overall effects of chemotherapy (CT) combined with TT and CT alone on advanced BTC.AimTo conduct a meta-analysis of the available evidence on the efficacy of CT combined with TT for advanced BTC.MethodsThe PubMed, EMBASE, ClinicalTrials, Scopus and Cochrane Library databases were systematically searched for relevant studies published from inception to August 2022. Only randomized clinical trials (RCTs) including comparisons between the combination of gemcitabine-based CT with TT and CT alone as first-line treatment for advanced BTC were eligible (PROSPERO-CRD42022313001). The odds ratios (ORs) for the objective response rate (ORR) and hazard ratios (HRs) for both progression-free survival (PFS) and overall survival (OS) were calculated and analyzed. Subgroup analyses based on different targeted agents, CT regimens and tumor locations were prespecified.ResultsNine RCTs with a total of 1361 individuals were included and analyzed. The overall analysis showed a significant improvement in ORR in patients treated with CT + TT compared to those treated with CT alone (OR = 1.43, 95%CI: 1.11-1.86, P = 0.007) but no difference in PFS or OS. Similar trends were observed in the subgroup treated with agents targeting epidermal growth factor receptor (OR = 1.67, 95%CI: 1.17-2.37, P = 0.004) but not in the subgroups treated with agents targeting vascular endothelial growth factor receptor or mesenchymal-epithelial transition factor. Notably, patients who received a CT regimen of gemcitabine + oxaliplatin in the CT + TT arm had both a higher ORR (OR = 1.75, 95%CI: 1.20-2.56, P = 0.004) and longer PFS (HR = 0.83, 95%CI: 0.70-0.99, P = 0.03) than those in the CT-only arm. Moreover, patients with cholangiocarcinoma treated with CT + TT had significantly increased ORR and PFS (ORR, OR = 2.06, 95%CI: 1.27-3.35, PFS, HR = 0.79, 95%CI: 0.66-0.94).ConclusionCT + TT is a potential first-line treatment for advanced BTC that leads to improved tumor control and survival outcomes, and highlighting the importance of CT regimens and tumor types in the application of TT.

Project description:ObjectiveThe treatment of biliary tract (BTC) cancer remains relatively limited, especially in the setting of advanced BTC. Immune checkpoint inhibitors (ICIs) have shown some effects in a variety of solid tumors, but their efficacy and safety in patients with advanced BTC are still elusive, which require in-depth analysis.MethodsThe clinical information of 129 patients diagnosed with advanced BTC between 2018 and 2021 were retrospectively reviewed. All patients were treated with chemotherapy, while a portion of them (64 patients) were treated with ICIs, the other 64 patients were not. Therefore, we divided the patients into two groups, SC (standard chemotherapy) and CI (chemotherapy in combined with immunotherapy), then we analyzed the benefit of adding ICIs according to efficacy, adverse events, progression-free survival (PFS), progressive disease (PD), and the influence of various factors and effectiveness.ResultsThe mean PFS was 9.67 months for CI group and 6.83 months for SC group. The PFS was prolonged by 2.84 months with ICI addition, and the difference was statistically significant (t = 3.114, 95% CI: 1.06-4.74, p < 0.001). The objective response rate (ORR) was 32.81% (21/64) for the CI group versus 10.77% (7/65) for the SC group, and the disease control rate (DCR) was 79.69% (51/64) versus 67.69% (44/65), respectively. Regression analysis showed that factors such as changes in CA19-9, the level of PD-L1 expression, tobacco and alcohol, and the neutrophil-lymphocyte (NLR) ratio all influenced PFS (p < 0.05 for all these factors). For the treatment-related adverse events (TRAEs), the highest grade 3-4 adverse effects were thrombocytopenia in 7.75% (10/129) and neutropenia in 3.1% (4/129), immune-related adverse events (irAEs) occurred in 32.8% (21/64), and all were grade 1-2.ConclusionsOur results showed that ICIs combined with chemotherapy exhibited good antitumor activity with acceptable safety and could be recommended as first-line treatment for patients with advanced BTC.

Project description:Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs). We explored the safety and efficacy of toripalimab plus gemcitabine and S-1 (GS) as the first-line treatment for advanced BTCs. At a one-sided significance level of 0.025, a total of 50 patients could provide 80% power to show the efficacy at targeted progression-free survival (PFS) rate at 6 months of 70% versus 40% for the combined treatment. This single-arm, phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment. The regimen was as follows: toripalimab (240 mg, i.v., d1), gemcitabine (1,000 mg/m2, i.v., d1 and d8), and S-1 (40-60 mg bid p.o., d1-14, Q21d). The primary endpoint was progression-free survival. The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The associations between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations were explored. Patients were enrolled from January 2019 to August 2020, with a median follow-up time of 24.0 months (IQR: 4.3-31.0 months). The 6-month PFS rate was 62%. The median PFS was 7.0 months (95% CI: 5.0-8.9 months), and median OS was 15.0 months (95% CI: 11.6-18.4 months). Forty-nine patients completed the evaluation for tumor response. The ORR was 30.6% (95% CI: 17.2%-44.0%), and the disease control rate was 87.8% (95% CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%), and immune-related colitis (2%). Among them, the grade III/IV immune-related adverse events (irAEs) were skin rash and colitis. In addition, biomarker analysis showed that negative PD-L1 expression and SMARCA4 mutation were significantly associated with worse survival outcomes, while no significant associations were observed for TP53, KRAS, or CDKN 2 A mutation as well as TMB. In conclusion, our data suggest that a regimen of toripalimab plus GS could improve PFS and OS with a good safety profile as a first-line treatment option for advanced BTC and warrants further verification.

Dataset Information

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

Publications

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

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