Treatment Of Advanced Biliary Cancer Research Articles

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce Tcell paralysis.

Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n= 9) and matched healthy donors (n= 8). Following anti-PD-1 treatment, CD14+ monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14CTX) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14CTX can directly suppress CD4+ Tcells and induce SOCS3 expression in CD4+ Tcells, rendering them functionally unresponsive. The CD14CTX gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce Tcell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance.

Mutational landscape and tumor mutation burden (TMB) feature of biliary cancer.

e16670 Background: Biliary cancer are relatively rare, highly aggressive and have poor prognoses. Most biliary cancers are diagnosed in the advanced and metastatic stages. Chemotherapy is the main treatment of advanced biliary cancer. We focus on gene mutation and tumor mutation burden (TMB) of biliary cancer. Methods: We retrospectively reviewed one hundred and fifty-six cases of biliary cancer. One hundred and fifty-six tumor tissues and 35 plasma samples were subjected to next-generation sequencing (NGS), which enables simultaneously assess snv, indel, rearrangements and cnv variations at least 59 genes (range 59-1021 genes). Results: Fifty-eight patients were intrahepatic cholangiocarcinoma (IHCC), 50 were extrahepatic cholangiocarcinoma (EHCC) and 48 were gall bladder cancer (GBC). From tissue samples, the commonly mutated genes were different in three groups. TP53 was the most frequently mutated gene among the three groups (IHCC 43%, EHCC 58%, GBC 79%). KRAS (33%), TERT (16%), LRP1B (16%), IDH1/2 (10%) were usual in IHCC. KRAS (28%), SMAD4 (20%), STK11 (18%), ARID1A (12%) were usual in EHCC. And ERBB2 (19%), LRP1B (17%), TERT (15%), MLL3 (15%) were usual in GBC. TP53, LRP1B and MLL3 had a higher frequency in GBC than cholangiocarcinoma (p < 0.05), and KRAS was more common in cholangiocarcinoma than GBC (p < 0.05). 72.4% IHCC, 76.0% EHCC and 60.4% GBC had gene mutation associated with target therapies, which involved in multiple signal pathway, such as IDH1/2, FGFR, ERBB1/2/3, MET, PIK3CA, PTEN, BRCA, etc. Thirty-five patients had paired tissue and plasma samples, 21 stage Ⅲ/Ⅳ, 11 stage Ⅱ and 3 unknown. The concordance between tissue and plasma was 53% in all patients and was higher in stage Ⅲ/Ⅳ than stage Ⅱ (p < 0.05). One hundred and thirty-three tissue samples assessed TMB, the mean TMB was highest in the GBC group, followed by EHCC and IHCC (7.1 vs 5.5 vs 3.9 muts/Mb, p < 0.05). The proportion of TMB-H (defined 9.0 muts/Mb as cutoff value) was higher in GBC than IHCC and EHCC. Conclusions: IHCC, EHCC, and GBC have distinctive mutational landscapes and TMB features. It maybe guide different target therapy and immunotherapy strategies in the clinic. ctDNA has promising potential in biliary cancer.

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies.

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.

Clinical study of gemcitabine combined with S-1 in the treatment of advanced biliary tract cancer

Objective To evaluate the recent efficacy and safety of gemcitabine combined with S-1 in the treatment of advanced biliary tract cancer. Methods From August 2014 to May 2017, 27 patients with advanced biliary tract cancer confirmed by pathology in the First People's Hospital of Zhengzhou received gemcitabine(1 000mg/m2, day 1 and 8) and S-1(80mg/m2, day 1-14) every three weeks.The recent efficacy and toxicities were observed after two cycles of chemotherapy. Results All of the 27 patients were evaluated, 1 patient(3.7%) achieved CR, 6 patients(22.2%) with PR, 12 patients(44.4%) with SD, 8 patients(29.6%) with PD.The total response rate was 25.9%(7/27), the disease control rate was 70.4%(19/27). The main toxicities were gastrointestinal reactions and myelosuppression, no chemotherapy-related death was observed. Conclusion Gemcitabine combined with S-1 in the treatment of advanced biliary tract cancer is safe and effect. Key words: Digestive system neoplasms; Biliary tract neoplasms; Bile duct neoplasms; Drug therapy; Antineoplastic combined chemotherapy protocols; Adverse effects; Gemcitabine; Tegafur

The A.L.A.N. score identifies prognostic classes in advanced biliary cancer patients receiving first-line chemotherapy

BackgroundChemotherapy is the mainstay treatment for advanced biliary cancer (ABC). Best supportive care and clinical trials are currently alternative options. The identification of a prognostic score that can be widely applied to daily practice has the potential to better inform clinical management of ABC patients. MethodsA cohort of 123 ABC patients undergoing first-line chemotherapy was used as an exploratory cohort to define the prognostic value of laboratory tests routinely performed in clinical practice. Kaplan–Meier analysis was used to investigate the association between the variables and overall survival (OS). Those variables that were statistically significant at the multivariate analysis were combined in a multiplex score. Performance of the novel prognostic score was confirmed in a validation cohort of 60 ABC patients. ResultsBaseline actual neutrophil count, lymphocytes-monocytes ratio, neutrophil-lymphocytes ratio and albumin (A.L.A.N.) correlated with OS at the multivariate analysis in the exploratory cohort. When combined in the multiplex, A.L.A.N. score was able to identify three classes of ABC patients with significantly different OS (high-risk: median OS, 5 months; intermediate-risk: median OS, 12 months and low-risk: median OS, 22 months; p:<0.001). The score performed well in the different subtypes of ABC and was independent of stage, performance status and chemotherapy regimen. The performance of the A.L.A.N. score was confirmed in a validation cohort of cholangiocarcinoma patients (high-risk: median OS, 4.3 months; intermediate-risk: median OS 9.3 months, low-risk: median OS 13 months; p:0.005). ConclusionsThe A.L.A.N score can be derived by variables routinely recorded in clinical practice and can provide prognostic assessment of ABC patients considered for first-line treatment.

NAP-CAPABIL: Pilot study of NAB-paclitaxel in combination with capecitabine as second line treatment of advanced biliary cancer.

e16156Background: Advanced biliary tract cancer (ABTC) is highly aggressive malignancy, with 5 year overall survival of < 10%. While first-line chemotherapy improves survival and quality of life (Q...

Gemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: Final analysis of a randomized phase II trial (BINGO).

4032 Background: Gemcitabine-platinum chemotherapy (CTx) regimens are widely accepted as first-line standard of care for patients (pts) with advanced biliary cancers (ABC). EGFR overexpression has been observed in ABC, suggesting that the combination with anti-EGFR monoclonal antibodies may be appropriate. Methods: Patients with ABC, WHO performance status (PS) 0-1, and without prior palliative CTx were eligible for this international, open-label, two-stage, non-comparative, randomized phase II trial. Patients received GEMOX (gemcitabine, 1 g/m² [10 mg/m²/min] at day [D]1 + oxaliplatin, 100 mg/m² at D2, arm A) or GEMOX + cetuximab (500 mg/m² at D1 or 2, arm B), every 2 weeks. The primary endpoint was crude 4-month progression-free survival (PFS) rate (H0, &lt;40%; H1, ≥60%; planned sample size, 100 pts, increased to 150 pts by amendment to allow subgroup analyses). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and toxicity (NCI-CTC v3.0). Exploratory endpoints included early metabolic response as assessed by PET at 1 month, and tumor KRAS mutational analysis. Results: From Oct. 2007 to Dec. 2009, we enrolled 150 pts (median age, 62 years; male, 57%; metastatic, 79%; cholangiocarcinoma, 84%; median follow-up, 30 months) (Table). Conclusions: GEMOX-cetuximab regimen was well tolerated and met its primary endpoint (4-month PFS ≥60%). However, median PFS and OS were similar in both arms. Exploratory analyses (e.g., KRAS tumor status) are underway to identify pt subgroups deriving benefit from the addition of cetuximab to CTx. [Table: see text]

Recent advances in gastrointestinal oncology--updates and insights from the 2009 annual meeting of the American society of clinical oncology.

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.

A multicenter, randomized phase II trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer: Interim analysis of the BINGO trial

4520 Background: There is no standard regimen for palliative chemotherapy of advanced biliary cancers. The GEMOX regimen is an option (BJC 2008). EGFR over-expression has been observed in advanced biliary cancers suggesting that the combination with anti-EGFR monoclonal antibodies may be appropriate. Methods: Patients with advanced biliary cancer, WHO performance status 0–1, and without prior palliative chemotherapy were eligible for this international, open-label, two-stage, randomized phase II trial. Patients received GEMOX (gemcitabine, 1000 mg/m2 [10 mg/m2/min] at day [D]1; oxaliplatin, 100 mg/m2 at D2) alone (arm A) or with cetuximab (500 mg/m2 at D1 or 2, arm B), every 2 weeks. Randomization was stratified according to tumor stage and location, center, and prior treatments. The primary endpoint was 4-month crude progression-free survival (PFS) rate (H0 hypothesis, &lt; 40%; H1, ≥ 60%; planned sample size, 50 patients per arm). Secondary endpoints were response rate, PFS, overall survival, toxicity, early response assessment by PET, and blood/tumor EGFR signalling pathway member analyses. A data safety monitoring board-approved interim analysis was performed at the end of the first stage (18 patients per arm, minimal follow- up 4 months). Results: From October 2007 to October 2008, we enrolled 101 patients (median age, 62 yrs; male, 60%; metastatic, 86%; non-gallbladder, 76%). Among the 36 patients at the time of the interim analysis, the median number of treatment cycles was 6 and 8 in arms A and B, respectively. 76% (arm A) and 67% (arm B) had NCI-CTC grade 3–4 toxicity, mainly cytopenia (41%/39%), peripheral neuropathy (modified Levi's scale grade 2–3: 29%/33%), fatigue (6%/22%), gastrointestinal toxicity (12%/17%), and rash/hypersensitivity (0%/17%). The 4-month PFS rate was 44% (95% CI, 20–70) and 61% (95% CI, 36–83) in arms A and B, respectively. Conclusions: The GEMOX-cetuximab regimen seems well tolerated in patients with advanced biliary cancer. Adding cetuximab to GEMOX showed promising activity and therefore the trial was continued. Updated results on the whole population for primary and secondary endpoints will be available at the meeting. [Table: see text]

Two Consecutive Phase II Studies of 5-Fluorouracil/Leucovorin/Mitomycin C and of Gemcitabine in Patients with Advanced Biliary Cancer

Introduction: Carcinoma of the biliary system is a rare tumor entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for advanced biliary carcinoma, we have performed two consecutive studies to evaluate the clinical potential of 5-fluorouracil, leucovorin and mitomycin C as well as the novel antimetabolite gemcitabine in this disease. Patients and Methods: A total of 39 consecutive patients suffering from locally inoperable or metastatic biliary cancer were enrolled in the study between March 1994 and October 1997. Twenty patients were treated with leucovorin 200 mg/m² and 5-FU 400 mg/m², both given as intravenous bolus on days 1–4, and mitomycin C 8 mg/m² on day 1 (group A). Treatment cycles were repeated every 28 days. The second cohort included 19 patients, who received gemcitabine 1200 mg/m² on days 1, 8 and 15 with a 2-week interval before the next treatment cycle (group B). Treatment was continued for a maximum of 6 cycles in the absence of progressive disease in both groups, and endpoints of the study were responses rates, survival and toxicity. Results: In group A, 5 patients (25%) had a partial response (PR), 6 additional patients (30%) had stable disease (SD) and 9 patients (45%) progressed during treatment. The median survival was 9.5 months (range, 3–14.5) with the median time to progression being 4 months (range, 3–9). In group B, 3 patients achieved a PR (16%), 4 showed SD (21%), while the remaining 12 patients had progressive disease. A median survival of 6.5 months (range, 2–11.5) was obtained, and the median time to progression was 2.5 months (range, 1–6+). Toxicity was generally mild in both treatment arms, 6 patients in group A required dose reductions, while no dose adaptation had to be performed for gemcitabine. Conclusion: Our data suggest that treatment of advanced biliary cancer is feasible and can be safely performed with both regimens applied in our study. While administration of gemcitabine has resulted in only mild toxicities, its exact impact on the management of advanced biliary cancer should be evaluated in a controlled trial.