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      Toripalimab in advanced biliary tract cancer

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          Abstract

          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/m 2, 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.

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          • Toripalimab plus GS for aBTC

          • mPFS and mOS: 7.0 and 15.0 months

          • Acceptable tolerability

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          Most cited references23

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

            Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.
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              Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study

              Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours.
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                Author and article information

                Contributors
                Journal
                Innovation (Camb)
                Innovation (Camb)
                The Innovation
                Elsevier
                2666-6758
                10 May 2022
                12 July 2022
                10 May 2022
                : 3
                : 4
                : 100255
                Affiliations
                [1 ]Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
                [2 ]Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
                [3 ]Department of Medicine, Shanghai OrigiMed Co., Ltd., Shanghai 201114, China
                [4 ]Center of Evidence-Based Medicine, Fudan University, Shanghai 200032, China
                Author notes
                []Corresponding author liu.houbao@ 123456zs-hospital.sh.cn
                [∗∗ ]Corresponding author liu.tianshu@ 123456zs-hospital.sh.cn
                [5]

                These authors contributed equally

                Article
                S2666-6758(22)00051-0 100255
                10.1016/j.xinn.2022.100255
                9125659
                35615603
                f565edb9-1287-48f1-a5ac-7a636969f5fd
                © 2022 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 January 2022
                : 25 April 2022
                Categories
                Report

                biliary tract cancers,immunotherapy,programmed death ligand-1,chemotherapy,phase ii clinical trial

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