Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study

Ueno, Makoto; Ikeda, Masafumi; Morizane, Chigusa; Kobayashi, Satoshi; Ohno, Izumi; Kondo, Shunsuke; Okano, Naohiro; Kimura, Kazuhiro; Asada, Suguru; Namba, Yoshinobu; Okusaka, Takuji; Furuse, Junji

doi:10.1016/s2468-1253(19)30086-x

Cited by 261 publications

(260 citation statements)

References 29 publications

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“…Currently, there were several reports of ICIs alone or in combination with chemotherapy treating advanced BTCs in small sample size [12,13,22]. There was one unresolved question of whether the addition of ICIs had potential to reverse the resistance of gemcitabine-or cisplatin-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study

Feng

Liu

Zhao

et al. 2020

Preprint

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Background: The prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptable low. This study aimed to determine the efficacy, safety and predicting biomarkers of immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.Methods: In this open-label, single-arm, phase Ⅱ trial, chemo-immunology combination therapy consisting of gemcitabine 1000mg/m2, cisplatin 75mg/m2 plus nivolumab 3mg/kg was administered every 3 weeks for up to 6 cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was objective response rate (ORR). Secondary outcomes included safety, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The exploratory objectives were to assess biomarkers for predicting clinical response and prognosis.Results: 32 patients with a median age of 60 (range 27-69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI, 10.8-14.8) months. 27 response-evaluable patients received a median of 4 (IQR, 3-6) cycles combination therapy, of which 15 (55.6%) patients achieved objective response, including 5 (18.6%)with complete response (CR), and the DCR was 92.6%. 2 of 6 patients in cohort A who were refractory to gemcitabine or cisplatin-based chemotherapy achieved 1 CR and 1 partial response. 13 of 21 chemotherapy-naive patients (61.9%) in cohort B achieved objective response. The median PFS of all patients in cohort A+B was 6.1 months. The median OS was 8.5 months with 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy change of serum sFASL, MCP-1 and IFN-γ were correlated with prognosis.Conclusions: Nivolumab in combination with gemcitabine and cisplatin offer promising efficacy and manageable safety profile for patients with advanced BTCs.

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Section: Discussionmentioning

confidence: 99%

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study

Feng

Liu

Zhao

et al. 2020

Preprint

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“…Median OS and PFS were 15.4 and 4.2 months, respectively, with the combined therapy. Of note, 11 of 30 patients had an objective response [97].…”

Section: Ici In Combination and Other Immunotherapiesmentioning

confidence: 95%

Immune Therapy for Liver Cancers

Hilmi

Vienot

Rousseau

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.

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“…Although the OS and PFS of pembrolizumab as a second-line therapy are not fully satisfactory, it is worth considering because no standard salvage chemotherapy regimen for advanced BTCs in progression after gemcitabine and platinum compounds has yet been identified. The results of the phase 1 study (JapicCTI-153098) investigating the safety and tolerability of nivolumab monotherapy or in combination with cisplatin plus gemcitabine for patients with unresectable or recurrent BTC suggested that nivolimab had a manageable safety profile and signs of clinical activity [67]. Additionally, a recent report of the phase 1 study of durvalumab (anti-PD-L1 mAb) with or without tremelimumab (anti-CTLA-4 mAb) suggested that their combination might become a promising regimen for patients with advanced BTC after conventional chemotherapy [68].…”

Section: Msi Status and Treatment With Icis For Biliary Tract Cancermentioning

confidence: 99%

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

et al. 2019

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Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

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Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study

Cited by 261 publications

References 29 publications

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study

Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: results from a phase II study

Immune Therapy for Liver Cancers

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

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