A phase II single arm study of Nivolumab with stereotactic Ablative radiation Therapy after induction chemotherapy in CHOlangiocarcinoma (NATCHO)

Abstract

Background Intrahepatic cholangiocarcinoma (CCA) is amongst the most common primary liver tumors worldwide. CCA carries a bad prognosis prompting research to establish new treatment modalities other than surgery and the current chemotherapeutic regimens adopted. Hence, this trial explores a new therapeutic approach, to combine stereotactic body radiation therapy (SBRT) and immunotherapy (Nivolumab), and asses its clinical benefit and safety profile after induction chemotherapy in CCA. Methodology This is a Phase II open-label, single-arm, multicenter study that investigates Nivolumab (PD-1 inhibitor) treatment at Day 1 followed by SBRT (30 Gy in 3 to 5 fractions) at Day 8, then monthly Nivolumab in 40 patients with non-resectable locally advanced, metastatic or recurrent intrahepatic or extrahepatic CCA. Eligible patients were those above 18 years of age with a pathologically and radiologically confirmed diagnosis of non-resectable locally advanced or metastatic or recurrent intrahepatic or extrahepatic CCA, following 4 cycles of cisplatin-based chemotherapy with an estimated life expectancy of more than 3 months, among other criteria. The primary endpoint is the progression free survival (PFS) rate at 8 months and disease control rate (DCR). The secondary endpoints are overall survival (OS), tumor response rate (TRR), duration of response, evaluation of biomarkers: CD3 + , CD4 + and CD8 + T cell infiltration, as well as any change in the PD-L1 expression through percutaneous core biopsy when compared with the baseline biopsy following 1 cycle of Nivolumab and SBRT. Discussion SRBT alone showed promising results in the literature by both inducing the immune system locally and having abscopal effects on distant metastases. Moreover, given the prevalence of PD-L1 in solid tumors, targeting it or its receptor has become the mainstay of novel immunotherapeutic drugs use. A combination of both has never been explored in the scope of CCA and that is the aim of this study. Trial registration ClinicalTrials.gov NCT04648319, April 20, 2018.

The fibrosis-4 index is a prognostic factor for cholangiocarcinoma patients who received immunotherapy

“…The combination of durvalumab with gemcitabine and cisplatin as a first-line treatment for cholangiocarcinoma has been approved as an indication for durvalumab. Additional clinical studies using immune checkpoint inhibitors as a first-line treatment for cholangiocarcinoma are underway (26,27). At present, before immunotherapy, the most effective method for assessing possible tumor response and predicting the efficacy of immunotherapy is to biopsy the tumor tissue for PD-L1 immunohistochemistry staining.…”

Evaluating the Therapeutic Potential of Durvalumab in Adults with Locally Advanced or Metastatic Biliary Tract Cancer: Evidence to Date

“… 60 , 61 Radiation therapy has also been shown to induce an immune response and increase expression to tumor antigen, which may be further enhanced by immune checkpoint inhibition. 62 Ongoing studies as of January 2024 evaluating durvalumab in advanced or metastatic BTC are listed in Table 2 .…”

Management of Unresectable Cholangiocarcinoma Using Modern Radiation Therapy Techniques

“…They propose a regiment of four cycles of cisplatin followed by nivolumab and an SBRT schedule of 30 Gy in three to five fractions. 44 This, however, is only a design and therefore has not published any results yet is exemplary of the direction further investigation could follow. Not enough data on immunotherapy and SBRT in the treatment of cholangiocarcinoma are available otherwise.…”