Immunotherapies in clinical development for biliary tract cancer

Abstract

Introduction: Cancers of the biliary tract (BTC) are aggressive malignancies with limited treatment options and an overall dismal prognosis. In recent years, two concepts, namely precision oncology and immune oncology (IO) have profoundly influenced and, in some cancers, even revolutionized tumor treatments. While positive data from randomized trials have led to the incorporation of targeted concepts for genetically select BTC patients, IO is not yet implemented in clinical practice. Areas covered: We discuss published results from completed, as well as from ongoing studies on IO in BTC, based on a literature search on Pubmed and information provided by clinicaltrials.gov in October 2020. Apart from monotherapy, we outline IO-based combination approaches and highlight pivotal studies whose results will likely influence the future development of relevant concepts in BTC. Expert opinion: Despite partially positive signals, IO thus far disappointed in unselected BTC populations and should currently not be considered as a preferred systemic treatment in patients with microsatellite stable disease outside of clinical trials. In the coming years, a better understanding of the molecular mechanisms underlying resistance to checkpoint inhibition, and the identification of positive predictive biomarkers will be important for the successful integration of IO into treatment concepts for BTC patients.

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

“…In fact, molecularly targeted therapies have been tested in BTC patients harboring specific druggable alterations, especially in iCCAs where agents targeting isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) aberrations have entered into clinical practice [16][17][18][19][20][21][22]; in addition, following the results observed in several hematological and solid malignancies, immune checkpoint inhibitors (ICIs) have been explored and are currently being investigated in BTC (Table 1) [23][24][25]. However, most BTC patients receiving ICIs as a monotherapy or in combination with other anticancer agents do not achieve response, and the mechanisms behind the variations in the response to immunotherapy in this setting have been poorly studied [26]. Based on these premises, the identification of biomarkers able to predict responses to ICIs and the understanding of resistance mechanisms in non-responders represent high unmet needs.…”

A Novel Combination of Bevacizumab with Chemotherapy Improves Therapeutic Effects for Advanced Biliary Tract Cancer: A Retrospective, Observational Study

“…A recently published expert opinion also suggested that immunotherapy should not be considered as a preferred systemic treatment in BTC patients with microsatellite stable disease outside of clinical trials. However, they also pointed out that immunotherapy-based combinations and highlight pivotal studies will likely influence the future development of relevant concepts in BTC [35]. These trials include the phase III, double-blind TOPAZ-1 study, which randomly allocates treatmentnaïve patients to GC plus durvalumab versus GC in combination with placebo, and the KEYNOTE-966 study, which is currently evaluating the role of pembrolizumab combined with GC versus GC plus placebo (Table 7) [36].…”

IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer

“…39 To date, however, clinical data for PD-1 or PD-L1 inhibitors in BTC are limited to small studies or sub analyses from basket trials focusing on pre-treated patients. [40][41][42] The antitumor activity of single-agent anti-PD-1/PD-L1 antibodies, including atezolizumab, in BTC patients, is modest, and in most cases response rates have not exceeded 10%. [43][44][45][46][47][48][49] Consistent with other solid tumors, responses were durable in a small subgroup of responsive patients.…”