Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier?

Background: Immunotherapy has been shown to improve outcomes for patients with cancer. Biliary tract cancers are a group of lethal diseases, and immunotherapy is an exciting new strategy to treat patients in advanced stages. Role of immunotherapy in biliary cancers: Durvalumab, an anti-PD-L1 antibody, is a new immunotherapy option for patients with advanced biliary cancers. In a randomized phase III trial, the combination of durvalumab and chemotherapy improved disease outcomes, including overall survival, in patients with advanced biliary cancers regardless of PD-L1 expression. Future perspective: Promising new combinations with new and potent antibodies or antiangiogenics are under development. Combinations with new immunotherapy agents targeting CTLA-4 or OX40 can enhance T-cell activation and improve outcomes compared with single anti-PD-1/PD-L1 agents. Furthermore, ctDNA is being used as an alternative to tissue genomic analysis and can be used to identify actionable targets. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.

New treatment strategies for advanced biliary cancers with chemoimmunotherapy combinations have been shown to lead to better tumor responses and overall survival compared with chemotherapy alone. The combination of durvalumab, cisplatin and gemcitabine may become a new standard of care for advanced disease despite the modest improvement in median overall survival of less than 2 months. Promising combinations with anti-CTLA-4 antibodies or antiangiogenics are underway with the objective of improvement in survival. Although multiple combinations are available with the potential to establish a new standard of care, concerns regarding toxicities should also be evaluated. In this review, we will discuss the most important studies involving immunotherapy in biliary cancers as well as future perspectives in the field.

Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications.

INTRODUCTION: Cholangiocarcinoma (CCA) is a heterogeneous group of aggressive biliary malignancies. While surgery and liver transplantation are the only potentially curative modalities for early-stage disease, limited options are available for most patients with incurable-stage disease. Survival outcomes remain dismal. Recent molecular profiling efforts have led to improved understanding of the genomic landscape of CCA and to the identification of subgroups with distinct diagnostic, prognostic, and therapeutic implications. AREAS COVERED: : We provide an updated review and future perspectives on features of cholangiocarcinogenesis that can be translated into therapeutic biomarkers and targets. We highlight the critical studies that have established current systemic chemotherapy and targeted therapeutics, while elaborating on novel targeted and immunotherapeutic approaches in development. Relevant literature and clinical studies were identified by searching PubMed and www.ClinicalTrials.gov. EXPERT OPINION: : While therapies targeting the various molecular subgroups of CCA are rapidly emerging and changing treatment paradigms, their success has been limited by the genetic heterogeneity of CCA and the plasticity of the targets. Novel strategies aiming to combine immunotherapy, chemotherapy, and molecularly targeted therapeutics will be required to offer durable clinical benefit and maximize survival.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Timing of palliative care access and outcomes of advanced cancer patients referred to an inpatient palliative care consultation team in Brazil.

OBJECTIVE: Little is known about the outcomes of cancer patients referred to palliative care (PC) teams in developing countries. Our aim was to examine the timing of PC access and outcomes of patients with advanced cancer referred to an inpatient PC consultation team in Brazil. METHOD: Retrospective study of consecutive patients with advanced cancer admitted to a tertiary care general hospital (April 2015-December 2016) and referred for the first time to an inpatient PC consultation team. Patients' demographics, clinical features, time from first consult to death or discharge, and outcomes on medication use, clinical interventions, and end-of-life preferences were retrieved. An analysis was performed before and after PC. RESULT: One hundred eleven patients were included. Median age was 68; 72% had an Eastern Cooperative Oncology Group performance status ≥3. The median timing of PC access was 9 days (first interquartile = 3, third interquartile = 19). The use of analgesics (from 75% to 85%, p = 0.001) and opioids (from 50% to 73%, p < .001) increased. A lower proportion was receiving antibiotics (68% vs 48%, p < 0.001), thromboprophylaxis (44% vs 26%, p < 0.001), antihypertensives (28% vs 15%, p = 0.001), and antiemetic agents (64% vs 54%, p = 0.027). Chemotherapy use was lower (39-25%, p < 0.001). More patients had an end-of-life preference (39% to 25%, p < 0.001) and were not willing to receive intubation (32% vs 60%, p < 0.001), intensive care treatment (30% vs 55%, p < 0.001), cardiopulmonary resuscitation (35% vs 62%, p < 0.001), and artificial nutrition (22% vs 34%, p < 0.001). SIGNIFICANCE OF RESULTS: Although PC referrals occurred exceedingly late during the cancer disease trajectory, positive changes were observed in medication profiles, clinical interventions use, and end-of-life preferences of patients with advanced cancer referred to a specialized inpatient PC consultation team in Brazil. Further efforts are needed to improve early palliative cancer care in developing countries.