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Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide with an estimated 432 242 deaths occurring in 2018. This estimate, in conjunction with the findings that pancreatic ductal adenocarcinoma incidence is rising and that pancreatic ductal adenocarcinoma has the highest case-fatality rate of any solid tumour, highlights the urgency for designing novel therapeutic strategies to combat this deadly disease. Through the efforts of the global research community, our knowledge of the factors that lead to the development of pancreatic ductal adenocarcinoma, its progression, and the interplay between tumour cells and their surrounding microenvironment have improved substantially. Although these scientific advances have not yet translated into targeted or immunotherapy strategies that are effective for most patients with pancreatic ductal adenocarcinoma, important incremental progress has been made particularly for the treatment of specific molecular subgroups of tumours. Although PD-1 inhibitors for mismatch-repair-deficient tumours and NTRK inhibitors for tumours containing NTRK gene fusions are the most recent targeted agents approved by the US Food and Drug Administration, olaparib for germline BRCA-mutated pancreatic ductal adenocarcinoma is expected to be approved soon in the maintenance setting. These recent advances show the accelerated pace at which pancreatic ductal adenocarcinoma drugs are achieving successful clinical outcomes. Here we review the current understanding of the pathophysiology of pancreatic ductal adenocarcinoma, recent advances in the understanding of the stromal microenvironment, current standard-of-care treatment, and novel therapeutic targets and strategies that hold promise for improving patient outcomes. We predict that there will be major breakthroughs in the treatment of pancreatic ductal adenocarcinoma in the next 5–10 years. These breakthroughs will result from the increased understanding of the treatment barriers imposed by the tumour-associated stroma, and from the development of novel approaches to re-engineer the tumour microenvironment in favour of effective anticancer responses.

Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7–15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11–39]). Grade 3–4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. F Hoffmann-La Roche–Genentech.

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.

The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient’s tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.

Biliary tract cancers (BTCs), consisting of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, are an aggressive, heterogeneous malignancy. They are most often diagnosed in the locally advanced or metastatic setting, at which point treatment consists of systemic therapy or best supportive care. Our understanding of the tumor microenvironment and the molecular classification has led to the identification of targetable mutations, such as isocitrate dehydrogenase 1 and fibroblast growth factor receptor 2. Despite the identification of these genomic alterations, until recently, little advancement had been made in the first-line setting for advanced BTC. While immunotherapy (IO) has revolutionized the treatment of many malignancies, the use of IO in BTC had yielded limited results prior to TOPAZ-1. In this review, we discuss the systemic therapeutic advances for BTC over the past decade, the rationale for immunotherapy in BTC, prior trials utilizing IO in BTC, and current and emerging immune-based therapeutic options. We further analyze the culmination of these advances, which resulted in the approval of durvalumab with gemcitabine and cisplatin for the first-line treatment of BTC per TOPAZ-1. We also discuss the results of KEYNOTE-966, which similarly reported improved clinical outcomes with the use of pembrolizumab in combination with gemcitabine and cisplatin.

Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA. Responses to immune checkpoint inhibitors in patients with pancreatic ductal adenocarcinoma (PDA) remain low and alternative combinatorial approaches are warranted. Here the authors report the results of a phase 2 clinical trial of entinostat (histone deacetylases inhibitor) and nivolumab (anti-PD-1 inhibitor) in patients with metastatic PDA.

Colorectal cancer is the third most common cancer diagnosis in the world, and the second most common cause of cancer-related deaths. Despite significant progress in management strategies for colorectal cancer over the last several decades, metastatic disease remains difficult to treat and is often considered incurable. However, for patients with colorectal liver metastases (CRLM), surgical resection offers the best opportunity for survival, can be curative, and remains the gold standard. Unfortunately, surgical treatment options are underutilized. Misperceptions regarding resectable and unresectable CRLM likely play a role in this. The assessment of factors that impact resectability status like medical fitness, technical considerations, and disease biology can be difficult, necessitating careful multidisciplinary input and discussion. The identification of ideal operative time windows that align with the multimodal management of these patients can also be perplexing. For all patients with CRLM it may therefore be advantageous to obtain surgical evaluation at the time of discovering liver metastases to mitigate these challenges and minimize the risk of undertreatment. In this review we summarize current surgical management strategies for CRLM and discuss factors to be considered when determining resectability.

Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS pathway and a therapeutic target in RAS-driven cancers. Although tumor responses to MEK inhibition are rarely durable, MEK inhibitors have shown substantial activity and durable tumor regressions when combined with systemic immunotherapies in preclinical models of RAS-driven tumors. MEK inhibitors have been shown to potentiate anti-tumor T cell immunity, but little is known about the effects of MEK inhibition on other immune subsets, including B cells. We show here that treatment with a MEK inhibitor reduces B regulatory cells (Bregs) in vitro, and reduces the number of Bregs in tumor draining lymph nodes in a colorectal cancer model in vivo. MEK inhibition does not impede anti-tumor humoral immunity, and B cells contribute meaningfully to anti-tumor immunity in the context of MEK inhibitor therapy. Treatment with a MEK inhibitor is associated with improved T cell infiltration and an enhanced response to anti-PD1 immunotherapy. Together these data indicate that MEK inhibition may reduce Bregs while sparing anti-tumor B cell function, resulting in enhanced anti-tumor immunity.

Background Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis. Results From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40–69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%). Conclusions The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087). KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.