Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life.

A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.

Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response.

PD-L1 thresholds predict efficacy of immune checkpoint inhibition in first-line treatment of advanced gastroesophageal adenocarcinoma. A systematic review and meta-analysis of seven phase III randomized trials.

Background: High expression of programmed death-ligand 1 (PD-L1) has been recognized as a marker of improved efficacy of immunotherapy in gastroesophageal adenocarcinoma (GEA); however, the optimal PD-L1 cut-off is still debated. The aim of the present review was to analyze available phase III trials and to identify the appropriate PD-L1 expression cut-off for GEA.

Methods: Phase III trials investigating the efficacy of anti-programmed cell death protein 1 (PD-1) therapies in addition to standard chemotherapy versus standard chemotherapy in the first-line setting were selected.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known.

Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS.

Development of a Practical Nomogram for Personalized Anemia Management in Patients Treated with Ataxia Telangiectasia and Rad3-related Inhibitor Camonsertib.

Purpose: Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors for the development of significant anemia complicate the selection of a "one-size-fits-all" ATR inhibitor (ATRi) dose and schedule, possibly leading to suboptimal therapeutic doses in patients at low risk of anemia.

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial.

Importance: Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.

Objective: To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.

Design, Setting, And Participants: The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017.

HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling.

Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin.

Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing?

The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib.

Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study.

Purpose: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting.

Methods: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea).

Results: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab.

Nutritional index for immune-checkpoint inhibitor in patients with metastatic gastro-esophageal junction/gastric cancer.

Background: Nutritional status is strongly associated to prognosis in metastatic gastrooesophageal junction (mGOJ)/gastric cancer (GC) patients. The aim of the present study was to develop an immune-checkpoint inhibitor (ICI)-specific nutritional index (NI).

Methods: Ten serum and anthropometric nutritional markers derived from blood tests or CT scans were analyzed at baseline in patients treated with second-line ICI and correlated with overall survival (OS).

Mind the target: circulating tumour DNA in gastrointestinal malignancies.

Purpose Of Review: Circulating tumour DNA (ctDNA) is an appealing minimally invasive tool with significant theranostic potential. In this review, we highlighted recent studies evaluating three major applications of ctDNA in gastrointestinal malignancies.

Recent Findings: ctDNA demonstrated a strong prognostic value in colorectal and gastroesophageal cancers in assessing minimal residual disease after radical surgery.

Combination immune checkpoint blockade in advanced untreated gastroesophageal adenocarcinoma: Seeking biomarkers for durable benefit.

The CheckMate 649 trial, recently published in Nature, established chemotherapy plus nivolumab as a standard in advanced, treatment-naive gastroesophageal adenocarcinoma, with best results seen in patients with high PD-L1 expression and microsatellite unstable tumors. In contrast, nivolumab plus ipilimumab, compared with chemotherapy, showed early progression and no overall survival benefit.

Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial.

Purpose: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors.

Trifluridine/tipiracil in the treatment of gastric cancer.

Trifluridine/tipiracil is a compound drug, approved in 2015 by the US FDA, and in 2016 by the EMA, for the treatment of chemorefractory metastatic colorectal cancers, after the phase III RECOURSE trial demonstrated significant benefit. Another phase III trial (TAGS) showed significant improvement of overall survival and progression-free survival in refractory gastric cancer and gastroesophageal junction cancer, leading to further approval from the FDA on February 2019, followed by Japan in August 2019 and the EU in September 2019. As promising results have already been observed in the chemorefractory gastric and gastroesophageal-junction cancers, ongoing trials are assessing the use of trifluridine/tipiracil with other standard of care agents, aiming to further improve the survival rate of these patients.