Emerging drugs for the treatment of gastrointestinal stromal tumour

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs

Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST

Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.     

Role of c-mesenchymal–epithelial transition pathway in gastric cancer

Introduction: Gastric cancer is the fourth most common cancer burden worldwide; many patients show incurable disease at the time of diagnosis and prognosis remains unfavorable. Recently, new findings on gastric cancer biology led to the preclinical and clinical development of new compounds aiming to improve the overall survival and to preserve quality of life and reducing chemotherapy-related toxicities. Patients with human epidermal growth factor receptor 2 (HER2) overexpression/amplification have experienced benefit from the integration of trastuzumab to the standard chemotherapy. Ramucirumab has been recently approved in second line for treatment of gastric cancer.

Areas covered: Drugs targeting molecules such as anti c-mesenchymal-epithelial transition (MET), mammalian target of rapamycin inhibitors, polo-like kinase 1 inhibitors are under investigation or in preclinical or early clinical development. Approximately 10 – 20% of gastric cancer presented an increased MET gene copy numbers; inappropriate activation of MET promotes cellular proliferation, cell motility, invasiveness and angiogenesis and is associated with more aggressive phenotype and with a lower survival.

Expert opinion: The role of c-MET has been extensively evaluated both in Asian and Western population, even if data are far from being conclusive. The activation of MET/hepatocyte growth factor pathway is a negative prognostic factor, and it could partially explain the resistance to EGFR/HER2 inhibitors acting as a rescue pathway likewise in other tumors.     

Investigational drugs targeting fibroblast growth factor receptor in the treatment of non-small cell lung cancer

Introduction: Fibroblast growth factor receptor (FGFR) due to its central role in regulating cell survival, is a promising target for cancer therapeutics. Dysregulation of the FGFR pathway has been observed in several malignancies, including non-small cell lung cancer (NSCLC) particularly in patients with squamous histology.

Areas covered: The aim of this article is to review the most relevant findings of clinical trials investigating drugs targeting FGFR pathway: such as FGFR tyrosine kinase inhibitors (TKIs), FGFR monoclonal antibodies and FGF ligand traps in NSCLC patients.

Expert opinion: At present, clinical activity of drugs targeting FGFR in NSCLC is disappointing. Further studies are needed in order to better identify patients who might benefit from these drugs and to clarify the mechanisms of resistance to these compounds.     

Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings

Introduction: There are considerable interests in the development of novel small-molecule CD73 inhibitors for the treatment of cancers, autoimmune diseases, precancerous syndromes, and other diseases associated with CD73 activity.

Areas covered: The application claims novel substituted benzothiadiazine derivatives as CD73 inhibitors for the treatment of cancer, precancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Many of the exemplified compounds have pIC50 values between 5 to 8.4 against CD73.

Expert Opinion: These benzothiadiazine derivatives provide good leads for the discovery of potent CD73 inhibitors for the treatment of cancer and other diseases mediated by adenosine and its action on adenosine receptors.     

Emerging tyrosine kinase inhibitors for the treatment of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is the fifth most diagnosed cancer in the world and the third leading cause of death. Unfortunately, when diagnosed two thirds of patients have an advanced disease for which only palliative treatment can be proposed and most likely systemic therapy.

Areas covered: As of today only one systemic therapy is validated in the treatment of advanced HCC, a tyrosine kinase inhibitor (TKI): Sorafenib. Treatment options are therefore lacking. With the advent of Sorafenib other TKIs have been studied with some disappointing results. Many explanations can be found to the failure of these tested TKIs such as the underlying cirrhosis leading to rapidly serious adverse events, or trial design imperfections.

Expert opinion: Taking into account these failures, new trials with more appropriate designs have led to recent success with multi-target TKIs (Regorafenib and Lenvatinib). This multi-target approach allows to overcome the molecular heterogeneity of advanced HCC which is associated with multiple simultaneously dysregulated signaling pathways. On the contrary, another lead is to study target a specific TKI such as c-MET inhibitors or TGFβR inhibitors in HCC sub-populations with promising results in early phase trials. These results will have to be validated in the ongoing phase III trials.     

Pharmacological interventions for stress ulcer prophylaxis in critically ill patients: a mixed treatment comparison network meta-analysis and a recursive cumulative meta-analysis

Background: Proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RA), sucralfate and antacids are the commonly administered agents for stress ulcer prophylaxis (SUP) in critically ill patients. The authors of this paper have conducted a network meta-analysis to compare the efficacy of these agents in SUP.

Methods: Electronic databases were searched for randomized controlled trials, cohort studies and conference abstracts for studies comparing a SUP agent in critically ill patients to another active SUP agent or placebo. Overt, occult and clinically significant upper gastro-intestinal (UGI) bleeding, all-cause mortality, pneumonia, gastric colonization and ICU length of stay were considered as the outcome measures. A random effects model was used to generate pooled estimates.

Results: A total of 53 studies (4258 participants) were included. The pooled estimates were in favor of PPI and sucralfate for the overt UGI bleeding. PPI and H2RA bolus were associated with increased risk of gastric colonization and pneumonia.

Conclusions: SUP in critically ill patients was not associated with any benefit with regard to clinically significant bleeding episodes. However, PPI and sucralfate significantly reduces overt UGI bleeding. On the contrary, PPI and H2RA bolus are associated with an increased risk of gastric colonization and pneumonia.     

Directing the use of DDR kinase inhibitors in cancer treatment

Introduction: Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1.

Areas covered: We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use.

Expert opinion: Novel DDR inhibitors present promising candidates in cancer treatment and have the potential to elicit synthetic lethal effects. In order to fully exploit their potential and maximize their utility, identifying highly penetrant predictive biomarkers of single agent and combinatorial DDR inhibitor sensitivity are critical. Identifying the optimal drug combination regimens that could used with DDR inhibitors is also a key objective.     

Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type-2 inflammation: a patent evaluation (WO2017/058370)

Introduction: Activity modulators of carbonic anhydrases hold great potential for several therapeutic applications against ophthalmologic and neurological disease, cancer, and infectious diseases. The involvement of carbonic anhydrase in the regulation of mast cell response opens new ways for the treatment of mastocytosis, allergic inflammation, and parasite infection.

Areas covered: The application claims the use of carbonic anhydrase activity modulators (inhibitors or activators) for treating allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis, or mast cell–mediated inflammation.

Expert opinion: Although there is a lack of essential biological data, this patent proposes a new type of applications for carbonic anhydrase inhibitors and deserves further studies. This may lead to new advances in the field of carbonic anhydrase with potential therapeutic implications in the management of type-2 inflammation.     

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors

Introduction: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity.

Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1.

Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.     

Novel drugs in clinical development for hepatocellular carcinoma

Introduction: Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit.

Areas covered: This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC.

Expert opinion: In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.     

Olaparib for the treatment of breast cancer

Introduction: Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations.

Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed.

Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.     

Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015

Introduction: There are dozens of drugs in development for AD with billions of dollars invested. Despite the massive investment in AD drugs and a burgeoning pipeline, there have been more setbacks and failures than treatment successes.

Areas covered: The classes of drugs that have failed to date include the monoclonal antibodies, the gamma secretase inhibitors, dimebon, neurochemical enhancers, and one tau drug. Data for these compounds were sought through a PubMed search and a clinicaltrials.gov search.

Expert opinion: The obvious question to be posed is: Why are they failing? Is the treatment of symptomatic dementia too late? Are the therapeutic targets incorrect? Are the clinical methodologies imprecise, misleading, or inaccurate? This review summarizes the drugs that have failed during 2010–2015 and offers possible theories as to why they have failed.     

The safety of Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia

Introduction: The approval of ibrutinib has revolutionized the therapeutic landscape of chronic lymphocytic leukemia (CLL). Currently ibrutinib is indicated for patients that are both treatment naïve as well as those with relapsed CLL. Ibrutinib is generally well-tolerated with durable responses that improve over time in most patients. Important toxicities include atrial fibrillation and bleeding.

Areas cover: This review covers the pharmacokinetics, pharmacodynamics, safety and efficacy of ibrutinib in the treatment of CLL. We also compare ibrutinib with other kinase inhibitors and chemoimmunotherapy regimens using data from clinical trials. A literature search utilized the PubMed database.

Expert opinion: Despite the efficacy and tolerability of ibrutinib, important questions remain, which include selection of patients receiving ibrutinib in the first and subsequent lines of treatment, optimal dosing, sequential use of ibrutinib versus other kinase inhibitors and combination therapy. Prospective studies should incorporate minimal residual disease (MRD) status as a clinical endpoint to determine whether patients can be taken off kinase inhibitors.     

Safety of alectinib for the treatment of metastatic ALK-rearranged non-small cell lung cancer

Introduction: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) may derive significant clinical benefit from targeted therapies against this driver mutation, but progression is virtually inevitable. Alectinib is a next-generation ALK inhibitor that provides a novel treatment option for this group of patients.

Areas covered: In this review, we summarize the overall safety and tolerability of alectinib. Specifically, we cover cardiovascular, gastrointestinal, hepatic, musculoskeletal, and respiratory adverse events. The safety profile of alectinib is also described in special populations and in comparison with other ALK inhibitors.

Expert opinion: Alectinib is a well-tolerated tyrosine kinase inhibitor and should be considered for patients with ALK-rearranged NSCLC. The question then arises as to how to choose a next-generation ALK inhibitor in the second-line setting. Understanding acquired resistant mechanisms has become essential. Whether or not to use alectinib in the first-line setting is extremely controversial, but we anticipate its approval for this indication and availability in more countries in the near future.     

Methods of selecting combination therapy for colorectal cancer patients: a patent evaluation of US20160025730A1

Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide. Targeted therapy drugs (TTDs) are a valid treatment, epithelial growth factor receptor (EGFR) inhibitors being one of the most commonly used for CRC patients. However, this treatment is only useful for patients with wild-type KRAS (wtKRAS) and is effective only on about 40 to 60% of this subset due to the high plasticity of ErbB network.

Areas covered: The invention proposes the use of ErbB protein levels and ErbB receptor dimer formation as biomarkers for selecting, predicting and monitoring CRC patients showing sensitivity to the action of EGFR inhibitors to benefit from the combination therapy of EGFR and HER2 inhibitors. The in vitro data on Lim1215 cells suggest the over-activation of HER3 signaling pathway in response to the use of EGFR inhibitors on monotherapy; the use of HER2 or HER3 or MEK inhibitors in combination with EGFR inhibitors reversed this activation.

Expert opinion: To assess the clinical applicability of this invention, further studies are needed since the conclusions are derived solely based on the data obtained from only one CRC cell line (Lim1215). Furthermore, other biofactors/mutations should be considered to assure the potential benefits of the combination therapies proposed.     

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.     

Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer

Introduction: Central nervous system (CNS) metastases represent an important cause of morbidity and mortality in non-small cell lung cancer (NSCLC) patients. Local approaches of neurosurgery (usually for single brain lesions), whole brain radiotherapy, and stereotactic radiosurgery are often withheld for the treatment of NSCLC-derived brain metastases (BMs). However, systemic treatment is consistently emerging as an option for patients with asymptomatic BMs, which could allow for delaying cranial radiotherapy at symptomatic/radiological progression.

Areas covered: Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases. Among these, EGFR- and ALK-TKIs will be discussed more in detail owing to their superior efficacy in this context.

Expert opinion: Up-front systemic treatment should be considered for patients with asymptomatic, multiple BMs, as recently acknowledged by the European Society of Medical Oncology guidelines. Nevertheless, it must be emphasized that the best treatment strategy for NSCLC-derived BMs has to be defined within a multidisciplinary team.     

Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.