Ganetespib for small cell lung cancer

Introduction: Heat shock proteins (Hsps) are part of a complex network of chaperone proteins that are critically involved in the conformational maturation of intracellular proteins and regulate their degradation via the proteasome system Hsps (especially Hsp70 and Hsp90) are upregulated in many cancers and are potentially attractive therapeutic targets. Ganetespib is a potent non-geldanamycin analogue, and avoids the toxicities associated with older analogues due to its small molecular weight, lipophilicity and the absence of the benzoquinone moiety; strong pre-clinical data support its evaluation in lung cancer, especially small cell lung cancer (SCLC).

Areas covered: The chemical structure of ganetespib, the biology of Hsp90 in cancer and the pharmacokinetic and pharmacodynamic data related to ganetespib are summarized; data from preclinical studies and multiple Phase I-III clinical trials, with a focus on its evaluation in SCLC are reviewed.

Expert opinion: Recent progress made in the treatment of refractory SCLC with immune checkpoint inhibitors and DLL3-directed antibody-drug conjugate have made the development of ganetespib particularly challenging in SCLC. Hsp90 remains a critical therapeutic target. Hsp90 inhibitors with a wider therapeutic index and combinations with drugs targeting iHsp90 co-chaperones such as Cdc37 or Protein Kinase 2 may need to be explored in the future.     

C-MET inhibitors for advanced non-small cell lung cancer

Introduction: The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naïve patients. The challenges ahead are in the identification of the molecular subtypes that benefit most.

Areas covered: This review summarizes the current understanding of c-MET biology in relation to studies evaluating c-MET inhibitors in the treatment of NSCLC.

Expert opinion: MET inhibitors have the potential to benefit subsets of NSCLC patients with specific genetic alterations. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to MET inhibitors, whereas overexpression, amplification and point mutations of MET seem more challenging subgroups to target. Combination with other target agents, such as EGFR inhibitors, may represent a promising therapeutic strategy in specific areas (e.g. EGFR-TKI resistance).     

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.     

Treating brain metastases in non-small cell lung cancer patients: what have we learnt from pharmaceutical recent clinical trials?

Introduction: Brain metastases (BMs) develop in up to 40% of patients with non-small cell lung cancer (NSCLC). In many recent practice-changing clinical trials, patients with BM were included; however, only few trials reported intracranial efficacies in either post hoc or pre-planned analysis. Clinically meaningful intracranial efficacy data of novel agents have not been completely disclosed.

Areas covered: The authors performed a systemic review of recent pharmaceutical clinical trials, mainly pivotal or practice-changing trials. Some of the prospective clinical trials focused on patients with NSCLC and BM. The authors collected and compared intracranial efficacy reports of chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), ALK inhibitors, and immune checkpoint inhibitors.

Expert opinion: Many clinical trials, especially those on ‘brain-active’ EGFR-TKIs and ALK inhibitors, have robust reports of intracranial efficacies either as post hoc or pre-planned analysis. Physicians should interpret this data with caution and apply the results to patients accordingly. For the design of future clinical trials, enrolling patients with only BM, incorporating novel risk classifications, pre-planning intracranial efficacy endpoints, reporting prior local brain therapies, and applying novel response evaluation criteria are emerging trends in this area.     

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.     

Developments in pharmacotherapy for treating metastatic non-small cell lung cancer

Introduction: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available.

Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.     

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.     

Cathepsin B and L inhibitors: a patent review (2010 - present)

Introduction: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad-spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L.

Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present.

Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents.     

Cardiovascular safety of therapies for type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.     

The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke

Introduction: The 70-kDa heat shock protein (Hsp70) is a cytosolic chaperone which facilitates protein folding, degradation, complex assembly, and translocation. Following stroke, these functions have the potential to lead to cytoprotection, and this has been demonstrated using genetic mutant models, direct gene transfer or the induction of Hsp70 via heat stress, approaches which limit its translational utility. Recently, the investigation of Hsp70-inducing pharmacological compounds, which, through their ability to inhibit Hsp90, has obvious clinical implications in terms of potential therapies to mitigate cell death and inflammation, and lead to neuroprotection from brain injury.

Areas covered: In this review, we will focus on the role of Hsp70 in cell death and inflammation, and the current literature surrounding the pharmacological induction in acute ischemic stroke models with comments on potential applications at the clinical level.

Expert opinion: Such neuroprotectants could be used to synergistically improve neurological outcome or to extend the time window of existing interventions, thus increasing the numbers of stroke victims eligible for treatment.     

Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials

Introduction: A new pharmacological class, Janus kinases (JAK) inhibitors, has been shown to be effective and safe for the treatment of inflammatory bowel diseases (IBDs). The aim of this review is to provide an overview of the JAK inhibitors currently under investigation in phase I and II clinical trials for patients with Crohn’s disease and ulcerative colitis and the possible future perspectives for the treatment of IBD patients with this class of drugs.

Areas covered: This review describes the JAK–STAT pathway and analyzes the efficacy and safety of new small molecules such as filgotinib, upadacitinib, TD-1473, peficitinib, and Pf-06651600/Pf-06700841, showing data from phase I and II trials.

Expert Opinion: JAK inhibitors, if approved by the regulatory authorities, could represent a novel and intriguing drug class. In the next years, the approach to patients with IBD will become increasingly personalized.     

Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors

Introduction: For several decades’ cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules.

Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors. We also provide molecular structural basis of CHK-1inhibitors binding to CHK-1.

Expert opinion: Available data from both pre-clinical and early clinical studies illustrates potential efficacy of this class of molecules when combined with antimetabolites in treating both solid and hematologic malignancies. In addition, there might be an additive role in combining this class of molecules to PARP inhibitors, platinum chemotherapy, or radiation therapy in p53 or BRCA mutated tumors. The safety of the aforementioned combination needs to be closely evaluated in the ongoing clinical trials.     

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.     

Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib.

Areas covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed.

Expert opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.     

Investigational drugs for nasopharyngeal carcinoma

Introduction: Nasopharyngeal carcinoma (NPC) is endemic to Southern China and Asia and is etiologically associated with the Epstein Barr virus (EBV). Whole exome and genome sequencing (WES, WGS) studies of NPC have reported several actionable therapeutic targets, and that the mutational load of NPC maybe comparable to that of squamous head and neck cancer. These unique biological characteristics have been exploited as potential targets and a wide range of investigational drugs are being investigated in clinical trials.

Area covered: This review focused on the latest clinical development of the most promising classes of investigational agents in the treatment of advanced NPC. These include inhibitors of tumor angiogenesis, kinase signaling pathways and immunotherapy.

Expert opinion: Checkpoint inhibitors and EBV-specific T-cell therapy have shown promising activity in early phase clinical trials, and are being further evaluated in randomized studies. For patients whose tumors express genetic alterations that are known to predict response to kinase inhibitors, novel trial designs such as an ‘Umbrella’ study may be considered given the abundance of targeted agents that are now available for clinical evaluation. It is envisioned that regulatory approval for new drugs for advanced NPC will occur in the near future.     

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.     

MEK inhibitors under development for treatment of non-small-cell lung cancer

Introduction: The mitogen-activated protein kinase (MAPK) pathway is intimately implicated in the molecular pathogenesis of non-small-cell lung cancer (NSCLC). Aberrant MAPK signaling resulting from the upstream activating mutations converges on mitogen-activated protein kinase kinase 1/2 (MEK1/2), making MEK inhibition an attractive strategy for the treatment of NSCLC. Several MEK inhibitors have demonstrated anticancer activity in patients with NSCLC.

Areas covered: In this article, we discuss the biological rationale for the use of MEK inhibitors and summarize the clinical experience with MEK1/2 inhibitors for the treatment of NSCLC, from initial phase I studies to phase II/III studies, both as monotherapy or in combination with other anticancer agents.

Expert opinion: Trametinib in combination with the BRAF inhibitor dabrafenib represents the first MEK1/2 inhibitor containing regimen that is approved for advanced BRAF^V600E-mutant NSCLC. Other MEK1/2 inhibitors that are also in advanced stages of clinical development include selumetinib, cobimetinib, and binimetinib. Several studies of MEK inhibitor combination therapies are underway, including trials using combined MEK inhibition and immune checkpoint blockade. Further research aimed at discovering biomarkers of response and resistance to MEK1/2 inhibitors will be needed to develop rational combination strategies for the treatment of NSCLC driven by aberrant MAPK signaling.     

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.     

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 evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients

Introduction: Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM.

Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors.

Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.