Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia

Introduction: BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patients

Areas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents. Published English-language literature was reviewed regarding currently available TKIs; clinical trials repositories were reviewed to identify novel agents recently investigated or under active study.

Expert opinion: We recommend discussion with patients and enrolment on an appropriate clinical trial where feasible. In situations where no trials are available, or if patients decline enrolment, we recommend use of an appropriate BCR-ABL directed TKI, selected on the basis of an evaluation of patient risk factors and side effect profile. Allogeneic stem cell transplant continues to have a role though this is generally limited to cases with advanced phases of disease or in cases with resistance-conferring mutations.     

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.     

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib

Introduction: In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment.

Areas covered: Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported. Limited attention to long-term events or more in general, to the impact of AEs on patient quality of life (QoL), remains a problem. Ponatinib is active against all BCR-ABL1 mutants, including T315I, and is widely used to treat patients who developed resistance to other TKIs in any CML phase; however, only limited data is available on the possible role of ponatinib for intolerant patients.

Expert opinion: We review the different definitions of intolerance used in sponsored trials and in clinical practice, and we discuss how such definitions impact on the management of AEs. We summarize how to evaluate QoL during treatment with TKIs and how to include ponatinib among possible option for intolerant patients.     

Targeting the EGFR T790M mutation in non-small-cell lung cancer

Introduction: The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation.

Areas covered: This review is focused on the implications of tumor heterogeneity for targeting the T790M in patients with NSCLC.

Expert opinion: Pre-clinical and clinical data suggest that the T790M is heterogeneously expressed in tumors that become resistant to first- and second-generation EGFR TKIs. These findings have important implications for the molecular diagnostic of the T790M mutation. Indeed, the analysis of both the circulating free tumor DNA (ctDNA) isolated from plasma and the tumor tissue might provide complimentary information to identify patients carrying the T790M mutation. However, further studies are needed to better understand the influence of tumor heterogeneity on the activity of drugs targeting the T790M.     

The safety of Bosutinib for the treatment of chronic myeloid leukemia

Introduction: Tyrosine kinase inhibitors (TKIs) are a potentially lifelong treatment for patients with chronic myeloid leukemia (CML). Adverse events (AEs) associated with TKIs are significant impediments in the daily life of patients that can impact compliance, and efficacy.

Areas covered: This is a review on safety of bosutinib in the treatment of chronic phase CML. Data is extracted from the latest updates of bosutinib phase I/II and III trials.

Expert opinion: Bosutinib is an effective agent against all phases of CML presently approved for the treatment in patients with resistance or intolerance to prior TKI therapy. Bosutinib has a unique toxicity profile characterized by early and transient diarrhea. Otherwise, the AE profile of bosutinib is comparable to other TKIs, with the exception of cardiovascular AEs that are infrequent in bosutinib-treated patients. Similar to other TKIs, the minimum effective dose of bosutinib remains unknown. Better definition of the optimal effective dose may spare, for those patients otherwise benefitting from treatment, unnecessary AEs.     

Pharmacokinetic drug evaluation of pazopanib for the treatment of uterine leiomyosarcomas

Introduction: Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy.

Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS.

Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.     

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.     

Prognostic factors for survival following initiation of second-line treatment with everolimus for metastatic renal cell carcinoma: evidence from a nationwide sample of clinical practice in the United States

Objective: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials.

Research design and methods: Two separate chart sets (2009 – 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI).

Main outcome measures: Prognostic factors for OS have been identified and validated in separate samples.

Results: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months – higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 – 2 risk factors, 63% for 3 risk factors and 22% for 4 – 5 risk factors (log-rank p < 0.001).

Conclusion: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.     

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach.

Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies.

Expert opinion: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.     

An in-depth review of chemical angiogenesis inhibitors for treating hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is a frequent and severe complication of cirrhosis. Most HCC patients initially present with or progress to advanced stage disease and require systemic treatment. As hypervascularization is a major characteristic of HCC, antiangiogenic drugs have been tested.

Areas covered: In this review, we summarize data on the use of drugs targeting the angiogenesis. Despite many trials, in 2017 only 3 drugs, all antiangiogenic, have demonstrated efficacy in first (sorafenib, lenvatinib) or second line (regorafenib) treatment of advanced HCC. The heterogeneous mechanisms of action and the major reasons for failure of most trials are discussed. An English-language, abstract-based literature review was performed by a PubMed-based strategy.

Expert opinion: Currently all trials based on purely antiangiogenic compounds (bevacizumab, linifanib, brivanib and ramucirumab) or drugs with strong antiangiogenic properties (sunitinib) have failed (increased toxicity, minor efficacy and/or flaws in trial design); sorafenib, lenvatinib and regorafenib are multityrosine kinase inhibitors and their efficacy can be partly related to another mechanism of action. We need to better refine future trials design (randomized phase 2, good stratification factors and marker-enriched patient selection) in order to progress toward customized treatment, perhaps in association with immunotherapy.     

Clinical development of mTor inhibitors for renal cancer

Introduction: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90–95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options.

Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials.

Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.     

Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis

Background: A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.

Methods: The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.

Results: Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (OR_PETO:3.26; 95%CI:1.12 to 9.50), nilotinib (OR_PETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (OR_PETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (OR_PETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.

Conclusions: Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.     

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.     

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.     

Which tyrosine-kinase inhibitor to use first in chronic phase chronic myelogenous leukemia?

Introduction: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder distinctly characterized by the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. The resulting translocation leads to the development of the BCR-ABL1 oncogene, a constitutively active fusion protein, which leads to uncontrolled cell proliferation and reduced apoptosis and has a clear association with driving the malignant activity of CML cells.

Areas covered: Given that the BCR-ABL1 oncogene is a known key cause of CML, it has led to the development of numerous small molecule tyrosine-kinase inhibitors (TKIs), which target the specific oncogene mutation in CML. Presently, there are three FDA-approved TKI agents, imatinib, dasatinib and nilotinib, for the treatment of frontline CML. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents.

Expert opinion: Imatinib, dasatinib and nilotinib are all effective at yielding hematological, molecular and cytogenetic responses in patients with newly diagnosed CML. Frontline therapy may depend on physician experience, patient age and ability to tolerate therapy, and with the lack of data comparing all three agents alongside each other, imatinib, dasatinib, or nilotinib may all be suitable frontline choices.     

Hepatocellular carcinoma treatment: a comparative review of emerging growth factor receptor antagonists

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Over the last decade, sorafenib has been the only available therapeutic option for advanced HCC, although regorafenib recently showed a survival benefit compared with placebo in a second-line setting.

Areas covered: This review discusses key published and ongoing studies with targeted agents in HCC, molecular targets of HCC, the mechanism of resistance to sorafenib, and the role of biomarker-enriched clinical trials.

Expert opinion: The multiplicity of drivers and the existence of substantial molecular heterogeneity limit the benefits of targeted therapies in HCC. Based on molecular biology developments, a few biomarker-enriched clinical trials that target candidate driver genes are ongoing, and the outcomes of these are highly anticipated. Poor availability of tumor tissue and tumor heterogeneity in patients with HCC make liquid biopsy a very attractive option, although this technique remains to be validated.     

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.     

Oral chemotherapy for the treatment of hepatocellular carcinoma

Introduction: Many clinical trials have been conducted with chemotherapies in patients with advanced hepatocellular carcinoma (HCC). However, few agents have shown efficacy. It is thought that the efficacy of some agents might have resulted from the heterogeneity of tumors, insufficient dosages due to liver cirrhosis, and post-therapy effects. In recent years, immune checkpoint inhibitors have shown promising clinical activity and safety in patients with advanced HCC.

Areas covered: The authors provide an overview of chemotherapies used for the treatment of HCC, including ongoing trials. The authors also provide their expert opinion on the subject area and provide their future perspectives.

Expert opinion: Based on favorable phase III clinical trial data, sorafenib and lenvatinib are considered promising agents for HCC as first-line systemic chemotherapy. Moreover, regorafenib and cabozantinib are useful second-line therapies after the failure of sorafenib. Furthermore, in early phase clinical trials, immune checkpoint inhibitors and the combinations of these inhibitors and molecular targeted agents have demonstrated promising activity. Therefore, better survival results are expected from future phase III clinical trials.     

A safety review of the medications used to treat atopic dermatitis

Introduction: Atopic dermatitis (AD) is a common disease in children and adults which causes severe physical discomfort and psychosocial distress. Recently novel therapies for AD have been FDA approved for use which creates the need to review the safety surrounding current FDA approved AD medications.

Areas covered: Published clinical studies involving topical and oral FDA approved medications for AD are included in this review. Authors used PubMed research database to search for clinical trials involving AD patients.

Expert opinion: AD is a common disease which currently has limited FDA approved medications. Given the chronicity of this disease, medications are needed which control disease while minimizing side effects to allow for long term use. Newer approved medications show promise but safety data is limited given their relatively new utilization for AD.