Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison

Objective: Comparing the benefit–risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit–risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects’ baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation.

Methods: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial.

Results: Responses were more frequent and durable with ponatinib (n?=?70 MAIC-adjusted) than with bosutinib (n?=?119) – complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan–Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n?=?97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events.

Conclusions: Based on these surrogate measures of patient benefit–risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.     

Tyrosine kinase inhibitors in acute and chronic leukemias

INTRODUCTION: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients. AREAS COVERED: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML). EXPERT OPINION: There are now more potent BCR-ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side-effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied.     

Tyrosine kinase inhibitors to treat liver cancer

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern.

Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways.

What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC.

Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies.     

Lestaurtinib,a multitargeted tyrosinse kinase inhibitor: from bench to bedside

Importance of the field: Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade.

What the reader will gain: The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent.

Take home message: Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.     

Forthcoming receptor tyrosine kinase inhibitors

Receptor tyrosine kinases play a significant role in carcinogenesis and have been successfully targeted with monoclonal antibodies and small-molecule inhibitors. There have been recent developments in the understanding of receptor tyrosine kinase signal transduction which have enabled better drug development. The use of receptor tyrosine kinase inhibitors in clinical practice has expanded the knowledge on cancer biology, in particular the understanding of resistant mutations and strategies to overcome such resistance. This has driven drug development from single kinase inhibitors to multi-kinase inhibitors and high-affinity kinase inhibitors. Finally, as the use of receptor tyrosine kinase inhibitors grows in clinical practice, more is learned about appropriate patient selection for such therapies. This is an exciting time in cancer therapeutics, highlighted by the advent of effective targeted therapy with receptor tyrosine kinase inhibitors.     

Tyrosine kinase inhibitors in cancer treatment (Part II)

In the last few years, enormous progress in the field of signal transduction inhibition has been made. Many companies have entered the field. Along with the epidermal growth factor receptor (EGFR) tyrosine kinase, many other tyrosine kinases have been identified as interesting targets for drug discovery projects. X-ray data of more than 40 crystal structures of protein kinases, in most cases complexed with an inhibitor, have been published. Pharmacophore models for the binding of inhibitors in the ATP-binding site of protein kinases have been developed that are generally applicable, enabling the rational design of tyrosine as well as serine/threonine kinase inhibitors. It has been proven by numerous examples that the ATP-binding of protein kinases is an exciting target for the design of anticancer drugs. In many cases, it has also been demonstrated that through rational design it is possible to modify a lead structure in such a way that inhibitors with an altered selectivity profile are obtained. Chemical optimisation of several lead structures led to development candidates with potent in vitro and in vivo activity fulfilling the pharmacodynamic, pharmacokinetic, toxicological and technical (synthesis, formulation) requirements for a clinical candidate. Currently, there are seven tyrosine kinase inhibitors in early phases of clinical trials. In addition, several candidates are close to entering Phase I trials this year or at the beginning of next year. It is expected that positive results from clinical trials will greatly contribute to the clinical proof of concept of the value of signal transduction inhibition and will greatly stimulate further research in this area. This review is a continuation of a review with the same title of last year and summarises published patent literature and related publications between 1997 and September 1998.     

酪氨酸激酶抑制剂治疗慢性粒细胞白血病的不良反应及临床对策

酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)抑制BCR-ABL融合基因,使慢性粒细胞白血病(chronic myelocytic leukemia,CML)患者能够较长期生存。患者使用TKIs早期出现不良反应都较轻,可自行恢复或者给予对症处理和选择其他TKIs。而TKIs长期的使用的安全性问题国内少有报道,本文通过查阅国内外文献,综述TKIs引起的骨髓、皮肤、胃肠、肝和胰、骨骼肌、肺、液体潴留、心血管方面的不良反应以及其临床对策。     

Bcr-Abl tyrosine kinase inhibitors: a patent review

Introduction: Breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors.

Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compounds that are in clinical trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chemical features.

Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a number of patented compounds could enter clinical trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

Dasatinib for the treatment of Philadelphia chromosome-positive leukemias

Introduction: Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI), which was developed to treat patients with chronic myelogenous leukemia (CML), who had failed or were intolerant to therapy with imatinib.

Areas covered: In this article, we review preclinical and clinical studies with dasatinib for the therapy of Philadelphia (Ph)-positive leukemias.

Expert opinion: Dasatinib is very effective in the setting of CML resistance or intolerance to imatinib, particularly in patients in chronic phase (CP). Dasatinib is also effective against most BCR-ABL1 mutations that arise during therapy with imatinib. Further studies have confirmed activity of dasatinib as a single-agent, and combined with chemotherapy, for the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+-ALL). More recently, randomized trials have demonstrated that dasatinib is superior to imatinib in the initial therapy of patients with CML, and the drug was approved by the FDA for this indication in 2011.     

针对T315I突变的Bcr—Abl酪氨酸激酶抑制剂研究进展

BCR-ABL是一种由bcr基因和c-abl原癌基因融合产生的致癌基因。该基因表达的Bcr-Abl癌蛋白是慢性粒细胞白血病的病理学基础。因此研发选择性的Bcr-Abl酪氨酸激酶抑制剂成为治疗慢性粒细胞白血病的一种有效策略。目前已有数个Bcr-Abl酪氨酸激酶抑制剂获准上市。然而,Abl激酶结构域的突变或其他原因导致肿瘤耐药性的出现,其中T315I突变是最重要的突变之一,引发的耐药性更是难以克服。重点介绍了针对T325I突变的Bcr-Abl酪氨酸激酶抑制剂的研究进展。     

Tyrosine kinase inhibitors: potential use and safety considerations in HIV-1 infection

Introduction: Infection caused by HIV-1 is nowadays a chronic disease due to a highly efficient antiretroviral treatment that is nevertheless, unable to eliminate the virus from the organism. New strategies are necessary in order to impede the formation of the viral reservoirs, responsible for the failure of the antiretroviral treatment to cure the infection.

Areas covered: The purpose of this review is to discuss the possibility of using tyrosine kinase inhibitors (TKIs) for the treatment of HIV-1 infection. These inhibitors are successfully used in patients with distinct cancers such as chronic myeloid leukemia. The most relevant papers have been selected and commented.

Expert opinion: The family of TKIs are directed against the activation of tyrosine kinases from the Src family. Some of these kinases are essential for the activation of CD4 + T cells, the major target of HIV-1. During acute or primary infection the CD4 + T cells are massively activated, which is mostly responsible for the generation of the reservoirs, the spread of the infection and the destruction of activated CD4 + T cells, infected or not. Consequently, we discuss the possibility of using TKIs as adjuvant of the antiretroviral treatment against HIV-1 infection mostly, but not exclusively, during the acute/recent phase.     

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.     

Dawn of Aurora kinase inhibitors as anticancer drugs

With the current standard chemotherapy regimens only ～ 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.     

Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia

Introduction: Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome.

Areas covered: In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity.

Expert opinion: So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.     

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.     

蛋白酪氨酸激酶抑制剂的研究进展

目的综述蛋白酪氨酸激酶(protein tyrosine kinase,PTK)抑制剂类抗肿瘤药物的研究进展。方法根据已报道的PTK抑制剂的相关文献,将其分为国外已经上市、国外处于临床研究和我国自主研发的PTK抑制剂进行具体介绍。结果 PTK在细胞内的信号转导中起着重要的作用,与肿瘤细胞的生长、增殖、分化和凋亡密切相关,目前已经有多种结构的PTK抑制剂类抗肿瘤药物上市或进入临床研究。结论随着PTK的作用机制及构效关系研究的不断深入,该类药物终将成为治疗肿瘤的有效药物。     

Selective tyrosine kinase inhibitors

The tyrosine specific protein kinases (TK) are a subgroup of the largest known gene family, the kinases. Latest estimates suggest that there are over 2000 kinases encoded in the human genome [1]. TKs catalyse the transfer of phosphate to the phenolic hydroxyl of tyrosine residues in substrate proteins, consequently modifying the target protein properties. By working in concert with tyrosine phosphatases, which drive the reverse process, the TKs provide a switching system resulting in the transduction of signals from cell surface receptor to the nucleus. Inappropriate activation of TKs can lead to abnormal, dysregulated cellular proliferation and many of the known oncogenes are kinases. Naturally, there has been great interest in TKs as potential molecular targets for developing drugs for the treatment of cancer and results from the first clinical trials are now being published. Preclinical research is also focused on other therapeutic applications of TK inhibitors. This review concentrates on TK inhibitors which are either already in the clinic or likely to enter Phase I studies in the near future.     

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.     

Tyrosine kinase inhibitors as novel drugs for the treatment of diabetes

Introduction: Some inhibitors of tyrosine kinase, as imatinib, erlotinib and sunitinib have antihyperglycemic effects but the mechanisms are not totally clear.

Areas covered: It is well established that insulin resistance and beta-cell failure are hallmarks of type 2 diabetes mellitus (DM2). The present review will discuss the molecular mechanisms that account for insulin resistance and beta-cell failure in DM2, and also the effect of tyrosine kinase inhibitors in these processes.

Expert opinion: A better understanding of how these drugs improve the two most important mechanisms of DM2 associated with suggestions of clinical studies will lead to improve the treatment of this disease.     

Tyrosine kinase inhibitors under investigation for the treatment of type II diabetes

Introduction: Type 2 diabetes is characterized by hyperglycemia that is the result of β-cell failure in the setting of peripheral insulin resistance. It is estimated that greater than 300 million individuals worldwide have diabetes. Tyrosine kinase inhibitors (TKIs), which are used to treat a variety of cancers, appear to have antihyperglycemic effects.

Areas Covered: This review summarizes studies that have investigated the use of TKIs in animal models of diabetes. Additionally, the authors review case series describing the effects of TKIs on glucose levels in adults taking these drugs for FDA approved indications.

Expert opinion: Given the scope and size of the worldwide diabetes epidemic, reports of amelioration or possible cure of the disease warrant special attention. TKIs appear to lower glucose levels in some, but not all individuals. Multi-center prospective studies are needed in which patient with diabetes treated with TKI undergo phenotyping to identify responders versus non responders to allow for precision medicine.