Drug safety evaluation of lenvatinib for thyroid cancer

Introduction: Lenvatinib is an oral multitargeted tyrosine kinase inhibitor of VEGFR1,2,3,4, FGFR1,2,3,4, PDGFR-α as well as RET and KIT signaling network. Its activity against radioiodine-resistant differentiated thyroid cancer (DTC) has been recently demonstrated. Patients, who were given lenvatinib, showed significantly longer median progression free survival than placebo group, 18.3 vs 3.6 months, respectively. This review is focused on lenvatinib safety profile in patients treated due to DTC and medullary thyroid carcinoma. Among the most frequent lenvatinib-related adverse events (AEs) were hypertension, proteinuria, diarrhea, appetite decrease, weight loss, nausea and stomatitis. Although a lot of them were manageable, in 35–68% of patients dose reduction was required. Nevertheless, only 15% of subjects withdrew the drug due to its toxicity.Areas covered: published results of clinical trials phase II and III investigating both safety and efficacy of lenvatinib in thyroid cancer.Expert opinion: Lenvatinib shows acceptable safety profile in patients with thyroid carcinoma. Treatment-related side effects are usually manageable by dose modifications or by concomitant non-pharmacological and pharmacological treatment. However, the early recognition of any potential drug toxicity is crucial to avoid serious complications as well as to keep a patient on drug as long as the treatment is beneficial.     

Sorafenib for the treatment of thyroid cancer: an updated review

Introduction: Sorafenib (Nexavar) is an oral multi-kinase inhibitor targeting B-type Raf kinase (BRAF) (both wild type and BRAF^V600E), VEGFR1, VEGFR2, VEGFR3, PDGFRβ and RET (also RET/PTC) influencing both differentiated thyroid cancer (DTC) cell proliferation and angiogenesis.

Areas covered: Encouraging results achieved in numerous Phase II trials were confirmed in a Phase III study conducted in radioiodine-refractory DTC. Sorafenib compared to placebo significantly prolongs progression-free survival, 10.8 versus 5.8 months, respectively. However, its administration resulted mainly in disease stabilization. No complete remission was obtained in any study. Beneficial effects were also demonstrated for medullary and anaplastic thyroid cancer; however further studies fulfilling evidence based medicine criteria are necessary. Its toxicity profile is convergent with other VEGFR inhibitors. The most common treatment-related side-effects involve skin toxicity (predominantly hand-foot skin reaction, different rashes and alopecia), gastrointestinal disturbances (diarrhea, abdominal pain), constitutional adverse reactions (anorexia, weight loss, fatigue) and hypertension. Although most adverse reactions are manageable, > 50% of patients required dose reduction.

Expert opinion: Sorafenib constitutes the first line treatment option in advanced, radioiodine-refractory DTC. However, there are still no data on its efficacy in patients progressed after another tyrosine kinase inhibitor. Other applications of the drug, such as use as adjuvant therapy to 131-I treatment, requires further studies.     

Population pharmacokinetic analysis of sorafenib in patients with solid tumours

AIMS

To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.

METHODS

PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.

RESULTS

A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h⁻¹ (3.6–22.3 l h⁻¹), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.

CONCLUSIONS

Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.     

The safety of vandetanib for the treatment of thyroid cancer

ABSTRACT

Introduction: The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.

Areas covered: The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.

Expert opinion: Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.     

索拉非尼治疗急性髓系白血病的研究进展

作为一种新型多激酶抑制剂,索拉非尼(sorafenib)已被美国FDA批准用于治疗肾细胞癌、肝细胞癌和分化甲状腺癌。而近年来的研究显示通过抑制FMS样酪氨酸激酶-3的活性,该药可发挥一定的抗白血病作用,特别是FMS样酪氨酸激酶-3近膜区的内部串联重复序列(FMS-like tyrosine kinase-3-internal tandem duplication,FLT3-ITD)突变阳性的急性髓系白血病。笔者通过查阅国内外相关文献,对其在治疗急性髓系白血病的药理作用、药物代谢动力学、临床疗效和安全性等方面的研究进展作一综述。     

The discovery and development of vandetanib for the treatment of thyroid cancer

Introduction: Thyroid cancer represents over 90% of all endocrine malignancies, with medullary thyroid carcinoma (MTC) accounting for 5 – 9% of them. Patients with early-stage disease have a favorable prognosis, but once distant metastasis develops, survival drops to 50% or less. Although surgery remains effective for early-stage disease, patients with advanced disease pose a challenge as traditional therapies have not provided long-term benefits. Vandetanib, initially developed to target other receptors, demonstrated anti-rearranged during transfection (anti-RET) kinase activity. This led to preclinical studies followed by recent human clinical trials, culminating in its FDA approval in April 2011 for application in the treatment of symptomatic or progressive MTC in patients with surgically unresectable, locally advanced or metastatic disease.

Areas covered: The authors provide a review of the discovery strategy and preclinical development of vandetanib. The authors also provide some insight into the clinical development and the drug's post-launch situation.

Expert opinion: Vandetanib has been shown to improve progression-free survival in MTC patients, but its impact on overall survival is still inconclusive. Further data analysis will be needed to answer the question of whether it impacts overall survival in MTC. Despite its advancements, vandetanib still lacks durable efficacy, carries moderate toxicity and has issues with drug resistance over time, not to mention issues of cost. There is a significant need for additional research to discover and develop improved therapeutic strategies for this difficult disease.     

An evaluation of brigatinib as a promising treatment option for non-small cell lung cancer

ABSTRACT

Introduction: Brigatinib is a second-line inhibitor for the treatment of rearranged anaplastic lymphoma kinase (ALK) in lung cancer patients which has significant activity against brain metastases. This tyrosine kinase inhibitor (TKI) overcomes a wide range of ALK mutations which confer therapeutic resistance and is increasingly applied in first-line therapy due to improved benefit for patients compared to crizotinib, the current standard of care.

Areas covered: The authors review the development and characteristics of brigatinib and discuss the optimal clinical use and sequence of the application of ALK inhibitors in patients progressing under therapy.

Expert opinion: ALK-rearranged NSCLC can be treated with a broad range of approved and novel inhibitors at various stages of therapy, including the second-line therapeutic brigatinib. Besides this TKI, the second-line ALK inhibitors alectinib and ceritinib, as well as the third-line lorlatinib are approved for the treatment of ALK-positive NSCLC patients. The main challenge is to find sequences and combinations of ALK inhibitors which provide the best benefit for the patients.     

A phase I surrogate endpoint study of SU6668 in patients with solid tumors

PURPOSE: To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies. EXPERIMENTAL DESIGN: Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m(2)/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668. RESULTS: Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cl(oral)) measured on day 1 was 6.3 +/- 2.7 L/hr/m(2), yielding a mean AUC of 16.6 +/- 4.3 mg/L.hr. By day 22, the Cl(oral) was 40% more than that observed on day 1. CONCLUSION: It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.     

The safety of regorafenib for the treatment of gastrointestinal stromal tumors

Introduction: The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose.

Areas covered: Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST – Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST.

Expert opinion: Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.     

乐伐替尼治疗恶性肿瘤的研究进展

乐伐替尼是一种口服的多靶点酪氨酸激酶受体抑制剂,用于放射性碘难治性分化型甲状腺癌的单药治疗以及与依维莫司联合治疗晚期肾细胞癌。近年越来越多的临床数据展示出了该药在未来抗肿瘤治疗中的巨大潜力。本文将对其作用机制、研究历程、临床试验以及最新研究进展进行综述,以求使读者能够更全面地了解和认识乐伐替尼并且为我国的临床实践提供建议。     

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.

Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.

Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

A safety evaluation of omacetaxine mepesuccinate for the treatment of chronic myeloid leukemia

ABSTRACT

Introduction: Therapy of chronic myeloid leukemia (CML) has been completely transformed by the development of tyrosine kinase inhibitors (TKIs). However, a subset of patients will fail TKI therapy due to resistance or intolerance. Omacetaxine mepesuccinate (OM), a protein translation inhibitor, is currently the only approved therapy that does not directly target the kinase domain. It has activity for CML patients irrespective of the phase or underlying kinase domain mutation status.

Areas covered: We searched the MEDLINE database for articles published in English on homoharringtonine or omacetaxine from 1970 to present. This article reviews the pharmacokinetics of OM and its clinical evolution for the treatment of CML pre- and post TKI development. Toxicity profile, drug administration and future directions are also discussed.

Expert opinion: OM represents a unique addition to the CML therapeutic armamentarium with its distinct mechanism of action and activity. The adverse event profile is manageable and with subcutaneous administration at the approved dose, cardiac toxicity is no longer a concern. The recent approval of home administration will facilitate access to this therapy and increase patient compliance. We conclude with specific scenarios where OM use should be considered in CP and AP-CML patients in the era of TKI therapy.     

Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer

ABSTRACT

Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting.

Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC.

Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.     

Sorafenib for the treatment of renal cancer

OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) is the first major study to compare an angiotensin II Type 1 antagonist losartan (Cozaar?, Merck) with an ACE inhibitor captonpril (Capoten?, Elan) after myocardial infarction in patients with left ventricular dysfunction. Patients were assigned to a target dose of losartan 50 mg/day and captopril 50 mg t.i.d., as tolerated. The primary end point was all-cause mortality and there were 499 (18%) and 447 (16%) deaths in the losartan and captopril group, respectively (p = 0.07). However, there were significantly more cardiovascular deaths with losartan (420, 15%) than with captopril (363, 13%; p = 0.03). Losartan was better tolerated than captopril with fewer patients discontinuing medication (17 versus 23% for losartan and captopril, respectively). In conclusion, if tolerated, captopril should remain the preferred treatment for patients after complicated acute myocardial infarction.     

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.     

Type III or allosteric kinase inhibitors for the treatment of non-small cell lung cancer

Introduction: In recent times, there has been much interest in the development of pharmacological kinase inhibitors that treat NSCLC. Furthermore, treatment options have been guided by the development of a wide panel of synthetic small molecule kinase inhibitors. Most of the molecules developed belong to the type I class of inhibitors that target the ATP-binding site in its active conformation. The high sequence similarity in the ATP-binding site among members of the kinase families often results in low selectivity and additional toxicities. Also, second mutations in the ATP-binding site, such as threonine to methionine at position 790, have been described as a mechanism of resistance to ATP-competitive kinase inhibitors. For these reasons, alternative drug development approaches targeting sites other than the ATP cleft are being pursued. The class III or allosteric inhibitors, which bind outside the ATP-binding site, have been shown to negatively modulate kinase activity.

Areas covered: In this review, the authors discuss the most well-characterised allosteric inhibitors that have reached clinical development in NSCLC.

Expert opinion: Great progress has made in developing inhibitors with entirely new modes of action. That being said, it is important to highlight that despite their apparent simplicity, biochemical assays will remain at the core of drug discovery activities to better explore these new opportunities.     

A phase I study of oral ZD 1839 given daily in patients with solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group

Summary Purpose: To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), the biological active (BA) dose and the pharmacokinetics (PK) of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa) when administered continuously as a once daily dose in patients with advanced, incurable solid tumours. Patients and methods: Twenty-eight patients were enrolled in cohorts of three from three National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) centers. ZD1839 was given at doses from 150 to 800 mg daily orally and patients underwent a pretreatment and a 28 day post treatment tumor biopsy, while PK sampling was performed on days 8, 15, 22, 29, and a toxicity assessment every 28 days. Results: All twenty-eight patients were evaluable for non-hematological and hematological toxicity. Twenty-seven were evaluable for response. The MTD was not reached but DLT included reversible rash and diarrhea. One patient with urachal cancer had a transient 55% decrease in tumor size and two other patients (breast and non-small cell lung cancer) had minor responses; three additional patients had pharmacodynamic evidence of target effect. PK demonstrated steady state within the first 2 weeks of dosing and dose dependent exposure. Conclusion: It appears that ZD 1839 at a dose of 800 m/day was tolerable, although some patients required dose modification for diarrhea. Doses above 250 m/day demonatrate biologic activity and could be consider for future study in a variety of EGFR positive tumor types.     

Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis

Aims

To investigate the overall incidence and risk of hypertension in cancer patients who receive axitinib and compare the differences in incidences between axitinib and the other four approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

Methods

Several databases were searched, including Pubmed, Embase and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned axitinib at a starting dose of 5 mg orally twice daily with data on hypertension available. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials.

Results

A total of 1908 patients from 10 clinical trials were included. The overall incidences of all grade and high grade hypertension in cancer patients were 40.1% (95% CI 30.9, 50.2%) and 13.1% (95% CI 6.7, 24%). The use of axitinib was associated with significantly increased risk of all grade (RR 3.00, 95% CI 1.29, 6.97, P = 0.011) and high grade hypertension (RR1.71, 95% CI 1.21, 2.43, P = 0.003). The risk of axitinib associated all grade and high grade hypertension in renal cell carcinoma (RCC) was significantly higher than that in non-RCC. Additionally, the risk of hypertension with axitinib was substantially higher than other approved VEGFR-TKIs, while the risk of all grade hypertension with axitinib was similar to pazopanib (RR 1.05; 95% CI 0.95-, 1.17, P = 0.34).

Conclusions

While sharing a similar spectrum of target receptors with other VEGFR-TKIs, axitinib is associated with an unexpectedly high risk of developing hypertension. Close monitoring and appropriate management for hypertension are recommended during the treatment.     

Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors

Aberrant expression or activation of protein tyrosine kinases, including Src and related Src family kinases, is a common occurrence in many human cancers, resulting in deregulation of expression of numerous mediators of cellular functions, including pro-angiogenic molecules. In addition, Src activation regulates vascular permeability of endothelial cells. How these processes contribute to tumor progression and metastasis are the subjects of this review. As Src-selective inhibitors have entered clinical trials for a number of solid tumors, further understanding of the roles of Src kinases in mediating tumor angiogenesis as well as modulating tumor/microenvironment interactions will provide insights into the best use of these inhibitors in treating patients afflicted with tumors in which Src is activated.