Vandetanib: An overview of its clinical development in NSCLC and other tumors

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.     

Vandetanib for the treatment of non-small-cell lung cancer

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Vandetanib, a novel multitargeted kinase inhibitor, in cancer therapy

In clinical trials thus far, single-targeted kinase inhibitors have shown only limited success in demonstrating survival benefits in cancer. This has led to the development of multitargeted kinase inhibitors capable of disrupting various mitogenic pathways in both cancer cells and associated vasculature. Vandetanib is a novel multitargeted kinase inhibitor exhibiting potent activity against vascular endothelial growth factor receptor-2 (VEGFR-2; kinase insert domain-containing receptor [KDR]) and, to a lesser extent, epidermal growth factor receptor (EGFR) and RET kinase. Vascular endothelial growth factor (VEGF) and VEGFR-2 play a pivotal role in regulating angiogenesis and vascular permeability in cancers. In addition to its antiangiogenic effects, vandetanib acts against EGFR, which is overexpressed or mutated in several solid tumors. Furthermore, vandetanib exerts activity against oncogenic RET kinase, the overexpression of which is common in medullary and papillary thyroid carcinomas. Therefore, the multitargeted kinase inhibitor vandetanib represents a new approach, targeting both tumor cells and tumor-associated endothelial cells. Preclinical studies of vandetanib have demonstrated antitumor efficacy against multiple human cancer xenografts in subcutaneous, orthotopic and metastatic models. Phase I clinical trials have demonstrated that vandetanib is well tolerated. Common adverse events included rash, diarrhea and asymptomatic QTc prolongation. Phase II clinical studies in patients with non-small-cell lung cancer have shown promising results, employing vandetanib as both monotherapy and in combination with docetaxel. Phase II studies in other cancers have likewise been initiated. This review summarizes preclinical and clinical studies of vandetanib for the treatment of cancers.     

Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study

Purpose The aim of this Phase II study was to assess the efficacy and safety of vandetanib in combination with docetaxel in patients with pretreated advanced breast cancer. Methods The primary study objective was to compare the number of progression events in patients receiving once-daily oral vandetanib (100 mg) in combination with docetaxel (100 mg/m² iv every 21 days) versus placebo plus docetaxel. Sixty-four patients were randomized to receive study treatment (n = 35, vandetanib; n = 29, placebo). Results A slightly greater number of patients had experienced a progression event by the data cut-off in the vandetanib group (24 [69%]) compared with the placebo group (18 [62%]); HR = 1.19, two-sided 80% CI: 0.79–1.81; two-sided P = 0.59), suggesting that the addition of vandetanib to docetaxel did not affect the risk of disease progression compared with placebo plus docetaxel. The safety and tolerability profile of the combination therapy reflected those of both drugs as monotherapy agents. Conclusions In patients with advanced breast cancer, vandetanib plus docetaxel was generally well tolerated. Clinical benefit was not different to that observed with placebo plus docetaxel. However, due to the small patient number it was not possible to yield robust results, further research is required to identify predictive factors for patient selection.     

Open-label phase I trial of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer

Summary   Background: Vandetanib (ZACTIMA™) is a once-daily oral inhibitor of vascular endothelial growth factor, epidermal growth factor and RET receptor tyrosine kinases. The safety and tolerability of vandetanib plus mFOLFOX6 was investigated in patients with advanced colorectal cancer (CRC). Methods: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of mFOLFOX6. Results: Seventeen patients received vandetanib 100 mg (n = 9) or 300 mg (n = 8) plus mFOLFOX6. The protocol definition of a tolerable dose (vandetanib-related dose-limiting toxicity [DLT] in less than two patients) was met in both dose cohorts, with one DLT of diarrhoea reported in each. Overall, the most common adverse events were diarrhoea, nausea and lethargy (all n = 11). There was no pharmacokinetic interaction between vandetanib and mFOLFOX6. Preliminary efficacy results included one complete response and three confirmed partial responses. Conclusions: In patients with advanced CRC, once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated.     

An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer

Pemetrexed is a novel antifolate antimetabolite that targets multiple folate-dependent enzymatic pathways and inhibits multiple enzymes involved in purine and pyrimidine synthesis. Its targets include pathways that, when amplified, are associated with reduced efficacy in conventional cytotoxic agents. As second-line treatment for advanced non-small cell lung cancer, (NSCLC) pemetrexed, when administered with folic acid and vitamin B_12, has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel. A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel. Newer targeted therapies, especially the epidermal growth factor receptor inhibitors gefitinib and erlotinib, have produced conflicting results and have only been compared with best supportive care and placebo. They should be compared directly to pemetrexed as second-line therapy in large, randomised studies of patients with advanced NSCLC. For patients with advanced recurrent NSCLC and good performance status who progress after first-line chemotherapy, pemetrexed should be considered as a new standard of care.     

An evaluation of pemetrexed in second-line treatment of non-small cell lung cancer

Pemetrexed is a novel antifolate antimetabolite that targets multiple folate-dependent enzymatic pathways and inhibits multiple enzymes involved in purine and pyrimidine synthesis. Its targets include pathways that, when amplified, are associated with reduced efficacy in conventional cytotoxic agents. As second-line treatment for advanced non-small cell lung cancer, (NSCLC) pemetrexed, when administered with folic acid and vitamin B12, has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel. A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel. Newer targeted therapies, especially the epidermal growth factor receptor inhibitors gefitinib and erlotinib, have produced conflicting results and have only been compared with best supportive care and placebo. They should be compared directly to pemetrexed as second-line therapy in large, randomised studies of patients with advanced NSCLC. For patients with advanced recurrent NSCLC and good performance status who progress after first-line chemotherapy, pemetrexed should be considered as a new standard of care.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

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.     

Docetaxel in non-small cell lung cancer: impact on quality of life and pharmacoeconomics

Lung cancer is one of the leading causes of cancer-related deaths in industrialised countries, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. A large proportion of patients present with advanced disease and are >65 years of age at the time of diagnosis. Systemic chemotherapy may be offered in an effort to improve survival and quality of life (QOL). Chemotherapy with platinum-based compounds has been shown to modestly improve survival and QOL, and is considered the standard of care as first-line treatment in patients with a good performance status. The last decade has seen the emergence of newer generation chemotherapy agents for the treatment of all cancer types. We review the evidence for the use of docetaxel, an antimicrotubular agent, in patients with advanced NSCLC. In this review, we evaluate not only the effects of docetaxel on survival, but also its impact on QOL and economic issues. Docetaxel is a potent anticancer agent with activity both as a single agent or in combination, and is used both as a first- and second-line treatment in advanced NSCLC. The improvements observed in patients' QOL and the cost effectiveness of docetaxel make it a very reasonable choice in older patients with good performance status and advanced disease who are candidates for chemotherapy.     

Docetaxel in non-small cell lung cancer: a review

Docetaxel (Taxotere, Aventis Pharma), a semisynthetic taxane targeting the beta-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel-platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

Alogliptin benzoate for the treatment of type 2 diabetes

Docetaxel (Taxotere?, Aventis Pharma), a semisynthetic taxane targeting the β-subunit of tubulin, has broad spectrum anticancer activity including non-small cell lung cancer (NSCLC). It is synergistic with platinum and radiation in preclinical models and has been tested clinically in every stage of NSCLC. Docetaxel–platinum combinations have an efficacy comparable to other newer-agent platinum doublets as first-line therapy in advanced NSCLC, and has been approved for use in this setting. Docetaxel was initially approved for NSCLC in the second-line setting following two Phase III trials demonstrating improved survival and quality of life. Ongoing clinical trials are investigating how best to combine docetaxel with thoracic radiotherapy in locally advanced disease. Preliminary studies evaluating docetaxel in the pre-operative setting have also been completed. Ongoing studies are focused on confirming the results observed with consolidation docetaxel in locally advanced NSCLC (SWOG 9504) and docetaxel in combination with molecularly targeted agents. This paper will review the pharmacology, preclinical, clinical and pharmacoeconomic data supporting the use of docetaxel in the treatment NSCLC.     

Docetaxel (Taxotere) - an update

The development of docetaxel, a member of the taxoid family, has been recent and rapid. Phase I studies recommend that a dose of 100 mg/m(2) be administered every three weeks in a 1-h infusion. These studies have also demonstrated that the major dose-limiting toxicity is neutropenia. Major clinical research projects are now being carried out for breast cancer, non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN) and gastric cancer. In advanced and metastatic NSCLC, Phase II studies have shown a response rate of 30 - 40%, and responses have been obtained in cis-platinum failures. In advanced and metastatic breast cancer, first-line treatment has yielded a response rate of 54 - 68%, and the rate for second-line response is only slightly lower, indicating an absence of cross-resistance. Phase II combination studies with docetaxel are in progress, and preliminary results are promising. The first Phase III study demonstrated preliminary response rates significantly higher than seen with doxorubicin, although survival data have not yet been published. Fewer results are available from SCCHN studies, but response rates have been encouraging (around 40%). Although further long-term data are needed to determine the precise role of docetaxel in combination with other drugs, it is apparent that this promising drug shows one of the best response rates for monotherapy in NSCLC and breast cancer.     

The current status of docetaxel for advanced non-small cell lung cancer

Docetaxel is an active single agent in both first- and second-line therapy of patients with advanced non-small cell lung cancer (NSCLC). Randomized trials versus best supportive care have documented an improvement in overall survival for docetaxel therapy in both settings. Docetaxel also produced a significant 1-year survival rate improvement when compared with vinorelbine or ifosfamide as second-line therapy. Docetaxel has been extensively investigated in phase I/II studies in combination with cisplatin, carboplatin, irinotecan and gemcitabine. Substantial activity has been demonstrated. In a randomized phase II trial comparing docetaxel plus cisplatin with docetaxel plus gemcitabine, the efficacy of the two regimens was almost identical (response rates 32 and 34%; 1-year survival rates 42 and 38%). However, the combination of docetaxel with gemcitabine was associated with significantly less grade III/IV neutropenia, diarrhea and nausea/vomiting. Three drug regimens combining docetaxel with, for example, gemcitabine and carboplatin or with ifosfamide and cisplatin, are producing very high response rates in phase II trials. Whether three-drug combinations including docetaxel will result in an improved outcome for patients with advanced NSCLC remains to be determined.     

Phase II trial of docetaxel with dexamethasone premedication in patients with advanced non-small cell lung cancer: the Canadian experience

We performed a Phase II trial to evaluate the activity and tolerability of docetaxel as a single agent in the treatment of advanced non-small cell lung cancer (NSCLC). Forty-four patients with metastatic and/or locally advanced NSCLC received i.v. docetaxel 100 mg/m2 every 3 weeks for a median of 4 (range 1–11) cycles. All patients received premedication with oral dexamethasone 8 mg twice daily for 5 days starting the day before chemotherapy. Seven partial responses were observed among 35 evaluable patients, and the overall response rate was 20% (95% CI 8-37). The median response duration was 5 months, median survival time was 10 months and the estimated 1-year survival rate was 42%. Treatment was generally well tolerated. Febrile neutropenia occurred in 10 patients (23%); neutropenic infection occurred in 4 patients, and led to 2 toxic deaths (both patients had borderline exclusion criteria). The corticosteroid premedication effectively reduced the overall incidence (34%) and severity (4% severe) of fluid retention, and delayed the median time to onset from cycle 4 to cycle 7. This study shows the promising efficacy of docetaxel as monotherapy in advanced NSCLC, and combination chemotherapy regimens incorporating docetaxel are now being evaluated in this clinical setting.     

Vandetanib: in medullary thyroid cancer

Vandetanib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor. The large (n=331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with unresectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. The PFS benefit with vandetanib was mostly consistent across patient subgroups based on baseline characteristics and disease status. Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown. Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug.     

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.     

Vandetanib for the treatment of lung cancer

INTRODUCTION: VEGF and EGFR are validated pathways for targeted therapy in non-small cell lung cancer (NSCLC). Once considered to be separate targets, VEGF and EGFR are now shown to have interconnected downstream pathways, potentiating the effectiveness of their dual signaling inhibition in cancer therapy. Molecules such as vandetanib that inhibit VEGFR and EGFR have also been reported to inhibit other receptors, including RET and additional kinases, and may be beneficial in treating patients with solid tumors. AREAS COVERED: This review covers the significance of targeting VEGF and EGFR in the treatment of NSCLC and the rationale behind their dual inhibition. Clinical trials that evaluate the use of vandetanib in the setting of refractory NSCLC are also explored. EXPERT OPINION: Vandetanib is currently not approved in the setting of NSCLC. However, its approval for medullary thyroid cancer makes it promising for identifying markers and potentially a NSCLC patient population who will benefit from the treatment.