The Clinical Development of Vandetanib: Updates on Ongoing Phase III Clinical Trials in Advanced Non—Small-Cell Lung Cancer

Vandetanib is a once-daily oral anticancer agent that selectively inhibits vascular endothelial growth factor—dependent tumor angiogenesis and epidermal growth factor receptor—dependent tumor cell proliferation and survival. In second/third—line NSCLC, significant improvements in progression-free survival (PFS) were observed in 2 phase II studies of vandetanib versus gefitinib (median PFS, 11.9 weeks vs. 8.1 weeks; hazard ratio [HR], 0.63; 1-sided P = .013) and docetaxel ± 100 or 300 mg vandetanib (median PFS, 18.7 weeks for vandetanib 100 mg plus docetaxel versus 12 weeks for docetaxel (HR, 0.64; 1-sided P = .037; for the 300-mg arm, HR, 0.83; P = .231). Higher objective response rates and disease control rates were also observed in the vandetanib arms, although overall survival was not significantly prolonged. In these studies, vandetanib has been generally well tolerated in clinical trials at daily doses of ≥ 300 mg, with common adverse events including rash, diarrhea, and QTc prolongation. Currently in NSCLC, 3 phase III registration trials have completed accrual, and 1 remains in progress. Each of these trials aims to further establish the efficacy and safety of vandetanib in the second/third—line setting (Table 1). Information on these studies, including their design, endpoints, and current status, will be presented. Ongoing work is also addressing the role of various biomarkers in the efficacy of vandetanib in NSCLC. Individualized treatment based on the presence of certain biomarkers might enhance efficacy of targeted therapies like vandetanib. A summary of planned biomarker analyses will also be presented.     

EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer

BackgroundZODIAC was a randomized phase III study of second-line treatment in patients with advanced non-small cell lung cancer (NSCLC) that evaluated the addition of vandetanib to docetaxel. The study showed a statistically significant improvement in progression-free survival and objective response rate, but not in overall survival for unselected patients. This study evaluated epidermal growth factor receptor (EGFR) gene mutation, copy number gain, and protein expression, and KRAS gene mutation, in pretreatment tumor samples as potential biomarkers predicting benefit from vandetanib as second-line treatment of NSCLC.Patients and methodsAfter progression following first-line chemotherapy, 1391 patients with locally advanced or metastatic (stage IIIB/IV) NSCLC were randomized 1 : 1 to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m² every 21 days) or placebo plus docetaxel in the ZODIAC study. Archival tumor samples (n = 570) were collected from consenting patients (n = 958) for predefined, prospective biomarker analyses.ResultsOf evaluable samples, 14% were EGFR mutation positive, 35% were EGFR FISH positive, 88% were EGFR protein expression positive, and 13% were KRAS mutation positive. Compared with the overall study population, in which progression-free survival (PFS) [hazard ratio (HR) = 0.79] but not OS (HR = 0.91) were significantly improved with vandetanib, there was greater relative clinical benefit for patients with EGFR mutation-positive tumors [PFS HR 0.51, confidence interval (CI) 0.25–1.06 and OS HR 0.46, CI 0.14–1.57] and EGFR FISH-positive tumors (PFS HR 0.61, CI 0.39–0.94 and OS HR 0.48, CI 0.28–0.84). Similarly, patients with EGFR mutation or FISH-positive tumor samples who received vandetanib had an increased chance of objective tumor response (odds ratios 3.34, CI 0.8–13.89, and 3.90, CI 1.02–14.82, respectively). There did not appear to be benefit for vandetanib in patients with KRAS mutation-positive tumors.ConclusionsHigh EGFR gene copy number or activating EGFR mutations may identify patient subgroups who receive increased clinical benefit from vandetanib in combination with docetaxel in second-line NSCLC.ClinicalTrials.govNCT00312377.     

Efficacy and safety of vandetanib, a dual VEGFR and EGFR inhibitor, in advanced non-small-cell lung cancer: a systematic review and meta-analysis

Background: Vandetanib, an oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, has attracted wide interest in treatment of advanced non-small-cell lung cancer (NSCLC). We aimed to assess its efficacy and safety via a systematic review and meta-analysis.Methods: Trials comparing vandetanib-based therapy and non-vandetanib therapy for advanced NSCLC were identified. Endpoints evaluated were progression-free survival (PFS), overall survival (OS), objective tumor response rate (ORR), and toxicity. Results: Seven trials including 4,492 patients were included in the analysis. As compared with placebo, vandetanib yielded a clear benefit for ORR (odds ratio (OR) = 2.04; 95% CI, 1.60-2.61; P < 0.001), and a clinically and statistically significant 25% improvement in PFS (hazard ratio (HR) = 0.75; 95% CI, 0.66-0.85; P < 0.001). However, these benefits did not translate into a significant improvement in OS (HR = 0.95; 95% CI, 0.88-1.04; P = 0.291). Subgroup analyses showed that vandetanib 100mg/d was associated with greater antitumor activity than 300mg/d when given in combination with chemotherapy. In addition, the pooled results demonstrated no statistically significant difference between vandetanib and single-targeted agents in PFS, ORR or OS. Vandetanib was associated with more frequent adverse events. Conclusions: Vandetanib, as compared with placebo, significantly increases ORR and PFS, but does not improve OS in the treatment of advanced NSCLC. As compared with single-targeted agent, vandetanib does not provide any efficacy advantage. Furthermore grade 3 or greater toxicity proved greater in the vandetanib arm.     

Combined Inhibition of the VEGFR and EGFR Signaling Pathways in the Treatment of NSCLC

Multitargeted agents represent the next generation of targeted therapies in solid tumors. The benefits of individually targeting the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling pathways have been clinically validated in recent years in a number of solid tumor types including non‐small cell lung cancer (NSCLC). Given the heterogeneity of this tumor type and potential crosstalk between these key signaling pathways (which are known to play a critical role in tumor growth, metastasis, and angiogenesis), dual inhibition of the VEGFR and EGFR signaling pathways has the potential to offer additional clinical benefits in NSCLC. A number of approaches to inhibiting both VEGFR and EGFR signaling are currently under investigation, including monotherapy with a multitargeted tyrosine kinase inhibitor (e.g., vandetanib, AEE788, XL647, BMS‐690514) or a combination of single‐targeted therapies (e.g., bevacizumab, cetuximab, erlotinib, gefitinib). Preclinical and early clinical data (phase I and II trials) support combined inhibition of the VEGFR and EGFR pathways in NSCLC. Overall, combined inhibition strategies are well tolerated and have shown promise in early clinical studies. Ongoing phase II and phase III trials will determine the clinical potential of a number of dual inhibition strategies in the treatment of advanced NSCLC.     

A randomized,phase II study of vandetanib maintenance for advanced or metastatic non-small-cell lung cancer following first-line platinum-doublet chemotherapy

Background

This randomized, phase II study investigated whether benefit could be obtained by giving vandetanib, an oral inhibitor of vascular endothelial and epithelial growth factor receptor, as a maintenance treatment in non-small cell lung cancer (NSCLC).

Methods

Patients were randomly assigned to either vandetanib or placebo after completion of 4 cycles of first-line chemotherapy. A progression-free survival (PFS) rate at 3 months was selected as the primary endpoint. We set a maximum PFS rate at 3 months to 30% (null hypothesis), and a minimum PFS rate at 3 months to 50% (alternative hypothesis).

Results

At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo arm were progression-free. The placebo arm was closed at the first stage. The vandetanib arm proceeded to the second stage, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. The alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median PFS was 2.7 months (95% CI, 1.9–4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9–2.6 months) in the placebo arm. The most common adverse events in patients receiving vandetanib were rash (77.3%) and diarrhea (60.0%).

Conclusions

Maintenance therapy with vandetanib for patients with NSCLC after standard platinum doublet chemotherapy is well tolerated and may prolong PFS compared with placebo, and needs additional investigation.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

Combined Inhibition of Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling in Non–Small-Cell Lung Cancer Therapy

Elucidation of molecular pathways that promote malignancies has led to the identification of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as key components involved in regulation of tumor proliferation and angiogenesis, respectively. Biologic agents that target these individual pathways have proven effective in treating patients with advanced Non—Small-cell lung cancer (NSCLC), adding to previously available therapies and often with fewer side effects. However, inhibition of a single molecular pathway does not account for alternate pathways or biologic adaptations that eventually lead to resistance. Therefore, combining EGFR and VEGF inhibition is currently under investigation as a means to overcome resistance and promote synergy. Erlotinib, an anti-EGFR agent, and bevacizumab, an anti-VEGF agent, are both approved in NSCLC, demonstrating single-agent activity. The phase II trials evaluating the combination of erlotinib and bevacizumab have shown efficacy as first-line therapy or in patients with previously treated NSCLC either alone or with chemotherapy. Dual inhibition of EGFR and VEGF pathways has also been accomplished by the novel agents vandetanib and XL647, which are able to target both pathways. Vandetanib has also demonstrated activity in patients with advanced NSCLC either alone or with chemotherapy in phase I/II studies. Another novel agent, XL647, has demonstrated promising single-agent activity in patients who have been resistant to previous anti-EGFR therapy. Further evaluation of combined EGFR and VEGF inhibition is under investigation.     

Lung cancer

Aging society is coming now, the ratio of elderly patients among all lung cancer patients has currently been increasing. It is necessary for elderly patients who are under-represented in clinical trials to study their suitable regimen. Thus, phase II and III clinical trials have been performed specifically for elderly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients all over the world. As for single agent chemotherapy, there is a strong rationale for docetaxel and vinorelbine in elderly patients with advanced NSCLC. Recently, there are phase I and II clinical trial for CPT-11 monotherapy, and gefitinib and TS-1 are reasonable options for elderly patients. Alimta is tolerable for elderly, and subset analysis is performed for the elderly with recurrent NSCLC. As platinum-based chemotherapy, there are several elderly subset analyses and JCOG 0207, which is a phase III trial now in progress comparing weekly cisplatin+weekly docetaxel and weekly docetaxel. In SCLC, there is no evidence of single agent chemotherapy but combination chemotherapy such as carboplatin+etoposide is recommended. A phase III study of carboplatin+etoposide versus amrubicin under way. These studies should aim to optimize several agents for elderly patients and prolong survival, palliative care.     

Targeted (and chemotherapeutic) agents as maintenance treatment in patients with metastatic non-small-cell lung cancer: current status and future challenges

Maintenance treatment has been intensively investigated in the field of advanced/metastatic non-small lung cancer in order to improve outcomes in this devastating disease. Two different approaches have been evaluated; the so-called continuation maintenance when the maintenance agent was part of initial therapy and is continued in the absence of disease progression ("maintained") or switch maintenance when a third agent is initiated after a defined number of cycles chemotherapy in the absence of disease progression. Several phase III trials with both chemotherapeutic and targeted agents have demonstrated either PFS prolongation (continuation maintenance) or both PFS and OS benefit (switch maintenance). Currently, erlotinib and pemetrexed are registered as maintenance treatment in patients with NSCLC not progressing after four cycles of standard platinum-based doublet chemotherapy. However, the development of maintenance treatment has raised a series of questions such as the role of treatment-free intervals, the timing of second-line treatment, selection of patients for maintenance treatment and selection of the most proper agent, and trial design issues such as optimal end-points. The purpose of this paper is to present and discuss the current trials investigating the main treatment paradigms and argue on the above mentioned questions.     

Cetuximab and Other Anti–Epidermal Growth Factor Receptor Monoclonal Antibodies in the Treatment of Non‐Small Cell Lung Cancer

Non‐small cell lung cancer (NSCLC) accounts for about 85% of all new diagnoses of lung cancer. Unfortunately, few NSCLC patients are suitable for radical treatment for curative intent. Because most patients with NSCLC have advanced disease at diagnosis, chemotherapy represents the standard of care, although, to date, a plateau has been reached with this approach. Improvements in the knowledge of tumor biology and mechanisms of oncogenesis have identified the epidermal growth factor receptor (EGFR), a member of the ErbB family, as a molecular target for NSCLC treatment. EGFR is commonly overexpressed in NSCLC and has been associated with impaired prognosis; therefore, its inhibition may lead, through the suppression of tumor proliferation, to improvement in clinical outcomes. Strategies to block EGFR include tyrosine kinase inhibitors, monoclonal antibodies, ligand‐linked toxins, and antisense approaches. This article focuses on the treatment of NSCLC with the anti‐EGFR monoclonal antibodies, including cetuximab, for which the largest amount of data in the literature exists. Recently, a phase III randomized trial performed in advanced NSCLC patients yielded a statistically significant survival advantage for patients treated with cetuximab plus chemotherapy versus chemotherapy alone. Other anti‐EGFR monoclonal antibodies, such as panitumumab, matuzumab, nimotuzumab, and ch806, are in different stages of development for the treatment of advanced NSCLC.     

Management of non-small cell lung cancer in elderly patients

Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. More than 50% of NSCLC patients are diagnosed over the age of 65 and approximately one-third of all patients with non-small cell lung cancer (NSCLC) are over the age of 70. Elderly patients tolerate chemotherapy poorly compared to their younger counterpart because of the progressive reduction of organ function and comorbidities related to age. For this reason, these patients are often not considered eligible for aggressive cisplatin-based chemotherapy, the standard medical treatment of advanced NSCLC. At present, for early stages there are no indications for adjuvant and neoadjuvant chemotherapy. Combined chemo-radiotherapy in locally advanced disease, particularly with concurrent approach should be investigated in specific trials before to be preferred in clinical practice to radiation therapy alone. In advanced disease, prospective phase II trials have demonstrated suitable toxicity profile and good antitumor activity for single agent chemotherapy with the recently developed drugs vinorelbine, gemcitabine and taxanes. Moreover, vinorelbine, compared to best supportive care in a phase III randomized trial, has proven to improve survival and quality of life. A phase III randomized trial showed that polychemotherapy with gemcitabine and vinorelbine does not improve any outcome as compared to single agent chemotherapy with vinorelbine or gemcitabine. In clinical practice, single agent chemotherapy should remain the standard treatment. Feasibility of cisplatin-based polychemotherapy remains an open issue and has to be proven prospectively. The two main research-lines to explore in the near future are the introduction of biological agents in the treatment schemes and the development of specifically designed schedules of platin-based regimens. However, practicing a multidimensional geriatric asessment for individualized treatment choice in NSCLC elderly patients is mandatory.     

Lenvatinib: Role in thyroid cancer and other solid tumors

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1–3 (VEGFR1–3), fibroblast growth factor receptors 1–4 (FGFR-1–4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.     

Alliance A082002 -a randomized phase II/III trial of modern immunotherapy-based systemic therapy with or without SBRT for PD-L1-negative,advanced non-small cell lung cancer

IntroductionTreatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(-) NSCLC when added to systemic therapy including immunotherapy.Materials and MethodsAlliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(-) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy vs. systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy.ConclusionsThis phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(-) NSCLC. It is now open in the National Clinical Trials Network (NCTN).     

Vinflunine -- an active chemotherapy for treatment of advanced non-small-cell lung cancer previously treated with a platinum-based regimen: results of a phase II study

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.     

Neglected and underrepresented subpopulations: elderly and performance status 2 patients with advanced-stage non-small-cell lung cancer

Elderly patients and those with performance status (PS) of 2 with non-small-cell lung cancer (NSCLC) have been habitually underrepresented in clinical trials. Therapeutic neglect and legitimate concerns about toxicity are responsible. Yet randomized phase III data in the elderly have demonstrated a survival benefit for single-agent chemotherapy compared with best supportive care, and retrospective analyses of fit elderly patients enrolled on platinum agent-based trials have shown similar survival rates, albeit more toxicity, compared with younger counterparts. To date, however, there are no phase III trials specific to the elderly population demonstrating a survival benefit for platinum agent-based combinations compared with the constituent nonplatinum single agent; such efforts are ongoing. Performance status is a critical prognostic factor in advanced-stage NSCLC. Retrospective analyses of multiple trials conducted before 1995 suggested that patients with advanced-stage NSCLC and compromised PS experienced substantial toxicity and virtually no benefit from systemic chemotherapy, leading most cooperative groups to suspend research in this cohort. But this trend has changed. A subset analysis of patients with a PS of 2 enrolled on a recent Cancer and Leukemia Group B trial showed a significant survival benefit for carboplatin in combination with paclitaxel compared with paclitaxel alone, and recent randomized phase II efforts evaluating platinum agent-based combinations have yielded median survival times of > 6 months with acceptable toxicity rates. Although the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction trials testing polyglutamated paclitaxel failed to show a survival advantage compared with standard agents, interest in testing new, less toxic agents continues. Future efforts will need to differentiate the reasons for compromised PS, be it tumor burden, comorbidity, or both.     

ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC

The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2–7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4–ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4–ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials.     

Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models

The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and 2 clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E- and KRAS/p53-driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non-small-cell lung cancer (NSCLC) patients (10 evaluable), including cases with KRAS mutations, repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses. The phase II trial in heavily pretreated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient (range, 0-5); 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583-, 665-, and 1,460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET (positron emission tomographic) response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted.     

Docetaxel in combination with platinum compounds for non small-cell lung cancer

Assessing the combination of docetaxel with cisplatin or carboplatin was based on their activity as single agents, their nonoverlapping toxicity profiles, and their lack of cross-resistance. Phase I studies of docetaxel in combination with cisplatin established that 75 mg/m2 of each agent could be administered with reasonable safety and appeared to be active in non small-cell lung cancer (NSCLC). We evaluated the docetaxel/cisplatin combination in patients with advanced NSCLC. The response rate was 32%, and the median survival was 11.5 months. Efficacy was comparable to that observed in the Australian and French trials with the same combination. This is now being evaluated further in two large randomized trials for patients with advanced NSCLC and has been incorporated into the combined modality programs for early-stage disease. Carboplatin, devoid of the nephrotoxicity and neurotoxicity associated with the parent cis-platin, was then combined with docetaxel. The recommended dose of docetaxel for further evaluation in combination with carboplatin (AUC=6 mg/mL.min) was 90 mg/m2 with filgrastim support and 80 mg/m2 without filgrastim support. Our phase II trial of the combination of docetaxel and carboplatin in advanced NSCLC demonstrated an overall response rate of 36%; median survival was 13.9 months, and 1-year survival was 52%. Comparable activity has been seen by other investigators, and the regimen is being evaluated in two randomized trials. The combination of docetaxel with either of the two platinum agents has reasonable activity in NSCLC, though the carboplatin/docetaxel doublet appears to have a better therapeutic index.