A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

INTRODUCTION: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. METHODS: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. RESULTS: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. CONCLUSIONS: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.

Bisphosphonate use in patients with lung cancer and bone metastases: recommendations of a European expert panel.

INTRODUCTION: Bisphosphonates (BPs) are effective in preventing, reducing the incidence, and delaying the onset of skeletal-related events in patients with bone metastases in a variety of solid tumors, including lung cancer. The purpose of this article is to review the current evidence for the use of BPs in lung cancer and to provide specific European recommendations to support the clinical practice of using BPs to treat patients with lung cancer with bone metastases. METHODS: An expert panel of European clinical oncologists and lung cancer specialists convened for two face-to-face meetings designed to review available evidence on the efficacy of BPs in lung cancer and to develop recommendations based on published literature and clinical practice experiences. RESULTS: The panel recommends screening patients with lung cancer for bone metastases at the initial staging of disease to assess symptomatic bone metastases and screen for asymptomatic bone metastases and to allow accurate monitoring of bone disease progression and initiate bone-specific therapy. Bone assessment should be based on positron emission tomography (if available) or bone scan. BPs should be added to the treatment of patients with lung cancer (with non-small cell lung cancer or small cell lung cancer) who develop bone metastases. In such patients, BPs must be considered part of metastatic lung cancer treatment to prevent and delay the occurrence of further bone metastases and skeletal-related events and to relieve pain where present. BP treatment should continue for as long as it is practically feasible in the absence of any significant adverse effects.

HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum.

Skin rash associated with HER1/epidermal growth factor receptor (EGFR) inhibitors is common. The lack of clinical and patient guidance for this often chronic and sometimes distressing side effect makes rash management and etiology investigation high priorities. To address this, oncologists and dermatologists with experience with HER1/EGFR inhibitors attended the HER1/EGFR Inhibitor Rash Management Forum. Recommendations include continued analysis of the correlation between rash and clinical outcome and improving the accuracy and reproducibility of terminology and grading systems. Because acne vulgaris has a unique pathology, and the pathology and etiology of rash are unclear yet distinct from acne vulgaris, using such terms as acne, acne-like, or acneiform should be avoided. Until there is a specific dermatological definition, rash is best described using phenotypic terms for its appearance and location. It is currently unknown which agents are best for treating rash. Clinical trials of rash treatments are urgently required, and suggestions for agents to consider are made based on current knowledge. The effect of dose reduction or interruption on rash should also be investigated. Secondarily infected rash may be more frequent than has been previously recognized, and some investigators favor empiric use of an oral antibiotic if this appears to be the case. Suggestions for patients include makeup to camouflage the rash and an emollient to prevent and alleviate skin dryness. The increasing use of HER1/EGFR-targeted agents makes managing rash important. We hope the outcomes from this Forum provide background for future studies.