Eckart Laack

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.

BACKGROUND Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. METHODS This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001). INTERPRETATION Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. FUNDING Eli Lilly.

Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial

BACKGROUND Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin. METHODS In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m(2) every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373. FINDINGS Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49-0·79; p<0·0001). The median progression-free survival, measured from randomisation, was 4·1 months (95% CI 3·2-4·6) for pemetrexed and 2·8 months (2·6-3·1) for placebo. Possibly treatment-related laboratory grade 3-4 adverse events were more common in the pemetrexed group (33 [9%] of 359 patients) than in the placebo group (one [<1%] of 180 patients; p<0·0001), as were non-laboratory grade 3-5 adverse events (32 [9%] of 359 patients in the pemetrexed group; eight [4%] of 180 patients in the placebo group; p=0·080); one possibly treatment-related death was reported in each group. The most common adverse events of grade 3-4 in the pemetrexed group were anaemia (16 [4%] of 359 patients), neutropenia (13 [4%]), and fatigue (15 [4%]). In the placebo group, these adverse events were less common: anaemia (one [<1%] of 180 patients), neutropenia (none), and fatigue (one <1%]). The most frequent serious adverse events were anaemia (eight [2%] of 359 patients in the pemetrexed group vs none in the placebo group) and febrile neutropenia (five [1%] vs none). Discontinuations due to drug-related adverse events occurred in 19 (5%) patients in the pemetrexed group and six (3%) patients in the placebo group. INTERPRETATION Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin. FUNDING Eli Lilly and Company.

Expression of CEACAM1 in Adenocarcinoma of the Lung: A Factor of Independent Prognostic Significance

PURPOSE To evaluate the prognostic relevance of CEACAM1 and sialyl Lewis X expression in adenocarcinomas of the lung. PATIENTS AND METHODS Paraffin wax sections of 93 patients with adenocarcinomas of the lung who underwent surgery between 1990 and 1995 were immunohistochemically investigated using monoclonal anti-CEACAM1 and sialyl Lewis X antibodies. The clinical course of all patients was followed up for a minimum of 5 years. RESULTS Sixty-one tumors were classified as CEACAM1-positive, and 32 were classified as CEACAM1-negative. Patients with CEACAM1-positive tumors had a significantly poorer overall (P =.00025) and relapse-free (P =.00029) survival than those with CEACAM1-negative tumors. Only three patients did not express the sialyl Lewis X glycotope, whereas 90 tumors (97%) were sialyl Lewis X-positive. In multivariate Cox regression analysis, next to tumor stage and sex, only the expression of CEACAM1 was a significant independent prognostic factor for survival. CONCLUSION Expression of CEACAM1 was an independent prognostic factor in our patient population and can be used to stratify patients with adenocarcinomas of the lung into low-risk and high-risk groups. In contrast, the expression of sialyl Lewis X was of no prognostic relevance because it was expressed in 97% of all investigated tumors, and most likely has no influence on the function of CEACAM1 in this tumor entity.

Epidermal Growth Factor Receptor-Related Tumor Markers and Clinical Outcomes with Erlotinib in Non-small Cell Lung Cancer: An Analysis of Patients from German Centers in the TRUST Study

Introduction: Relationships between clinical outcomes and epidermal growth factor receptor (EGFR)-related tumor markers were investigated in patients with advanced non-small cell lung cancer. Methods: Patients with stage IIIB/IV non-small cell lung cancer (0–2 prior regimens) received erlotinib (150 mg PO per day). Response and survival were evaluated, and tumor samples were assessed by immunohistochemistry (EGFR, phosphorylated mitogen-activated protein kinase, and phosphorylated AKT protein expression), fluorescence in situ hybridization (FISH; EGFR gene copy number), and DNA sequencing (EGFR, KRAS gene mutations). Results: Among 311 patients, 8% had a complete/partial response; the disease control rate was 66%. Median Overall survival (OS) was 6.1 months; 1-year survival rate was 27.2%. Two of 4 patients with EGFR mutations had tumor responses, versus 2/68 with wild-type EGFR (p = 0.014). Progression-free survival (PFS) (HR = 0.31) and OS (HR = 0.33) were significantly prolonged in patients with EGFR mutations. Response rate was significantly higher in patients with EGFR FISH-positive (17%) than FISH-negative tumors (6%), and both PFS (HR = 0.58) and OS (HR = 0.63) significantly favored patients with EGFR FISH-positive tumors; median OS was 8.6 months in the EGFR FISH-positive group. None of 17 patients with a KRAS mutation had a tumor response, but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance. Neither phosphorylated mitogen-activated protein kinase nor phosphorylated AKT immunohistochemistry status had a significant effect on PFS and OS with erlotinib. Conclusions: The presence of EGFR mutations and EGFR FISH-positive tumors may predispose patients to achieving better outcomes on erlotinib, but may have a beneficial impact on prognosis (irrespective of treatment). Prospective, placebo-controlled studies are needed to determine the predictive value of the putative biomarkers.

Elevated pretreatment serum concentration of YKL-40-An independent prognostic biomarker for poor survival in patients with metastatic nonsmall cell lung cancer.

The glycoprotein YKL‐40 is synthesized both by cancer cells and by tumor‐associated macrophages and plays a functional role in tumor progression. Consequently, high serum YKL‐40 levels have been associated with a poor prognosis in patients with several cancer types. However, the role of YKL‐40 has not been established in nonsmall cell lung cancer (NSCLC).

Lectin Histochemistry of Resected Adenocarcinoma of the Lung : Helix pomatia Agglutinin Binding Is an Independent Prognostic Factor

The worldwide incidence of adenocarcinoma of the lung is rising. Unfortunately, no significant prognostic marker beyond the classical TNM staging exists to stratify these patients for appropriate therapy. Because lectins, carbohydrate-binding proteins, have been shown to be useful prognostic markers in several other adenocarcinomas, a panel of lectins [Helix pomatia agglutinin (HPA), Phaseolus vulgaris leukoagglutinin, Ulex europaeus agglutinin, Maackia amurenis agglutinin, Sambucus nigra agglutinin] with different carbohydrate-binding specificities were tested for their prognostic relevance. Paraffin wax sections of 93 patients with adenocarcinomas of the lung who had undergone surgery between 1990 and 1995 were investigated by lectin histochemistry. Lectin-binding data and other known prognostic factors were correlated with survival. In univariate analysis, binding of HPA, Phaseolus vulgaris leukoagglutinin, and Ulex europaeus agglutinin to adenocarcinoma cells were prognostic indicators for overall and relapse-free survival, whereas Maackia amurenis agglutinin and Sambucus nigra agglutinin binding had no prognostic value. However, in a multivariate analysis next to stage and gender only HPA was a significant independent prognostic factor on survival. In conclusion, HPA binding was the primary marker-based predictor of prognosis in our patient population and allows to stratify patients with adenocarcinomas of the lung into a low- and a high-risk group.

Miliary never-smoking adenocarcinoma of the lung: strong association with epidermal growth factor receptor exon 19 deletion.

Miliary pattern of pulmonary metastases is a rarity in patients with lung cancer. We report five cases of patients with a never-smoking adenocarcinoma of the lung with such a pattern of metastases. In the tumor cells of all five patients, epidermal growth factor receptor (EGFR) mutation gene sequencing identified a deletion in exon 19 of the EGFR gene, and all five patients had a dramatic response to EGFR tyrosine kinase inhibitors. No echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) translocation was detected. We believe that the miliary never-soking adenocarcinoma of the lung is a distinct clinically relevant subgroup of the never-smoking non-small cell lung cancer. Physician should recognize this subgroup of patients with lung cancer when facing a picture of miliary pulmonary metastases in chest x-ray or computed tomography scan in patients with a history of never smoking and consider upfront therapy with EGFR tyrosine kinase inhibitors.

Everolimus in Combination with Pemetrexed in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Chemotherapy A Phase I Study Using a Novel, Adaptive Bayesian Dose-Escalation Model

Introduction: Pemetrexed is an established second-line therapy for non-small cell lung cancer (NSCLC). Everolimus has previously been shown to have some clinical activity when used as a single agent in NSCLC. The aim of this phase I study was to evaluate the safety and feasibility of combining pemetrexed with everolimus in patients with NSCLC who had disease progression after one previous treatment. Methods: Patients with stage IIIb/IV NSCLC and one previous chemotherapy regimen were enrolled. A Bayesian dose-escalation model was used to determine the feasible doses of daily or weekly everolimus combined with pemetrexed (500 mg/m2 q3w). The primary end point was rate of cycle 1 dose-limiting toxicities (DLTs). Secondary end points included safety, relative dose intensity of pemetrexed, pharmacokinetics, and tumor response. Results: Twenty-four patients received daily everolimus (2.5, 5, 7.5, or 10 mg) and 19 received weekly everolimus (30 or 50 mg) with pemetrexed. Cycle 1 DLTs in the daily regimen included febrile neutropenia, neutropenia, rash/pruritus, and thrombocytopenia; in the weekly regimen, DLTs included neutropenia and stomatitis. The most frequent grade 3/4 adverse events were neutropenia, dyspnea, and thrombocytopenia. Three partial responses were observed with everolimus 5 mg/d and two with 50 mg/wk. Pharmacokinetics did not suggest an influence of everolimus on pemetrexed parameters; pemetrexed resulted in a minor decrease in everolimus exposure with both daily and weekly regimens. Conclusions: Everolimus 5 mg/d or 50 mg/wk with the standard regimen of pemetrexed are feasible dosages in patients with stage IIIb/IV NSCLC.

Lessons learnt from gefitinib and erlotinib: Key insights into small-molecule EGFR-targeted kinase inhibitors in non-small cell lung cancer.

Improving treatment options and patient outcomes for those with non-small cell lung cancer (NSCLC) represents a significant worldwide challenge. Although traditional treatment strategies are widely accepted and initially successful, many tumors still fail to respond to available drugs. Therapeutic options for patients with NSCLC are therefore moving towards more individual and personalized treatment strategies. The first-generation tyrosine kinase inhibitors (TKIs), designed to target specific molecular pathways within the tumor, have paved the way towards tailored therapy. Promising experience with these agents has opened the door to a sudden surge of new drug advances. The development of these second-generation treatments offer the potential to further maximize patient benefit and provide greater therapeutic options for patients with advanced NSCLC. As the number of second-generation TKIs continues to grow, the efficacy and safety of new members of this class continue to be established in ongoing clinical trials.

A Pilot Study of Docetaxel and Trofosfamide as Second-Line ‘Metronomic’ Chemotherapy in the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

Background: The aim of this pilot study was to evaluate the efficacy and safety of a chemotherapy containing docetaxel and oral trofosfamide as a ‘metronomic’ secondline treatment of patients with metastatic non-small cell lung cancer (NSCLC). Patients and Methods: 21 patients with stage IV disease NSCLC who had progressed under first-line chemotherapy were enrolled. Previous chemotherapy was platinum-based in 15 patients (71.4%), whereas 6 patients (28.6%) had received platinum-free combination chemotherapy. Patients received docetaxel 25 mg/m2 on days 1, 8, and 15 every 4 weeks plus trofosfamide 50 mg per day. Results: A total of 62 chemotherapy cycles were administered. The median number of cycles per patient was 3. The overall response rate to chemotherapy was 19%, median overall survival was 6.9 months, the median progression-free survival 2.9 months, the 1-year survival rate 28.6%, and the 2-year survival rate 7.1%. No grade IV toxicity was observed. Conclusions: Our results suggest that the combination of docetaxel and trofosfamide in a metronomic schedule is active and well tolerable as second-line therapy in patients with metastatic NSCLC. The concept of metronomic chemotherapy promises to be a valuable addition to the existing treatment options in NSCLC and warrants further investigation in phase III studies.