[Show abstract][Hide abstract] ABSTRACT: Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC).
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Background
The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC).
Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2–21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194.
Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8–11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9–3·9] vs 2·7 months [2·6–2·8]; hazard ratio [HR] 0·79 [95% CI 0·68–0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8–36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5–12·6] vs 7·9 months [6·7–9·1]; HR 0·75 [95% CI 0·60–0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6–15·1] vs 10·3 months [95% CI 8·6–12·2]; HR 0·83 [95% CI 0·70–0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8–11·2] vs 9·1 months [8·4–10·4]; HR 0·94, 95% CI 0·83–1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three).
Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma.
The Lancet Oncology 01/2014; 15(2). · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary germ cell tumours with mediastinal location comprise 1-6% of mediastinal tumours and 2-5% of all germ cell tumours occurring in adults. They are identified mostly in the 3rd decade of life, in 90% of cases in men. The most common symptoms are dyspnea, chest pain, cough, fever and weight loss. The aim of the present study was the analysis of our own results of treatment of primary germ cell tumours with mediastinal location, and a review of the literature concerning this subject.
Five patients (4 males, 1 female) median age 27.8 years (range 23-30 years) treated in the period from 1999 to 2009 in Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Lung Cancer and Chest Tumours in Warsaw, due to germinal tumours with primary mediastinal location, entered the study.
All patients received chemotherapy according to the BEP regimen. All patients achieved an objective response to treatment. Two patients died due to disease progression in spite of II- and III-line treatment. Three patients are still in follow-up. The median survival time was 55.8 months (range 8.0-120.0 months).
Primary mediastinal germ cell tumours have worse prognosis than do those with gonadal location. Based on our observations and review of the literature, it can be concluded that the results of treatment of non-seminoma type germ cell tumours with primary mediastinal location remain poor. Patients who develop early recurrence or progression during first-line chemotherapy are particularly at risk of unfavourable outcome. Identification of new standards of treatment in tumours resistant to cisplatin require further studies evaluating the effectiveness of new generation cytostatic drugs.
Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc 01/2014; 82(2):116-24.
[Show abstract][Hide abstract] ABSTRACT: Introduction
A dose-determination study was conducted in untreated stage III NSCLC to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (1st cohort) or in combination with cisplatin (2nd cohort).
Three patients stage IIIAN2/IIIB NSCLC were expected at each dose-level with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with 60Gy total dose radiotherapy, NVBo was given from 60mg up to 180mg total-dose/week split on days 1, 3 and 5. Once the maximal tolerated dose (MTD) defined as 2 DLT in a dose-level was determined and the recommended dose of NVBo alone established, the trial assessed its recommended dose in combination with cisplatin 80mg/m2 every 3 weeks.
In the 1st cohort, 26 patients were enrolled. MTD was 160mg/week: 3 Grade (G) 3 oesophagitis and 1 G3 pneumonia as DLT out of 5 patients in this dose-level. In the recommended dose-level (150mg/week), only 1/6 patients experienced a DLT. In the 2nd cohort, 11 patients received NVBo weekly doses from 130mg to 150mg with cisplatin. Only 2 patients received 150mg/week NVBo, the trial closed before MTD was determined. Confirmed response rate was 42% and 55% in the 1st and 2nd cohort, respectively.
The recommended dose of this fractionated NVBo scheme as single agent concomitantly with radiotherapy for 6 weeks is 50mg day 1, 3, 5 (150mg/week); combined with cisplatin 80mg/m2 every 3 weeks, the dose should be 140-150mg/week adapted on hematology. The response rate is promising.
Clinical Lung Cancer 01/2014; · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer related death in Poland. About 85% of all lung cancer constitutes non-small cancer (NSCLC), in which the role of cytotoxic and molecularly targeted drugs is increasing. This article presents the current evidence- based recommendations for the use of these methods in clinical practice in NSCLC and malignant pleural mesothelioma.
Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc 01/2014; 82(2):133-49.
[Show abstract][Hide abstract] ABSTRACT: Oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with Non-Small Cell Lung Cancer (NSCLC) regardless of histological subtype. NAVoTrial 01 is the first study that explores this combination specifically in Non-Squamous (NS) NSCLC by assessing the feasibility of this doublet in an investigational approach (ratio 1:2). A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single agent after four cycles of combination was included in the study schedules as it reflected a trend in first-line treatment of NSCLC.
Stage IIIB/IV untreated/relapsed NS NSCLC patients received in a 3-week cycle pemetrexed 500 mg/m², and cisplatin 75 mg/m² day 1 (Arm A) or oral vinorelbine 80 mg/m² days 1, 8 (first cycle 60 mg/m²), cisplatin 80 mg/m² day 1 (Arm B). After 4 cycles, patients without progression received single agent maintenance with pemetrexed or oral vinorelbine.
Overall, 153 patients were randomized (ArmA/ArmB): 51/102. Disease Control Rate (%) was 76.5 (95% CI, 62.5-87.2)/75.0 (95% CI, 65.3-83.1), Response Rates (%) 31.4 (95% CI, 19.1-45.9)/24.0 (95% CI, 16.0-33.6), median progression-free survival (months) 4.3 (95% CI, 3.8-5.6)/4.2 (95% CI, 3.6-4.7), median survival (months) 10.8 (95% CI, 7.0-16.4)/10.2 (95% CI, 7.8-11.9). Main grade 3/4 hematological toxicities (%) were neutropenia 18.3/44.0, whereas febrile neutropenia was reported in 2% of patients in each arm.
Oral vinorelbine and cisplatin reported an efficacy in line with that achieved with a standard treatment as pemetrexed and cisplatin, coupled with an acceptable safety profile.
Clinical Lung Cancer 01/2014; · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated.
Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg.
Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease.
The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.
Cancer Chemotherapy and Pharmacology 11/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tigatuzumab, a humanized monoclonal DR5 agonist antibody induces apoptosis in human cancer cell lines. The objective of this study was to investigate the antitumor effects of tigatuzumab combined with carboplatin/paclitaxel in chemotherapy-naïve patients with metastatic/unresectable non-small cell lung cancer (NSCLC).
Patients with histologically or cytologically confirmed NSCLC stage IIIB/IV disease by RECIST (version 1.0) and ECOG-PS 0-1 were enrolled at 15 European sites. Patients received tigatuzumab or placebo intravenously with carboplatin/paclitaxel every 3 weeks (1 cycle) for up to 6 cycles. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate and safety.
97 patients were analyzed for efficacy (49 tigatuzumab; 48 placebo). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for tigatuzumab compared with 4.3 months (4.1, 5.8) for placebo. Median OS (95% CI) was 8.4 months (6.9, 16.3) for tigatuzumab versus 9.0 months (7.6, 14.5) for placebo. 12 patients (24.5%) in the tigatuzumab arm and 11 patients (22.9%) in the placebo arm had partial response. No patient had complete response. In a prospectively-defined Fc gamma receptor genotype subset (n=25), there was a non-significant trend toward increased PFS with tigatuzumab versus placebo (HR=0.47; 95% CI: 0.16, 1.35) but no difference in OS. Tigatuzumab was well tolerated. However, grade 3/4 neutropenia was reported in 10 patients (20.4%) receiving tigatuzumab compared with 4 patients (8.3%) receiving placebo.
Tigatuzumab was well tolerated but did not improve efficacy of carboplatin/paclitaxel in systemic therapy-naïve, unselected advanced NSCLC patients. Clinical trials identifier: NCT00991796.
Lung cancer (Amsterdam, Netherlands) 10/2013; · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Erlotinib is a reversible tyrosine kinase inhibitor of epidermal growth factor receptor (TKI EGFR). In Poland, as of July 2012, it is used in the treatment only of patients with non-small cell lung cancer (NSCLC) and with EGFR mutation gene after standard chemotherapy failure. The effectiveness of erlotinib in second- or third-line treatment of NSCLC patients without EGFR activating mutation gene remains debatable. Clinical trial results indicated that TKI EGFR showed an efficacy of 70‑80% in patients with EGFR mutations, while the clinical response to treatment among unselected Caucasian patients is only 10%. The present study was conducted in a group of 71 patients with inoperable, locally advanced or metastatic NSCLC treated with erlotinib as the second- or third-line therapy. Molecular tests (examination of EGFR mutation and gene amplification) were carried out retrospectively. Objective response rate, overall survival (OS) and progression-free survival (PFS) were calculated. Effects of clinical and molecular factors including the presence of EGFR mutations, EGFR gene amplification, patient performance status, rash, smoking status, time from diagnosis to start of therapy, weight loss and the serum LDH levels were analyzed. An objective response in the form of partial response occurred in only 5 patients (7%), who carried EGFR gene mutation. Median time to PFS for the entire group of patients was 1.5 months and median OS was 10 months. The strongest factors increasing the risk of progression in patients treated with erlotinib were the absence of activating mutations in the EGFR gene (6‑fold increased risk) and no treatment‑related rash (4.5‑fold increased risk). The most important factors affecting the risk of early mortality were poor performance status (HR 37.344; P>0.0001), no treatment-related rash (HR 14.9348; P=0.0002) and a short response time on the first-line chemotherapy (HR 9.519; P=0.0445).
[Show abstract][Hide abstract] ABSTRACT: Klasyczna charakterystyka czerniaka skóry obejmuje asymetrię zmiany, nierówny brzeg, heterogenność barw, oraz średnicę powyżej 5 mm. Współczesne dane wskazują, że ponad 50% czerniaków skóry nie spełnia tych kryteriów. Dlatego podstawą klinicznej diagnostyki różnicowej i kwalifikacji do biopsji wycinającej jest obecnie dermoskopia. Dla ustalenia rozpoznania i określenia najważniejszych czynników rokowniczych podstawowe znaczenie ma biopsja wycinająca podejrzanych w kierunku wczesnego czerniaka zmian barwnikowych skóry (wycięcie całej grubości skóry i powierzchownej warstwy tkanki tłuszczowej). Wczesne rozpoznanie i chirurgiczne usunięcie czerniaka nie tylko poprawia rokowanie, ale daje szansę wyleczenia u około 90% chorych. Kolejne etapy postępowania terapeutycznego obejmują kwalifikację chorych do radykalnego wycięcia blizny po biopsji wycinającej z właściwymi marginesami oraz wykonania biopsji węzła wartowniczego. W przypadku przerzutów w regionalnych węzłach chłonnych postępowaniem z wyboru jest wykonanie radykalnej limfadenektomii. Zaleca się włączanie chorych na czerniaki skóry o wysokim ryzyku nawrotu (przerzuty w węzłach chłonnych i/lub owrzodzenie pierwotnej zmiany) do prospektywnych badań klinicznych nad leczeniem uzupełniającym. Obecność przerzutów odległych wiąże się ze złym rokowaniem. W sytuacji wystąpienia uogólnienia nowotworu zaleca się do wykonania badania w kierunku mutacji genu BRAF. W stadium uogólnienia najbardziej właściwe jest stosowanie leczenia w ramach klinicznych badań. Długoletnie przeżycia dotyczą głównie chorych poddanych resekcji pojedynczych ognisk przerzutowych. W systemowym leczeniu – przede wszystkim pierwszej linii – u chorych z obecnością mutacji BRAF V600 znajduje zastosowanie wemurafenib (inhibitor BRAF), a w leczeniu drugiej linii stosowany może być – zgodnie z europejskimi wskazaniami rejestracyjnymi – ipilimumab (przeciwciało anty-CTLA4). Chemioterapia z udziałem dakarbazyny jest postępowaniem mniej wartościowym
Onkologia w Praktyce Klinicznej. 01/2013; 1(6):219-233.
[Show abstract][Hide abstract] ABSTRACT: The targeted treatment of advanced non-small-cell lung cancer (NSCLC) depends on confirmation of activating somatic EGFR mutation. The aim of the study was to evaluate the incidence of EGFR mutations in NSCLC detected in cytological and histological material and present literature review on European EGFR mutation incidence. 273 patients with confirmed NSCLC were entered into the study: 189 histological, paraffin-embedded materials, 12 fresh and 72 fixed cytological specimens. DNA was extracted from both types of material and the EGFR mutation in exons 18-21 was analyzed by direct sequencing. In addition the EGFR gene copy number in cases with sufficient histological material (110 patients) was evaluated by fluorescent in situ hybridization (FISH) technique. The percentage of EGFR somatic mutations was 10.62%. FISH positive results (amplification or high polysomy of EGFR gene) were identified in 33 patients (30.0%). The strongest clinicopathological correlation with the EGFR mutation was found for histological type (adenocarcinoma; p < 0.01), gender (females; p < 0.01) and FISH positive result (p < 0.05). This is the first, single institution study that estimates the EGFR mutation incidence in the Polish population. Cytological material recovered from fixed preparations and stained with hematoxylin and eosin showed DNA quality comparable to fresh tumor cells and histological samples.
International journal of clinical and experimental pathology 01/2013; 6(12):2800-12. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation.
The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4–12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188.
From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5–29·2) with tecemotide versus 22·3 months (19·6–25·5) with placebo (adjusted HR 0·88, 0·75–1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6–36·8) compared with 20·6 months (17·4–23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64–0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6–23·1] vs 24·6 months [18·8–33·0], respectively; adjusted HR 1·12, 0·87–1·44; p=0·38). Grade 3–4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups.
We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted.
Merck KGaA (Darmstadt, Germany).
The Lancet Oncology 01/2013; 15(1). · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic endocrine tumors (PETs) are rare neoplasms of this organ. The majority of PETs are tumors without hormonal activity. In this publication, we present the diagnostic and therapeutic guidelines for the management of these tumors proposed by the Polish Network of Neuroendocrine Tumors. These guidelines refer to biochemical and location diagnostics, including scintygraphy of somatostatin receptors, endoscopic ultrasonography and other anatomical and functional imaging methods. High importance is attached to correct histopathological diagnosis which determines further management of patients with PETs. Antitumor therapy requires multidirectional procedure, and therefore the rules of surgical treatment, biotherapy, chemotherapy and peptide receptor radionuclide therapy are discussed.
Endokrynologia Polska 01/2013; 59(1):68-86. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An increased interest in gastro-entero-pancreatic neuroendocrine neoplasms (GEP NENs) has recently been observed. These are rare neoplasms and their detection in recent years has improved. Over 50% of GEP NENs are carcinoids, and they are usually found incidentally during surgery in the small intestine and appendix and at diagnosis in distant metastases, mainly to the liver. There is a need for co-operation between specialists in various disciplines of medicine in order to work out the diagnostic and therapeutic guidelines. In this publication, we present general recommendations of the Polish Network of Neuroendocrine Tumours for the management of patients with GEP NENs, developed at the Consensus Conference which took place in Kamień Śląski in April 2013. Members of the guidelines working groups were assigned sections of the 2008 guidance to update. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - neuroendocrine neoplasms of the stomach and duodenum (including gastrinoma); - pancreatic neuroendocrine neoplasms; - neuroendocrine neoplasms of the small intestine and the appendix; - colorectal neuroendocrine neoplasms. The proposed recommendations by Polish and foreign experts representing different fields of medicine (endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathology) will be helpful in the diagnosis and treatment of GEP NENs patients. (Endokrynol Pol 2013; 64 (6): 418-443).
Endokrynologia Polska 01/2013; 64(6):418-443. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION:: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. METHODS:: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. RESULTS:: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. CONCLUSION:: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1823-1829. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.Methods:In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.Results:Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.Conclusion:Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug-drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.
British Journal of Cancer 09/2012; 107(8):1277-85. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. CONCLUSION Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.
Journal of Clinical Oncology 07/2012; 30(27):3337-44. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer (NSCLC), based on the importance of the signaling pathways involved in tumor growth, angiogenesis, and metastasis. This phase III trial investigated overall survival (OS) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC.
Patients previously treated with one to two chemotherapy regimens (including one platinum-based regimen) for recurrent NSCLC, and for whom erlotinib was indicated, were randomly assigned (1:1) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d, stratified by prior bevacizumab use, smoking history, and epidermal growth factor receptor expression. The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
In all, 960 patients were randomly assigned, and baseline characteristics were balanced. Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone (hazard ratio [HR], 0.922; 95% CI, 0.797 to 1.067; one-sided stratified log-rank P = .1388). Median PFS was 3.6 months versus 2.0 months (HR, 0.807; 95% CI, 0.695 to 0.937; one-sided stratified log-rank P = .0023), and ORR was 10.6% versus 6.9% (two-sided stratified log-rank P = .0471), respectively. Treatment-related toxicities of grade 3 or higher, including rash/dermatitis, diarrhea, and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm.
In patients with refractory NSCLC, sunitinib plus erlotinib did not improve OS compared with erlotinib alone, but the combination was associated with a statistically significantly longer PFS and greater ORR. The incidence of grade 3 or higher toxicities was greater with combination therapy.
Journal of Clinical Oncology 05/2012; 30(17):2070-8. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.
Lung cancer (Amsterdam, Netherlands) 04/2012; 77(2):376-82. · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Chemotherapy is the principal treatment method for patients with advanced non-small-cell lung cancer (NSCLC). Treatment with platinum-based and novel chemotherapeutic regimens, compared to monotherapy, slightly increases the response rates to 20-40%. The predictive and prognostic values of molecular factors are highly variable; however, data on clinical-demographic factors are still burdened by significant limitations. Objectives: The aim of this study was to assess the prognostic value of synaptophysin and chromogranin A protein expression in patients receiving palliative chemotherapy for advanced NSCLC. Methods: The study population consisted of 23 women and 116 men. The median age was 57.3 years. Expression of synaptophysin and chromogranin was assessed using a two-step model of immunohistochemical staining. Level 0 represented lack of activity, while level 1 represented its expression. Results: Expression of synaptophysin and chromogranin A was observed in 12 (8.6%) and 5 (3.6%) patients, respectively. The risk of death was significantly lower in patients with expression of synaptophysin (p = 0.008) and chromogranin A (p = 0.014). The 12- and 24-month survival rate of patients with synaptophysin expression was 64% (95% CI 0.35-0.93), while for patients without expression it was 46% (95% CI 0.36-0.56) and 16% (95% CI 0.07-0.25), respectively. The 12- and 24-month survival rate of patients with chromogranin expression was 80% (95% CI 0.44-1.00), while for chromogranin A-negative patients it was 47% (95% CI 0.37-0.57) and 19% (95% CI 0.10-0.28), respectively. We did not observe associations between expression of synaptophysin and chromogranin A and the other typical prognostic factors. Conclusions: Expression of synaptophysin and chromogranin A was associated with a longer median overall survival and might have prognostic value. These results should be confirmed in a prospective study.