Tuncay Goksel

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.

BACKGROUND Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. METHODS In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. FINDINGS Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. INTERPRETATION Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. FUNDING Eli Lilly.

Aflibercept and Docetaxel Versus Docetaxel Alone After Platinum Failure in Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: A Randomized, Controlled Phase III Trial

PURPOSE To compare the efficacy of aflibercept (ziv-aflibercept), a recombinant human fusion protein targeting the vascular endothelial growth factor (VEGF) pathway, with or without docetaxel in platinum-pretreated patients with advanced or metastatic nonsquamous non-small-cell lung cancer. PATIENTS AND METHODS In this international, double-blind, placebo-controlled phase III trial, 913 patients were randomly assigned to (ziv-)aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2). The primary end point was overall survival (OS). Other efficacy outcomes, safety, and immunogenicity were also assessed. RESULTS Patient characteristics were balanced between arms; 12.3% of patients had received prior bevacizumab. (Ziv-)Aflibercept did not improve OS (hazard ratio [HR], 1.01; 95% CI, 0.87 to 1.17; stratified log-rank P = .90). The median OS was 10.1 months (95% CI, 9.2 to 11.6 months) for (ziv-)aflibercept and 10.4 months (95% CI, 9.2 to 11.9 months) for placebo. In exploratory analyses, median progression-free survival was 5.2 months (95% CI, 4.4 to 5.6 months) for (ziv-)aflibercept versus 4.1 months (95% CI, 3.5 to 4.3 months) for placebo (HR, 0.82; 95% CI, 0.72 to 0.94; P = .0035); overall response rate was 23.3% of evaluable patients (95% CI, 19.1% to 27.4%) in the (ziv-)aflibercept arm versus 8.9% (95% CI, 6.1% to 11.6%; P < .001) in the placebo arm. Grade ≥ 3 adverse events occurring more frequently in the (ziv-)aflibercept arm versus the placebo arm were neutropenia (28.0% v 21.1%, respectively), fatigue (11.1% v 4.2%, respectively), stomatitis (8.8% v 0.7%, respectively), and hypertension (7.3% v 0.9%, respectively). CONCLUSION The addition of (ziv-)aflibercept to standard docetaxel therapy did not improve OS. In exploratory analyses, secondary efficacy end points did seem to be improved in the (ziv-)aflibercept arm. The study regimen was associated with increased toxicities, consistent with known anti-VEGF and chemotherapy-induced events.

Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaïve patients with advanced non-small cell lung cancer: A risk-benefit analysis of a large phase III study

BACKGROUND In a large phase III study, cisplatin and pemetrexed had non-inferior efficacy and better tolerability compared with cisplatin and gemcitabine in chemonaïve patients with non-small cell lung cancer (NSCLC). The current analysis characterised the clinical benefit (i.e. survival) relative to clinical risk (i.e. drug-related toxicity) of the doublets. PATIENTS AND METHODS A total of 1669 patients (of 1725 randomised) received 500 mg/m(2) pemetrexed IV followed by 75 mg/m(2) cisplatin IV on day 1 or gemcitabine 1250 mg/m(2) on days 1 and 8 and 75 mg/m(2) cisplatin on day 1, administered every 3 weeks for up to 6 cycles. Survival without toxicity (i.e. clinical benefit to risk) was defined as the time from randomisation to the first occurrence of any grade 3 or 4 drug-related toxicity or death, and was analysed using Kaplan-Meier and Cox methods. RESULTS In the overall patient population, survival without grade 3 or 4 drug-related toxicity was significantly longer for patients treated with cisplatin and pemetrexed versus cisplatin and gemcitabine (HR=0.70; P<0.001), as was survival without grade 4 drug-related toxicity (HR=0.83; P<0.001). For patients with non-squamous NSCLC, survival without toxicity with cisplatin and pemetrexed was superior to cisplatin and gemcitabine for grade 3 or 4 drug-related toxicity (HR=0.64; P<0.001) and for grade 4 drug-related toxicity (HR=0.77; P<0.001), whereas no treatment-arm difference was observed in the squamous subgroup. CONCLUSIONS Patients with non-squamous NSCLC treated with front-line cisplatin and pemetrexed have superior survival without toxicity (i.e. clinical benefit-to-risk profile) compared with patients treated with cisplatin and gemcitabine.

High dose rate endobronchial brachytherapy in the management of lung cancer: Response and toxicity evaluation in 158 patients

The aim of this study was to evaluate the symptomatic and endoscopic responses as well as the toxicities in 158 patients with endobronchial lung cancer treated with high dose rate endobronchial brachytherapy (HDR-EB). Forty-three patients with stage III NSCLC were treated with 60Gy external beam radiotherapy (ERT) and three applications of 5Gy each of HDR-EB (group A). Seventy-four patients who did not receive previous RT were treated with 30Gy ERT and two applications of 7.5Gy HDR-EB with palliative intent (group B). Forty-one patients with recurrent tumor who were irradiated previously were treated with three applications of 7.5Gy HDR-EB, with palliative intent (group C). In group A, bronchoscopic complete (CR) and overall response rates (ORR) were 67% and 86%, respectively. Symptomatic improvement was obtained in 58% of patients with cough, 77% of patients with dyspnea and 100% of patients with hemoptysis. Two and 5-year survival rates were 25.5% and 9.5%, respectively and the median survival time (MST) was 11 months. In group B, the bronchoscopic CR and ORR were 39% and 77%, respectively and 28% and 72% in group C. The symptomatic response rates were 57% and 55% for cough, 90% and 78% for dyspnea and 94% and 77% for hemoptysis, with a MST of 7 and 6 months in Groups B and C, respectively. Eighteen patients (11%) died of fatal hemoptysis (FH) with the median time to this event of 7 months. Treatment intent (p<0.001), total BED (p<0.001) and the number of HDR-EB fractions (p<0.001) were significant prognostic factors for FH. HDR-EB provides effective palliation in relieving the symptoms of patients with endobronchial lung cancer, however, there is a risk of developing FH that is associated with a high BED and multiple HDR-EB applications.

High dose rate endobronchial brachytherapy in combination with external beam radiotherapy for stage III non-small cell lung cancer.

INTRODUCTION A phase-II study was planned to test the effect of external beam radiotherapy in combination with endobronchial brachytherapy on the local control and survival of stage-III non-small cell lung cancer patients. MATERIALS AND METHODS Thirty patients with stage-III non-small cell lung cancer have been treated with 60 Gy external beam radiotherapy and 3 x 5 Gy HDR endobronchial brachytherapy to control tumor and to prolong survival. RESULTS Therapy regimen was found to be very effective for the palliation of major symptoms, palliation rates were 42.8% for cough, 95.2% for hemoptysis, 88.2% for chest pain and 80.0% for dyspnea. There was a 76.7% tumor response (53.3% complete, 23.3% partial) verified by chest CT scans and bronchoscopy. However, median locoregional disease free survival was 9+/-4 months (95% CI: 1-17) and it was only 9.6% at 5 years. Major side effects were radiation bronchitis (70.0%), esophagitis (6.6%) in the acute period and bronchial fibrosis (25%), esophagial fibrosis (12.5%) and fatal hemoptysis (10.5%) in the late period. Median survival was 11+/-4 months (95% CI: 4-18),and 5-year actuarial survival was 10%. Locoregional disease free survival (P=0.008) and the overall survival was longer (P<0.001) in the patients younger than 60, survival was also improved in the patients with complete response (P=0.019). There were no major complications during catheterisation; early side effects were quite tolerable but severe late complications were around 10%. CONCLUSIONS It is concluded that endobronchial brachytherapy in combination with external irradiation provides a good rate of response, however does not eradicate locoregional disease and does not prolong survival except for some subgroups such as younger patients.

Tc-99m MIBI SPECT in prediction of prognosis in patients with small cell lung cancer

PurposeThe purpose of this study was to evaluate whether the degree of technetium-99m methoxyisobutylisonitrile (MIBI) uptake and its retention in delayed imaging in small cell lung cancer (SCLC) was correlated with the response to multiagent chemotherapy and to investigate if there was a relationship between the survival time of patients with SCLC and Tc-99m MIBI SPECT tumor uptake parameters at the time of diagnosis.MethodsBetween 1998 and by December 2004, 40 patients with SCLC were studied with Tc-99m MIBI SPECT at the time of diagnosis. The patients were classified by a follow-up CT as good responders (complete or partial remission) and poor responders (stable disease or progressive disease). Following i.v. administration of 740 MBq Tc-99m MIBI, SPECT imaging at 30 minutes (early) and 2 hours (delayed) was performed. Regions of interests were placed over the tumors and contralateral normal lung tissue on one transverse section. The uptake ratio of the lesion to that in the contralateral normal lung was obtained from early images (early ratio; ER) as well as delayed images (delayed ratio; DR). The retention index (RI%) was measured as: RI% = [(DR - ER)/ER] x 100. Tc-99m MIBI tumor uptake parameters were compared with chemotherapeutic response and survival time.ResultsOf 40 patients, 29 patients were good responders (72.5%) and 11 patients were poor responders (27.5%). RI% of Tc-99m MIBI SPECT in the group of good response was significantly higher than in that with poor response (p < 0.05). On the other hand, there was no significant difference between the two groups with respect to ER or DR values. Four of 40 patients were still alive with disease (10%). The patient survival time varied from 1 to 70 months (mean survival time = 12.9 ± 13.4 months). There was no significant difference between the survival time of patients with respect to ER or DR of Tc-99m MIBI SPECT imaging. When median RI% was accepted as a cut-off value (-3.85%), patients with higher RI% values had a longer survival time (12 months) when compared with those with low RI% (8 months), p < 0.05.ConclusionOur results suggest that Tc-99m MIBI SPECT could accurately predict the chemotherapy response in patients with SCLC. RI% of Tc-99m MIBI SPECT is recommended to differentiate patients with a poor response to chemotherapy and good responders, and RI% of Tc-99m MIBI SPECT appears as the only parameter that may be useful in predicting the survival of patients with SCLC.

Quality of life results from the phase 3 REVEL randomized clinical trial of ramucirumab-plus-docetaxel versus placebo-plus-docetaxel in advanced/metastatic non-small cell lung cancer patients with progression after platinum-based chemotherapy

OBJECTIVES REVEL demonstrated that ramucirumab+docetaxel (RAM+DTX) improved overall survival, progression-free survival, and objective response rate in patients with advanced/metastatic non-small cell lung cancer with progression after platinum-based chemotherapy. This analysis examined quality of life (QoL) as assessed by the Lung Cancer Symptom Scale (LCSS) and clinician-reported functional status. MATERIALS AND METHODS The LCSS includes 6 symptom and 3 global items measured on a 0-100-mm scale; higher scores represent greater symptom burden. LCSS and ECOG PS data were collected at baseline, every 3-week cycle, the summary visit, and at the 30-day follow-up. LCSS total score and Average Symptom Burden Index (ASBI) were calculated. The primary analysis compared time to deterioration (TtD) between treatment arms for all individual items and summary scores, defined as increase from baseline by ≥ 15 mm using the Kaplan-Meier method and Cox regression. TtD to ECOG PS ≥ 2 was analyzed. RESULTS There were 1253 patients randomized to receive RAM+DTX or placebo+docetaxel (PL+DTX). Across all assessments, LCSS compliance was approximately 75% and balanced across arms. The mean (SD) baseline LCSS total score was 27.3mm (17.08 mm) on RAM+DTX and 29.6mm (17.59 mm) on PL+DTX. At 30-day follow-up, mean (SD) LCSS total score was 32.0 (19.03) on RAM+DTX and 32.5 (19.87) on PL+DTX. The TtD for all LCSS scores was similar between treatment arms. Stratified HRs (95% CI) for LCSS total score and ASBI were HR=0.99 (0.81, 1.22), p=0.932 and HR=0.93 (0.75, 1.15), p=0.514 with approximately 70% of patients censored. TtD to PS ≥ 2 was similar between treatment arms (HR=1.03 [95% CI: 0.85, 1.26], p=0.743) with approximately two-thirds of the patients censored. CONCLUSION In addition to improvement of clinical efficacy outcomes demonstrated in REVEL, these results suggest that adding ramucirumab to docetaxel did not impair patient QoL, symptoms, or functioning.

Success of a Smoking Cessation Program among Smoking Relatives of Patients with Serious Smoking-Related Pulmonary Disorders

The aim of the study was to investigate the success of a smoking cessation program among the smoking relatives of patients with serious smoking-related disorders and to determine whether having a relative with such a disorder influences the rate of success of the program. The relatives of patients with chronic obstructive pulmonary disease (COPD) and lung cancer who wanted to quit smoking were included in the smoking cessation program (group I, n = 34). During the same period, the same number of subjects with relatives free of any smoking-related diseases were included as a control group (group II, n = 34). Intensive behavioral therapy and motivational support was given to all subjects. Nicotine replacement therapy was administered to 10 subjects (29.4%) in group I and 14 subjects (41.2%) in group II. The subjects were evaluated in the 1st, 2nd, 4th, 8th and 12th week and subsequently every 3 months for a year in the outpatient clinic and proactive telephone interviews were performed periodically. In group I, 23.5% of subjects had a relative with COPD, 61.8% had relatives with lung cancer, and 14.7% had relatives with both COPD and lung cancer. The rate of quitting smoking was 79.4 and 73.5% on the 15th day and 41.2 and 38.2% at the end of the 1st year in groups I and II, respectively (p > 0.05). We observed that having a relative with serious smoking-related disorders did not motivate smokers to quit smoking.

REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. METHODS Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). RESULTS Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). CONCLUSIONS REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. CLINICAL TRIAL INFORMATION NCT01168973.