Quality of life with second or third line nab-paclitaxel-based regimens in advanced non-small-cell lung cancer.

Aim: Evaluate quality of life (QoL) in patients with advanced non-small cell lung cancer treated with second or third line nab-paclitaxel ± durvalumab. Patients & methods: Longitudinal QoL was assessed using Lung Cancer Symptom Scale, EuroQoL Five-Dimensions Five-Levels and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core. Results: QoL was generally stable through eight treatment cycles (both arms). Clinically meaningful improvement from baseline was noted in Lung Cancer Symptom Scale (overall constitutional score and three-item index [nab-paclitaxel + durvalumab]) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (global health status/QoL and emotional functioning [both arms] and pain [nab-paclitaxel + durvalumab]) analyses. EuroQoL Five-Dimensions Five-Levels domains were stable/improved or completely resolved at least once in 19-56% and 9-51% of patients, respectively. Conclusion: While QoL trends were promising, additional data are required to support these regimens in this setting.

ABOUND.2L+: A randomized phase 2 study of nanoparticle albumin-bound paclitaxel with or without CC-486 as second-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC).

BACKGROUND: This randomized phase 2 trial compared the efficacy and safety of second-line nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without the addition of CC-486 (an oral formulation of 5-azacytidine) in patients with advanced-stage, nonsquamous non-small cell lung cancer. METHODS: Patients were randomized to receive either nab-paclitaxel 100 mg/m2 on days 8 and 15 plus CC-486 200 mg daily on days 1 to 14 or single-agent nab-paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression-free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival. RESULTS: Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single-agent nab-paclitaxel arm). There was no benefit from the addition of CC-486 to nab-paclitaxel. The median progression-free survival was 3.2 months for the combination and 4.2 months for single-agent nab-paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single-agent nab-paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08-2.57). Grade 3 or greater treatment-related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single-agent nab-paclitaxel arm. CONCLUSIONS: Single-agent nab-paclitaxel was associated with promising outcomes and a tolerable safety profile as second-line treatment for patients with advanced-stage, nonsquamous non-small cell lung cancer. There was no benefit from the addition of CC-486 to nab-paclitaxel.

Patient selection for anti-PD-1/PD-L1 therapy in advanced non-small-cell lung cancer: implications for clinical practice.

Immune checkpoint inhibitors targeting PD-1 or PD-L1 represent a standard treatment option for patients with advanced non-small-cell lung cancer. However, a substantial proportion of patients will not benefit from these treatments, and robust biomarkers are required to help clinicians select patients who are most likely to benefit. Here, we discuss the available evidence on the utility of clinical characteristics in the selection of patients with advanced non-small-cell lung cancer as potential candidates for single-agent anti-PD-1/PD-L1 therapy, and provide practical guidance to clinicians on identifying those patients who are most likely to benefit. Recommendations on the use of immune checkpoint inhibitor in clinically challenging populations are also provided.

Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

BACKGROUND: Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS: In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING: F Hoffmann-La Roche/Genentech Inc.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.

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.

First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.

Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer.

Importance: Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective: To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants: This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures: Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results: Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status. Conclusions and Relevance: Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

Treatment outcomes by histology in REVEL: A randomized phase III trial of Ramucirumab plus docetaxel for advanced non-small cell lung cancer.

OBJECTIVES: Ramucirumab, a recombinant human immunoglobulin G1 monoclonal antibody inhibiting vascular endothelial growth factor receptor-2, increased overall survival (OS) combined with docetaxel versus docetaxel alone in non-small cell lung cancer (NSCLC) in the REVEL trial. Pre-specified exploratory analysis examined efficacy and safety by histology. MATERIALS AND METHODS: 1253 patients with NSCLC were randomized to receive ramucirumab (10mg/kg; n=628) plus docetaxel (75mg/m2) or placebo plus docetaxel (n=625) after disease progression on or after platinum-based therapy, with or without bevacizumab or maintenance therapy. OS was analyzed using Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Primary quality-of-life analysis was time to deterioration (TtD) of the Lung Cancer Symptom Scale (LCSS) scores using the Kaplan-Meier method and Cox regression. RESULTS: Median OS for adenocarcinoma was 11.2 months for ramucirumab-docetaxel (n = 377) and 9.8 months for placebo-docetaxel (n=348); HR=0.83 (95% CI: 0.69-0.99). In squamous disease, median OS was 9.5 months for ramucirumab-docetaxel (n=157) versus 8.2 months for placebo-docetaxel (n=171); HR 0.88 (95% CI: 0.69-1.13). Median OS for other nonsquamous was 10.8 months for ramucirumab-docetaxel (n=74) and 9.3 months for placebo-docetaxel (n=78); HR=0.86 (95% CI: 0.59-1.26). Treatment-emergent adverse events were comparable between treatment arms across histologic subgroups. TtD for LCSS scores was similar between treatment arms in the nonsquamous and squamous subgroups. CONCLUSION: REVEL demonstrated similar favorable efficacy and manageable safety for ramucirumab-docetaxel across histologic subgroups of NSCLC.

Randomized Prospective Biomarker Trial of ERCC1 for Comparing Platinum and Nonplatinum Therapy in Advanced Non-Small-Cell Lung Cancer: ERCC1 Trial (ET).

Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non-small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer.

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37-1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10-0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46-2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC.

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.

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. PATIENTS AND METHODS: Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. RESULTS: Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. CONCLUSION: Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer.

Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases.

BACKGROUND: Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitizing properties of erlotinib and its direct effect on brain metastases and systemic activity. METHODS: Eighty NSCLC patients with KPS of 70 and greater and multiple brain metastases were randomly assigned to placebo (n = 40) or erlotinib (100mg, n = 40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150 mg) until disease progression. The primary end point was neurological progression-free survival (nPFS); hazard ratios (HRs) were calculated using Cox regression. All P values were two-sided. RESULTS: Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI = 0.59 to 1.54; P = .84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI = 0.58 to 1.55; P = .83). The frequency of epidermal growth factor receptor (EGFR) mutations was low with only 1 of 35 (2.9%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70.0% in each arm), except for rash 20.0% (erlotinib) vs 5.0% (placebo), and fatigue 17.5% vs 35.0%. No statistically significant quality of life differences were found. CONCLUSIONS: Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases compared to placebo. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations.

Superior vena cava stent migration into the pulmonary artery causing fatal pulmonary infarction.

Migration of superior vena cava (SVC) stents is a well-recognised complication of their deployment, and numerous strategies exist for their retrieval. To our knowledge, only three cases of migration of an SVC stent to the pulmonary vasculature have previously been reported. None of these patients developed complications that resulted in death. We report a case of SVC stent migration to the pulmonary vasculature with delayed pulmonary artery thrombosis and death from pulmonary infarction. We conclude that early retrieval of migrated stents should be performed to decrease the risk of serious complications.