Lesley Seymour

Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group

PURPOSE Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy. PATIENTS AND METHODS Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial. RESULTS With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin. CONCLUSION Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.

Gene expression-based survival prediction in lung adenocarcinoma: A multi-site, blinded validation study

Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training–testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

Role of KRAS and EGFR As Biomarkers of Response to Erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21

PURPOSE To evaluate the effect of KRAS and epidermal growth factor receptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-controlled trial. PATIENTS AND METHODS We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation, and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFR deletion/mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to 10% tumor cellularity. KRAS mutation was analyzed by direct sequencing. RESULTS Thirty patients (15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61 (38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% for mutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFR FISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinib therapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFR FISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31), wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR = 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorer survival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005). CONCLUSION EGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.

Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials

PURPOSE Since our individual patient data (IPD) meta-analysis (MA) of supportive care and chemotherapy for non-small-cell lung cancer (NSCLC), published in 1995, many trials have been completed. An updated, IPD MA has been carried out to assess newer regimens and determine conclusively the effect of chemotherapy. METHODS Systematic searches for randomized controlled trials (RCTs) were undertaken, followed by central collection, checking, and reanalysis of updated IPD. Results from RCTs were combined to calculate individual and pooled hazard ratios (HRs). RESULTS Data were obtained from 2,714 patients from 16 RCTs. There were 1,293 deaths among 1,399 patients assigned supportive care and chemotherapy and 1,240 among 1,315 assigned supportive care alone. Results showed a significant benefit of chemotherapy (HR, 0.77; 95% CI, 0.71 to 0.83; P <or= .0001), equivalent to a relative increase in survival of 23% or an absolute improvement in survival of 9% at 12 months, increasing survival from 20% to 29%. There was no clear evidence that this effect was influenced by the drugs used (P = .63) or whether they were used as single agents or in combination (P = .40). Despite changes in patient demographics, the effect of chemotherapy in recent trials did not differ from those included previously (P = .77). There was no clear evidence of a difference or trend in the relative effect of chemotherapy across patient subgroups. CONCLUSION This MA of chemotherapy in the supportive care setting demonstrates conclusively that chemotherapy improves overall survival in all patients with advanced NSCLC. Therefore, all patients who are fit enough and wish to receive chemotherapy should do so.

Comparison of Gemcitabine Versus the Matrix Metalloproteinase Inhibitor BAY 12-9566 in Patients With Advanced or Metastatic Adenocarcinoma of the Pancreas: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group

PURPOSE To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer. METHODS Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned. RESULTS The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P <.001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P <.001). Quality-of-life analysis also favored gemcitabine. CONCLUSION Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.

Prognostic and Predictive Gene Signature for Adjuvant Chemotherapy in Resected Non–Small-Cell Lung Cancer

PURPOSE The JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT. PATIENTS AND METHODS Gene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified. The prognostic value of this gene signature was tested in four independent published microarray data sets and by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR). RESULTS A 15-gene signature separated OBS patients into high-risk and low-risk subgroups with significantly different survival (hazard ratio [HR], 15.02; 95% CI, 5.12 to 44.04; P < .001; stage I HR, 13.31; P < .001; stage II HR, 13.47; P < .001). The prognostic effect was verified in the same 62 OBS patients where gene expression was assessed by qPCR. Furthermore, it was validated consistently in four separate microarray data sets (total 356 stage IB to II patients without adjuvant treatment) and additional JBR.10 OBS patients by qPCR (n = 19). The signature was also predictive of improved survival after ACT in JBR.10 high-risk patients (HR, 0.33; 95% CI, 0.17 to 0.63; P = .0005), but not in low-risk patients (HR, 3.67; 95% CI, 1.22 to 11.06; P = .0133; interaction P < .001). Significant interaction between risk groups and ACT was verified by qPCR. CONCLUSION This 15-gene expression signature is an independent prognostic marker in early-stage, completely resected NSCLC, and to our knowledge, is the first signature that has demonstrated the potential to select patients with stage IB to II NSCLC most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine.

Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.

PURPOSE This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain. RESULTS Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01). CONCLUSION Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.

Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer

Despite aggressive surgical and chemotherapeutic interventions, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death in men and women with overall cure rates of less than 15%. Recent advances in our understanding of cellular signalling and its critical role in tumorigenesis has led to the development of novel therapies which may offer new hope. In particular, the epidermal growth-factor receptor superfamily is an attractive therapeutic target because it is commonly overexpressed in malignant disease, regulates many vital cellular processes, and seems to be a negative prognostic indicator. Several selective inhibitors of this family of receptors are currently being evaluated in several cancers including NSCLC. In this review we examine current preclinical and clinical evidence on monoclonal antibodies (cetuximab, ABX-EGF, EMD72000, MAb ICR62, h-R3, MDX-447, MDX-H210, trastuzumab, and 2C4), immunoconjugates (Y10, Ua30:2, Mab806), anti-EGF vaccine (YMB2000), and tyrosine kinase inhibitors (gefitinib, erlotinib, CI1033, GW572016, EKB 569, PKI166, PD158780, and TAK 165).

Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non–Small-Cell Lung Cancer

PURPOSE p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone. METHODS p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization. RESULTS Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio [HR] = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy. CONCLUSION p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.

ERCC1 Isoform Expression and DNA Repair in Non-Small-Cell Lung Cancer

BACKGROUND The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.).