Penelope Ann Bradbury

Immunotherapy for Lung Cancer

Abstract: Reports of tumor regression after infection date back as far as 1550 bc. In the twentieth century, Dr. William Coley, witnessing regression of a malignant tumor in one of his patients after a bacterial infection, developed the first cancer treatment vaccine derived from killed bacteria, with some reported success. However, despite decades of research, no specific, active tumor vaccine has been approved for the treatment of cancer. In lung cancer, initial attempts to modulate the immune system with nonspecific therapies were unsuccessful. However, more sophisticated specific vaccines have now been developed, and an increasing number are being evaluated in randomized phase 3 trials, raising hopes that vaccines may be an additional novel therapy for patients with lung cancer. This article reviews the following seven vaccines, which have entered randomized trials: L-BLP25 (Stimuvax), BEC-2, 1E10, PF-3512676 (Promune), melanoma-associated antigen A3 immunotherapeutic, granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy, and belagenpumatucel-L (Lucanix).

Economic Analysis: Randomized Placebo-Controlled Clinical Trial of Erlotinib in Advanced Non–Small Cell Lung Cancer

BACKGROUND The NCIC Clinical Trials Group conducted the BR.21 trial, a randomized placebo-controlled trial of erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor) in patients with previously treated advanced non-small cell lung cancer. This trial accrued patients between August 14, 2001, and January 31, 2003, and found that overall survival and quality of life were improved in the erlotinib arm than in the placebo arm. However, funding restrictions limit access to erlotinib in many countries. We undertook an economic analysis of erlotinib treatment in this trial and explored different molecular and clinical predictors of outcome to determine the cost-effectiveness of treating various populations with erlotinib. METHODS Resource utilization was determined from individual patient data in the BR.21 trial database. The trial recruited 731 patients (488 in the erlotinib arm and 243 in the placebo arm). Costs arising from erlotinib treatment, diagnostic tests, outpatient visits, acute hospitalization, adverse events, lung cancer-related concomitant medications, transfusions, and radiation therapy were captured. The incremental cost-effectiveness ratio was calculated as the ratio of incremental cost (in 2007 Canadian dollars) to incremental effectiveness (life-years gained). In exploratory analyses, we evaluated the benefits of treatment in selected subgroups to determine the impact on the incremental cost-effectiveness ratio. RESULTS The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was

Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes

94,638 per life-year gained (95% confidence interval =

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial

52,359 to

Vascular Endothelial Growth Factor Polymorphisms and Esophageal Cancer Prognosis

429,148). The major drivers of cost-effectiveness included the magnitude of survival benefit and erlotinib cost. Subgroup analyses revealed that erlotinib may be more cost-effective in never-smokers or patients with high EGFR gene copy number. CONCLUSION With an incremental cost-effectiveness ratio of

Genetic Polymorphisms and Head and Neck Cancer Outcomes: A Review

94 638 per life-year gained, erlotinib treatment for patients with previously treated advanced non-small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.

Matrix Metalloproteinase 1, 3, and 12 Polymorphisms and Esophageal Adenocarcinoma Risk and Prognosis

Objectives Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors that are more susceptible to cisplatin chemotherapy, which functions by causing DNA damage. We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n = 262) or without (n = 108) cisplatin. Methods Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism–cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. Results No associations with ERCC1 118 were found. Polymorphism–cisplatin interactions were highly significant in both OS (P = 0.002, P = 0.0001, and P<0.0001) and PFS (P = 0.006, P = 0.008, and P = 0.0007) for XPD 312, XPD 751, and ERCC1 8092, respectively. In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (CI): 0.1–0.5] to 0.31 (95% CI: 0.1–0.7). In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% CI: 1.1–5.5) to 3.73 (95% CI: 1.6–8.7). Haplotype analyses affirmed these results. Conclusion DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer.

Plasma Transforming Growth Factor α and Amphiregulin Protein Levels in NCIC Clinical Trials Group BR.21

BACKGROUND Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING Canadian Cancer Society Research Institute and Pfizer.

p53 Arg72Pro and MDM2 T309G Polymorphisms, Histology, and Esophageal Cancer Prognosis

Purpose: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The VEGF gene is polymorphic. We investigated the prognostic significance of three VEGF single nucleotide polymorphisms (SNP) in esophageal cancer. Experimental Design: Three hundred sixty-one patients were genotyped for three VEGF SNPs (−460T/C, 405G/C, and 936C/T) using DNA extracted from prospectively collected blood samples. The association of each individual SNP, and haplotypes of the three SNPs, on overall survival (OS) was investigated. Results: The variant allele of 936C/T was associated with improved OS compared with the wild-type genotype (log-rank P < 0.001). This association remained significant for OS after adjustments for age, gender, performance status, and disease stage [VEGF 936C/T: adjusted hazard ratio (AHR), 0.70; 95% confidence interval (95% CI), 0.49-0.99; P = 0.04; VEGF 936T/T: AHR, 0.11; 95% CI, 0.02-0.82; P = 0.03]. No independent associations were found for VEGF −460T/C and VEGF 405G/C. The CGC haplotype of the three VEGF SNPs (−460T/C, 405G/C, and 936C/T) combined was associated with reduced OS compared with all other patients (CGC/CGC: AHR, 1.51; 95% CI, 1.00-2.30; P = 0.05). Conclusions:VEGF 936C/T, and a haplotype of 460T/C, 405G/C, and 936C/T combined, has potential prognostic significance in esophageal cancer.

An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second-/third-line therapy in advanced non-small-cell lung cancer

Head and neck cancer (HNC) patients have variable prognoses even within the same clinical stage and while receiving similar treatments. The number of studies of genetic polymorphisms as prognostic factors of HNC outcomes is growing. Candidate polymorphisms have been evaluated in DNA repair, cell cycle, xenobiotic metabolism, and growth factor pathways. Polymorphisms of XRCC1, FGFR, and CCND1 have been consistently associated with HNC survival in at least two studies, whereas most of the other polymorphisms have either conflicting data or were from single studies. Heterogeneity and lack of description of patient populations and lack of accounting for multiple comparisons were common problems in a significant proportion of studies. Despite a large number of exploratory studies, large replication studies in well-characterized HNC populations are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(3):490–9)