Sandjar Djalalov, Jaclyn Beca, and Jeffrey S. Hoch, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital and Cancer Care Ontario; Sandjar Djalalov, Jaclyn Beca, Jeffrey S. Hoch, Murray Krahn, and Natasha B. Leighl, Canadian Centre for Applied Research in Cancer Control; Murray Krahn, Toronto Health Economics and Technology Assessment Collaborative; Ming-Sound Tsao and Natasha B. Leighl, Ontario Cancer Institute and Princess Margaret Cancer Centre, Toronto; and Jean-Claude Cutz, McMaster University, Hamilton, Ontario, Canada.
ALK-targeted therapy with crizotinib offers significant improvement in clinical outcomes for the treatment of EML4-ALK fusion-positive non-small-cell lung cancer (NSCLC). We estimated the cost effectiveness of EML4-ALK fusion testing in combination with targeted first-line crizotinib treatment in Ontario.
A cost-effectiveness analysis was conducted using a Markov model from the Canadian Public health (Ontario) perspective and a lifetime horizon in patients with stage IV NSCLC with nonsquamous histology. Transition probabilities and mortality rates were calculated from the Ontario Cancer Registry and Cancer Care Ontario New Drug Funding Program (CCO NDFP). Costs were obtained from the Ontario Case Costing Initiative, CCO NDFP, University Health Network, and literature.
Molecular testing with first-line targeted crizotinib treatment in the population with advanced nonsquamous NSCLC resulted in a gain of 0.011 quality-adjusted life-years (QALYs) compared with standard care. The incremental cost was Canadian $2,725 per patient, and the incremental cost-effectiveness ratio (ICER) was $255,970 per QALY gained. Among patients with known EML4-ALK-positive advanced NSCLC, first-line crizotinib therapy provided 0.379 additional QALYs, cost an additional $95,043 compared with standard care, and produced an ICER of $250,632 per QALY gained. The major driver of cost effectiveness was drug price.
EML4-ALK fusion testing in stage IV nonsquamous NSCLC with crizotinib treatment for ALK-positive patients is not cost effective in the setting of high drug costs and a low biomarker frequency in the population.
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.
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.
The incremental cost-effectiveness ratio for erlotinib treatment in the BR.21 trial population was $94,638 per life-year gained (95% confidence interval = $52,359 to $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.
With an incremental cost-effectiveness ratio of $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.
Comment In: J Natl Cancer Inst. 2010 Mar 3;102(5):287-820160167
We conducted a case-control study in the greater Toronto area to evaluate potential lung cancer risk factors including environmental tobacco smoke (ETS) exposure, family history of cancer, indoor air pollution, workplace exposures and history of previous respiratory diseases with special consideration given to never smokers.
445 cases (35% of which were never smokers oversampled by design) between the ages of 20-84 were identified through four major tertiary care hospitals in metropolitan Toronto between 1997 and 2002 and were frequency matched on sex and ethnicity with 425 population controls and 523 hospital controls. Unconditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between exposures and lung cancer risk.
Any previous exposure to occupational exposures (OR total population 1.6, 95% CI 1.4-2.1, OR never smokers 2.1, 95% CI 1.3-3.3), a previous diagnosis of emphysema in the total population (OR 4.8, 95% CI 2.0-11.1) or a first degree family member with a previous cancer diagnosis before age 50 among never smokers (OR 1.8, 95% CI 1.0-3.2) were associated with increased lung cancer risk.
Occupational exposures and family history of cancer with young onset were important risk factors among never smokers.
Cites: Environ Res. 1998 Feb;76(2):78-849515062
Cites: N Engl J Med. 2009 Sep 3;361(10):947-5719692680
Cites: Cancer Detect Prev. 1998;22(6):533-99824376
Cites: Am J Epidemiol. 1999 Jan 1;149(1):13-209883789
Cites: Cancer Epidemiol Biomarkers Prev. 1999 May;8(5):461-510350443
Cites: Am J Public Health. 1999 Jul;89(7):1009-1710394308
Cites: Br J Cancer. 1951 Mar;5(1):1-2014839198
Cites: Br J Ind Med. 1965 Jan;22:1-1214261702
Cites: Am J Epidemiol. 2005 Mar 1;161(5):412-2215718477
Cites: Am J Ind Med. 2005 Apr;47(4):349-5715776474
Cites: Scand J Work Environ Health. 2006 Feb;32(1):22-3116539169
Cites: Cancer Detect Prev. 2006;30(2):158-6716581199
The Department of Medical Imaging at the University Health Network in Toronto is performing a lung cancer screening study, utilizing low-dose computed tomography (LDCT) as the modality. Baseline and annual repeat results are reported on the first 3352 participants, enrolled between June 2003 and May 2007.
Enrollment was limited to those aged 50 years or older, with a smoking history of at least 10 pack-years, no previous cancer and general good health. A helical low-dose CT (LDCT) of the chest was performed using 120kVp, 40-60mA, images were reconstructed with 1-1.25mm overlapping slices. The primary objectives were the detection of parenchymal nodules and diagnosis of early stage lung cancer. Baseline LDCTs were termed positive if at least one indeterminate non-calcified nodule 5mm or larger in size, or non-solid nodule 8mm or larger in size was identified. Follow up periods for individuals with a positive baseline LDCT were determined by nodule characteristics.
The median age at baseline was 60 years (range 50-83), with a median of 30 pack-years of cigarette smoking (range 10-189). Baseline CT evaluations were positive in 600 (18%) participants. To date, 2686 (80%) of the participants have returned for at least one annual repeat screening LDCT. Biopsies have been recommended for 82 participants since the study began, and 64 have been diagnosed with screen-detected cancer (62 lung, two plasmacytoma of the rib). A total of 65 lung cancers have been diagnosed (62 screen-detected, 3 interim), 57 are NSCLC (82% with known stage are stage I or II) and the rate of surgical resection was 80%. Sensitivity and specificity of the protocol in successfully diagnosing early stage lung cancers were 87.7% and 99.3%, respectively.
Data indicate that LDCT can identify small lung cancers in an at-risk population. The diagnostic algorithm results in few false-positive invasive procedures. Most cancers are detected at an early stage, where the cancer is resectable with a greater potential for cure. Long-term follow up of lung cancer cases will be carried out to determine survival.
Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3.
National Cancer Institute of Canada Clinical Trials Group PA.3 (NCIC CTG PA.3) was a phase 3 study (n = 569) that demonstrated benefits for overall survival and progression-free survival with the addition of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to gemcitabine in patients with advanced pancreatic carcinoma (APC). Mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR gene copy number (GCN) were evaluated as predictive markers in 26% of patients who had tumor samples available for analysis.
KRAS mutation status was evaluated by direct sequencing of exon 2, and EGFR GCN was determined by fluorescence in situ hybridization (FISH) analysis. The results were correlated with survival, which was the primary endpoint of the trial.
KRAS analysis was successful in 117 patients, and EGFR FISH analysis was successful in 107 patients. KRAS mutations were identified in 92 patients (78.6%), and EGFR amplification or high polysomy (FISH-positive results) was identified in 50 patients (46.7%). The hazard ratio of death between gemcitabine/erlotinib and gemcitabine/placebo was 0.66 (95% confidence interval [CI], 0.28-1.57) for patients with wild-type KRAS and 1.07 (95% CI, 0.68-1.66) for patients with mutant KRAS (P value for interaction = .38), and the hazard ratio was 0.6 (95% CI, 0.34-1.07) for FISH-negative patients and 0.90 (95% CI, 0.49-1.65) for FISH-positive patients (P value for interaction = .32).
In a molecular subset analysis of patients from NCIC CTG PA.3, EGFR GCN and KRAS mutation status were not identified as markers predictive of a survival benefit from the combination of erlotinib with gemcitabine for the first-line treatment of APC.
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.
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.
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).
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.
Greater understanding of molecular pathways important in cell growth and proliferation of thoracic malignancies, particularly non-small cell lung cancer (NSCLC), has resulted in intense clinical and translational research. There is now considerable interest in personalizing treatment based on an understanding of tumor histology and molecular abnormalities. However, there is a multiplicity of data, often with discordant results resulting in confusion and uncertainty among clinicians.
We conducted a systematic review and a consensus meeting of Canadian lung cancer oncologists and pathologists to make recommendations on the use of biomarkers in NSCLC. PubMed covering 2005 to March 2010 was searched using MESH terms for NSCLC and randomized trials, plus text words for the biomarkers of interest. Conference proceedings from 2005 to 2009 ASCO, ESMO, IASLC, and USCAP were also searched. The articles were reviewed by pairs of oncologists and pathologists to determine eligibility for inclusion.
Ten oncologists and pathologists reviewed and summarized the literature at a meeting attended by 37 individuals. Draft recommendations were formulated and agreed upon by consensus process. There is some evidence that histology is prognostic for survival. There is evidence from multiple randomized clinical trials to recommend the following: histologic subtype is predictive of treatment efficacy and for some agents toxicity. Immunohistochemistry testing should be performed on NSCLC specimens that cannot be classified accurately with conventional H&E staining. As EGFR mutations are predictive of benefit from tyrosine kinase inhibitors, diagnostic NSCLC samples should be routinely tested for EGFR-activating mutations. Clinical data on K-RAS mutations are inconsistent, therefore testing is not recommended. There is insufficient evidence to recommend other biomarker testing. No biomarkers to date reliably predict improved efficacy for anti-VEGF therapy. Routine assessment for EML4/ALK mutations is not recommended at present, although emerging data suggest that it may become valuable in the near future.
Assessment of NSCLC biomarkers is becoming increasingly important. Therefore, adequate diagnostic material must be obtained for accurate histologic subtyping and relevant molecular biology assays.