Impact of EGFR and KRAS genotype on outcomes in a clinical trial registry of NSCLC patients initially treated with erlotinib or gefitinib

Jackman, David M.; Sequist, Lecia V.; Cioffredi, Leigh-Anne; Ruiz, Marielle Gallegos; Giaccone, G.; Miller, V. A.; Johnson, Benjamin

doi:10.1200/jco.2008.26.15_suppl.8035

Cited by 10 publications

(6 citation statements)

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“…Patients with KRAS mutations showed lower response rates and shorter survival than those with wild type KRAS in response to erlotinib plus chemotherapy in the TRIBUTE trial and single‐agent erlotinib in the BR.21 trial 50, 52. Similarly, data from a patient registry of 5 clinical trials performed in the United States and Europe indicated that KRAS mutations confer resistance to EGFR TKI therapy 54. Although these observations suggest that EGFR TKIs have less effect in tumors with KRAS mutations, there is no significant difference in survival between gefitinib and docetaxel when used for second‐line treatment of NSCLC in patients with KRAS mutated tumors 51.…”

Section: Integrating Trial Results Into Current Clinical Practice Andmentioning

confidence: 99%

Implications of key trials in advanced nonsmall cell lung cancer

Bonomi

2010

Cancer

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Many different targeted therapies with varying mechanisms of action have been added to standard first-line chemotherapy doublets in an effort to improve survival of patients with advanced nonsmall cell lung cancer (NSCLC). Only 2 targeted therapies-bevacizumab and cetuximab-have been associated with superior survival in phase 3 first-line studies. For both agents, the decision to enter phase 3 was based on results from randomized phase 2 trials, unlike other targeted therapies where the decision was made using either phase 1 or single study arm phase 2 results. There is also mounting evidence that patient selection will play a key role in the successful development of any targeted agent. Bevacizumab is indicated for patients with nonsquamous NSCLC who do not have certain comorbidities. Use of cetuximab is not restricted by safety factors, but may be focused on patients whose tumors are epidermal growth factor receptor (EGFR)-dependent; whether EGFR expression or absence of KRAS mutations are appropriate markers is still under study. By including randomized phase 2 trials in the development pathway, and by improving patient selection for individual agents (enriching trials with patients most likely to respond), it may be possible to enhance the success rate of future phase 3 clinical trials and, in turn, define future clinical practice with improved patient outcomes. Cancer 2010;116:1155-64. V C 2010 American Cancer Society.KEYWORDS: advanced NSCLC, first-line treatment, targeted therapy, bevacizumab, cetuximab, patient selection, molecular markers.Lung cancer is the second most common malignancy in both men and women in the United States, and the leading cause of cancer death. In 2008, an estimated 215,000 people will be diagnosed with lung cancer, representing 15% of all cancer diagnoses, and 161,840 people will die from it, accounting for 28.6% of all cancer deaths. 1 Approximately 85% of the cases are classified as nonsmall cell lung cancer (NSCLC), which comprises a heterogeneous group of histologies, including squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. 2 The high cancer death rate reflects the large percentage of cases diagnosed at an advanced stage as well as the plateau in effect achieved with cytotoxic chemotherapy in this setting. Historically, platinum doubletsÅwith taxanes, antimetabolites, or vinca agentsÅhave exhibited the best activity in advanced NSCLC, with objective response rates of 20% to 30% and median survival of 8 to 10 months. 3,4 Although doublet chemotherapy significantly improves response rates and 1-year survival compared with single-agent therapy, a meta-analysis showed that adding a third cytotoxic agent produces only a small increase in response rate and no improvement in survival compared with the doublet. 5 Recent efforts to improve outcome in NSCLC have focused on numerous targeted therapeutic approaches. Unfortunately, nearly all phase 3 studies in which a targeted therapy was added to first-line chemotherapy have had only limited success [6][7][8][9][10]...

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Section: Integrating Trial Results Into Current Clinical Practice Andmentioning

confidence: 99%

Implications of key trials in advanced nonsmall cell lung cancer

Bonomi

2010

Cancer

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“…This finding is not surprising, because KRAS mutations have been shown to be a poor predictor of response to EGFR inhibitor therapy in patients with NSCLC. 18,[38][39][40][41][42][43][44] However, a subgroup analysis of 90 patients in the SATURN study who had the KRAS mutation showed no significant difference in PFS between patients treated with erlotinib vs placebo (HR, 0.77; 95% CI, 0.50-1.19; P = .2246). 45 Although KRAS mutation has been associated with clinical outcomes with cetuximab in colorectal cancer, 46 no association was reported from analyses of multiple trials of cetuximab in combination with chemotherapy in patients with NSCLC.…”

Section: Epidermal Growth Factor Receptor and V-ki-ras2 Kirsten Rat Smentioning

confidence: 99%

Emerging Concepts in the Pathology and Molecular Biology of Advanced Non–Small Cell Lung Cancer

2011

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Non-small cell lung cancer (NSCLC) is traditionally classified histologically, but until recently, the histologic subtype has had little impact on the selection of therapy. Drugs such as pemetrexed and bevacizumab are indicated for specific NSCLC subtypes, and this type of stratification represents the first step toward individualizing therapy in NSCLC. Beyond histologic features, the status of molecular targets, such as the epidermal growth factor receptor (EGFR) gene, has been shown to correlate with response to treatment with EGFR tyrosine kinase inhibitors in patients with relapsed or refractory disease and in the first-line therapy setting. New therapies targeting the EGFR and other molecular aberrations are under way to help define specific subsets of patients responsive to certain molecularly targeted treatments. The role of pathologists in guiding treatment decisions will increase because molecular profiling, together with pathologic and histologic analysis, represents the future of personalizing medicine for patients with NSCLC.

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“…74 Clinical trials demonstrate that patients with mutant KRAS are unlikely to demonstrate a significant response to EGFR inhibitors, when compared with patients with wildtype KRAS; however, it is unclear whether poor response to therapy correlates with shorter survival (Table 3). 53,61,67,[75][76][77][78] In a retrospective study, patients with advanced NSCLC (n ϭ 73) and KRAS mutation who were treated with gefitinib or erlotinib experienced a significantly shorter time to progression (1.7 months versus 2.9 months; p ϭ 0.0025), but not a significantly shorter OS (5.0 months versus 9.4 months; p ϭ 0.62), when compared with patients with wild-type KRAS. 75 In a prospective trial of patients (n ϭ 101) with BAC or adenocarcinoma with BAC subtype who were treated with erlotinib, no patient with a KRAS mutation met Response Evaluation Criteria in Solid Tumors, when compared with patients with wild-type KRAS who had an RR of 32% (p Ͻ 0.01).…”

Section: Predictors Of Resistance To Egfr Inhibitorsmentioning

confidence: 99%

“…61 In contrast, a retrospective review of five clinical trials performed in Europe and the United States involving patients with NSCLC, who were treated with erlotinib or gefitinib, suggests that KRAS mutations are associated with resistance to EGFR-TKI therapy, at least when defined by response. 76 Additional prospective trials are needed to clarify the role of KRAS mutations in predicting benefit from EGFR-inhibitor therapy for patients with NSCLC.…”

Section: Predictors Of Resistance To Egfr Inhibitorsmentioning

confidence: 99%

Molecular Analysis-Based Treatment Strategies for the Management of Non-small Cell Lung Cancer

West¹,

Lilenbaum²,

Harpole

et al. 2009

Journal of Thoracic Oncology

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Even with the introduction of targeted agents and the establishment of multiple lines of therapy, the median survival for patients with advanced non-small cell lung cancer (NSCLC) does not considerably extend beyond 1 year. Emerging research suggests that clinical characteristics alone are insufficient for selecting patients for therapies that may confer significant survival benefit. The discovery of predictive and prognostic molecular markers such as gene mutations in EGFR and KRAS as well as high tumor expression levels of DNA repair pathway components ribonucleotide reductase subunit 1 and excision repair cross-complementing group 1 has sparked an interest in the development of individualized therapy as a strategy for increasing survival in patients with NSCLC. Techniques to analyze molecular biomarkers, such as immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction, and, more recently, gene microarray techniques, are being investigated for their potential to accurately predict an individual patient's response to therapy. Many prospective trials are still needed to clarify and confirm the utility of molecular biomarkers for guiding treatment selection, and continued participation in clinical trials is critical for the development of tools to provide customized treatment plans for patients with NSCLC.

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Impact of EGFR and KRAS genotype on outcomes in a clinical trial registry of NSCLC patients initially treated with erlotinib or gefitinib

Cited by 10 publications

References 0 publications

Implications of key trials in advanced nonsmall cell lung cancer

Implications of key trials in advanced nonsmall cell lung cancer

Emerging Concepts in the Pathology and Molecular Biology of Advanced Non–Small Cell Lung Cancer

Molecular Analysis-Based Treatment Strategies for the Management of Non-small Cell Lung Cancer

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