Clinical Outcomes and Biomarker Profiles of Elderly Pretreated NSCLC Patients from the BATTLE Trial

Background: Treating elderly non–small-cell lung cancer (NSCLC) patients in the salvage setting is challenging because of concerns of intolerance to therapy. Here we report outcomes (survival and toxicity) of elderly patients on the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. Methods: Two hundred and fifty-five chemorefractory NSCLC patients received tumor molecular analysis, and were randomized to erlotinib, erlotinib-bexarotene, vandetanib, or sorafenib. Retrospective subgroup analyses were conducted comparing outcomes among age groups (< 65 versus ≥ 65 years; < 70 versus ≥ 70 years; < 75 versus ≥ 75 years), treatments, and sex. Results: Median age was 62 years (range, 26–84); 38% were aged 65 years or more. No significant differences among age groups were seen in rates of biopsy-related pneumothorax, treatment-related death, compliance, grade 3 to 4 hematologic toxicities, response rate, nor overall survival. However, older women aged 65 years or more had more grade 3 to 4 nonhematologic toxicities (p = 0.05). Elderly men aged 65 years or more (p = 0.008) had a higher disease-control rate at 8 weeks and a better progression-free survival (PFS) (p = 0.0068). Elderly women aged 70 years or more had a trend toward higher 8-week disease-control rate (p = 0.06). Older men aged 65 years or more treated with vandetanib had a better median PFS (p = 0.03) whereas PFS of older women aged 70 years or more was worse (p = 0.03) compared with younger patients. Elderly men aged 70 years or more treated with sorafenib had a higher overall survival compared with younger men (p = 0.04). Tumor tissue biomarkers show distinct differences by sex and age. Conclusion: Fit elderly NSCLC patients should be considered for salvage targeted therapy. In this subset of patients, older men seem to have significant clinical benefit from certain agents. Tumor biomarker analysis demonstrates sex and age variations, and is hypothesis-generating.

[1]  M. Meyerson,et al.  Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  M. Borner,et al.  Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Y. Yatabe,et al.  Prognostic significance of cyclin D1 and retinoblastoma expression in combination with p53 abnormalities in primary, resected non-small cell lung cancers. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  C. Gridelli The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. , 2001, The oncologist.

[5]  W. Ryder,et al.  Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. , 1996, British Journal of Cancer.

[6]  R. Ramlau,et al.  Efficacy and Safety of Bevacizumab-Based Therapy in Elderly Patients with Advanced or Recurrent Nonsquamous Non-small Cell Lung Cancer in the Phase III BO17704 Study (AVAiL) , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[7]  M. Ladanyi,et al.  Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  W. Hong,et al.  Sorafenib treatment efficacy and KRAS biomarker status in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. , 2010 .

[9]  Yong Song,et al.  The Relationships between cyclin D1 Expression and Prognosis of Non-small Cell Lung Cancer , 2010, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[10]  L. Seymour,et al.  Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  S. Dacic,et al.  Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas , 2010, Modern Pathology.

[12]  V. Seshan,et al.  Prognostic and Therapeutic Implications of EGFR and KRAS Mutations in Resected Lung Adenocarcinoma , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[13]  T. Khoury,et al.  Eukaryotic initiation factor-4E and cyclin D1 expression associated with patient survival in lung cancer. , 2009, Clinical lung cancer.

[14]  M. Spitz,et al.  Clinicopathologic Characteristics of the EGFR Gene Mutation in Non–small Cell Lung Cancer , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[15]  M. Stokes,et al.  Trends and predictors of first-line chemotherapy use among elderly patients with advanced non-small cell lung cancer in the United States. , 2009, Lung cancer.

[16]  B. Milleron,et al.  Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial , 2011, The Lancet.

[17]  R. Gray,et al.  Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  E. Di Gennaro,et al.  Dose intensity correlate with survival in elderly patients treated with chemotherapy for advanced non-small cell lung cancer. , 2009, Lung cancer.

[19]  Edward S. Kim,et al.  The BATTLE trial: personalizing therapy for lung cancer. , 2011, Cancer discovery.

[20]  K. Kiura,et al.  Safety and efficacy of gefitinib treatment in elderly patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group Experience , 2005, Acta oncologica.

[21]  R. Herbst,et al.  Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  C. Amos,et al.  Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. , 2000, Cancer research.

[23]  E. Smit,et al.  Sorafenib in patients with advanced non-small cell lung cancer that harbor K-ras mutations: a brief report. , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[24]  Oliver Gautschi,et al.  Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. , 2007, Lung cancer.

[25]  J. Siegfried,et al.  Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero‐digestive tract , 2005, Molecular carcinogenesis.

[26]  R. Herbst,et al.  Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  N. Hanna,et al.  Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  Gefitinib in elderly and unfit patients affected by advanced non-small-cell lung cancer , 2003, British Journal of Cancer.

[29]  Yuh-Min Chen,et al.  Second-Line Therapy for Elderly Patients with Non-small Cell Lung Cancer Who Failed Previous Chemotherapy Is as Effective as for Younger Patients , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.