Characteristics, treatment patterns, and prognostic factors in small cell lung cancer transformation of advanced non-small cell lung cancer with epidermal growth factor receptor mutation after tyrosine kinase inhibitor therapy.
Ying-Ting LiaoChi‐Lu ChiangRuei-Lin SunYi‐Chen YehHsu-Ching HuangChia-I ShenYen-Han TsengYung‐Hung LuoYuh-Min ChenJacqueline Whang‐Peng
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e20569 Background: Small cell lung cancer transformation in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation following tyrosine kinase inhibitor (TKI) therapy poses a challenging clinical scenario. This study aims to explore the characteristics, treatment patterns, and prognostic factors associated with this transformation. Methods: A total of 41 patients with transformed SCLC (tSCLC) were included. Patient characteristics, treatment details, and laboratory data were collected. Re-biopsy specimens and subsequent treatments were analyzed. Statistical analyses were conducted to identify factors associated with treatment response and survival outcomes. Results: The median age of the patients was 61.7 years old, with a median time from TKI treatment to small cell transformation of 22.2 months. The majority were female (58.5%), never smokers (80.5%), with 53.7% having stage IVB disease prior to EGFR-TKI treatment. The most prevalent initial EGFR mutation was exon 19 deletion (56.1%), and afatinib (46.3%) was the most commonly used EGFR-TKI. EGFR mutation analysis was performed in 68.3% of the tSCLC specimen, and acquired T790M was detected in 7.1% of the patients. Treatment patterns after transformation included various systemic therapies, with the most (63.4%) receiving etoposide plus platinum (EP) based chemotherapy in the first line setting. Among all the patients, 56.1% received EGFR-TKI and 22% received immune checkpoint inhibitors (ICI) throughout the post-transformation treatment course. Anemia (Hgb < 10g/dL) and ever use of EP were significant factors associated with post-transformation survival. The median progression-free survival (PFS) of the first line treatment was 3.27 months, and the overall survival (OS) was 10.43 months post transformation. Conclusions: Small cell lung cancer transformation in advanced NSCLC with EGFR mutation after TKI therapy is associated with diverse clinical characteristics and dismal outcomes. We presented the complexity of managing these cases in real-world practice. Anemia and ever use of EP affected post-transformation survival. Further research is warranted to optimize therapeutic strategies for this unique subset of patients.Abstract Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non–small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. Experimental Design: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. Results: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients. Conclusions: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.
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Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and favourable tolerability in Phase II studies. We investigated whether EGFR expression levels could predict for response to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day(-1)) as part of a worldwide compassionate-use programme. Tissue samples were analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147 patients enrolled in our institution, 50 patients were evaluable for assessment of both clinical response and EGFR expression. The objective tumour response rate was 10% and disease control was achieved in 50% of patients. Although high EGFR expression was more common in squamous-cell carcinomas than adenocarcinomas, all objective responses were observed in patients with adenocarcinoma. Response and disease control with gefitinib were not associated with high EGFR expression. Overall, median survival was 4 months, and the 1-year survival rate was 18%. Strong EGFR staining correlated with shorter survival time for all patients. Gefitinib demonstrated promising clinical activity in this group of patients with NSCLC. These results have also shown that EGFR expression is not a significant predictive factor for response to gefitinib.
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Gefitinib is the current first-line treatment for advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutations. The possibility of using gefitinib as neoadjuvant therapy is interesting because of the low toxicity profile of tyrosine kinase inhibitors. Here we report the case of a 67-year-old nonsmoking woman affected by locally advanced lung adenocarcinoma, in whom one-year treatment with gefitinib rendered the tumor amenable to surgical removal. The results of ongoing clinical trials exploring the ability of preoperative gefitinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of EGFR mutations are urgently awaited.
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Gefitinib is the current first-line treatment for advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutations. The possibility of using gefitinib as neoadjuvant therapy is interesting because of the low toxicity profile of tyrosine kinase inhibitors. Here we report the case of a 67-year-old nonsmoking woman affected by locally advanced lung adenocarcinoma, in whom one-year treatment with gefitinib rendered the tumor amenable to surgical removal. The results of ongoing clinical trials exploring the ability of preoperative gefitinib to achieve better results than can be obtained with chemotherapy in patients selected on the basis of EGFR mutations are urgently awaited.
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Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor ( EGFR ) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild‐type (WT) or mutant (L858R) EGFR , and then expressed oncogenic K‐Ras 12V mutant in the latter transfectant. Although 293T cells expressing wild‐type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non‐transfected cells, the cells expressing the EGFR‐L858R were exquisitely sensitive. Consistently, phospho‐Akt levels were decreased in response to gefitinib in cells expressing EGFR‐L858R but not in cells with EGFR‐WT. In contrast, 293T cells expressing both EGFR‐L858R and oncogenic K‐Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K‐Ras 12V in the gefitinib‐sensitive pulmonary adenocarcinoma cell line PC‐9, which harbors an in‐frame deletion in the EGFR gene. The activated K‐Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho‐Akt, as well as phospho‐Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation. ( Cancer Sci 2007; 98: 357–363)
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To retrospectively evaluate the efficacy and safety of gefitinib in elderly patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations.Nine patients aged 70 years or older who had advanced NSCLC with mutations of the epidermal growth factor receptor gene were treated with gefitinib, 250 mg daily. Clinical data, types of epidermal growth factor receptor mutations, efficacy and toxicity of gefitinib were evaluated in these patients. Tumor responses were assessed by computed tomography scan using the Response Evaluation Criteria in Solid Tumors.Six patients showed a partial response, and the other three exhibited stable disease. The overall response rate was 66.7%. The median progression-free survival was 396 days, whereas the median over all survival was 523 days. No serious toxicities were observed.Gefitinib is very efficacious and safe for elderly patients with adenocarcinoma of the lung harboring an EGFR tyrosine kinase mutation. The present data support the use of gefitinib in this particular subgroup.
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