Kazuhiro Asami

Randomized Phase III Trial of Erlotinib Versus Docetaxel As Second- or Third-Line Therapy in Patients With Advanced Non–Small-Cell Lung Cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA)

PURPOSE To investigate the efficacy of erlotinib versus docetaxel in previously treated patients with advanced non-small-cell lung cancer (NSCLC) in an epidermal growth factor receptor (EGFR) -unselected patient population. PATIENTS AND METHODS The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate, safety, and analyses on EGFR wild-type tumors. Patients with stage IIIB or IV NSCLC, previous treatment with one or two chemotherapy regimens, evaluable or measurable disease, and performance status of 0 to 2 were eligible. RESULTS From August 2009 to July 2012, 150 and 151 patients were randomly assigned to erlotinib (150 mg daily) and docetaxel (60 mg/m(2) every 3 weeks), respectively. EGFR wild-type NSCLC was present in 109 and 90 patients in the erlotinib and docetaxel groups, respectively. Median PFS for erlotinib versus docetaxel was 2.0 v 3.2 months (hazard ratio [HR], 1.22; 95% CI, 0.97 to 1.55; P = .09), and median OS was 14.8 v 12.2 months (HR, 0.91; 95% CI, 0.68 to 1.22; P = .53), respectively. In a subset analysis of EGFR wild-type tumors, PFS for erlotinib versus docetaxel was 1.3 v 2.9 months (HR, 1.45; 95% CI, 1.09 to 1.94; P = .01), and OS was 9.0 v 10.1 months (HR, 0.98; 95% CI, 0.69 to 1.39; P = .91), respectively. CONCLUSION Erlotinib failed to show an improvement in PFS or OS compared with docetaxel in an EGFR-unselected patient population.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Beyond Progressive Disease: A Retrospective Analysis for Japanese Patients with Activating EGFR Mutations

Introduction: It is not determined whether the continuous use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is reasonable for patients with activating EGFR mutations, who have progressed with the drug. Methods: We retrospectively analyzed the data from 2002 to 2010 of consecutive patients who had advanced non–small-cell lung cancer (NSCLC) harboring activating EGFR mutations and showed radiological disease progression after EGFR-TKI treatment as the first-line or second-line setting. We classified them into two groups: continuous EGFR-TKI and switching to chemotherapy, and compared the clinical outcomes. Multivariate analysis for survival was performed including age, sex, Eastern Cooperative Oncology Group performance status (0–1/ 2–4), brain metastasis, EGFR mutations (deletions in exon 19 versus L858R), continuous EGFR-TKI (yes/no), and initiation of EGFR-TKI (first versus second). Results: A total of 551 NSCLC patients were screened for EGFR mutations in the period, and 186 patients had activating EGFR mutations. To explore the potential use of EGFR-TKI beyond progressive disease (PD), 64 patients were selected and analyzed. There were 13 men and 51 women, and median age was 65.5 years (range, 42–86). Among them, 31 patients had deletions in exon 19, and 33 had point mutation of L858R in exon 21. Thirty-nine patients were continuing EGFR-TKI beyond PD; 25 patients were switched to cytotoxic chemotherapy alone. The median overall survival was 32.2 months in the patients continuing EGFR-TKI, and 23.0 months in the patients switching to chemotherapy, presenting a significant difference between the two groups (p = 0.005). Cox analysis showed that continuous EGFR-TKI after PD (hazards ratio 0.42, 95% confidence interval: 0.21–0.83, p = 0.013) was associated with improved survival. Conclusion: Continuous use of EGFR-TKI beyond PD may prolong overall survival compared with switching to cytotoxic chemotherapy in patients with activating EGFR mutations. A prospective study will be needed to confirm our results.

Long Exposure of Environmental Tobacco Smoke Associated with Activating EGFR Mutations in Never-Smokers with Non–Small Cell Lung Cancer

Purpose: To examine an association between environmental tobacco smoke (ETS) and activating epidermal growth factor receptor (EGFR) mutations in never-smokers with non–small cell lung cancer (NSCLC). Experimental Design: A total of 126 never-smokers with NSCLC were prospectively included in this study. Detailed ETS information was obtained through a standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was evaluated as a sum of the number of the exposure years at home and/or workplace. EGFR and K-ras mutations were determined using real-time PCR amplification. Results: A total of 124 patients (98.4%) had ETS exposure with median CETS of 50 years (range: 0–118). Activating EGFR mutations were detected in 62.7% of the 126 patients and K-ras in 2 of 114 patients. The incidence of activating EGFR mutations was significantly higher in females than in males (67.6% vs. 26.7%; P = 0.002), and increased in quintile groups separated on the basis of CETS (shortest group = 44.0%, longest = 84.6%; P = 0.0033). In the multivariate logistic regression model, including gender, CETS, age, and family history of cancer, both gender and CETS were significantly associated with an incidence of activating EGFR mutations; the odds ratio for the EGFR mutations were 5.13 [95% confidence interval, CI = 1.47–18.0; P = 0.0105] for females and 1.02 (95% CI = 1.00–1.04; P = 0.0193) for each 1-year increment in CETS. Conclusions: Females and increased ETS exposure are closely associated with EGFR mutations in never-smokers with NSCLC. Clin Cancer Res; 17(1); 39–45. ©2010 AACR.

Continued treatment with gefitinib beyond progressive disease benefits patients with activating EGFR mutations.

BACKGROUND Gefitinib is an effective treatment for patients with non-small cell lung cancer who harbor activating epidermal growth factor receptor (EGFR) mutations. However, no optimal strategy has been established for these patients after gefitinib fails. The aim of this retrospective study was to assess the survival benefit of continued gefitinib treatment in these cases. PATIENTS AND METHODS We analyzed gefitinib responders with activating EGFR mutations who developed progressive disease (PD) during the course of therapy. Prognostic variables were analyzed using a Cox proportional-hazards model. RESULTS A total of 134 patients were retrospectively reviewed. Exon-19 deletion mutations and L858R point mutations were detected in 71 and 63 patients, respectively. Median survival time after PD with gefitinib was 14.3 months (95% confidence interval: 11.7-16.9). The median duration of continued gefitinib therapy beyond PD was 3.2 months. Statistical analysis showed that good performance status (0-1) (hazard ratio [HR]: 0.6), progression of a previously evaluated lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were independent prognostic factors. CONCLUSION Continuation of gefitinib beyond PD is an effective optional treatment in EGFR-mutated patients.

Histology and Smoking Status Predict Survival of Patients with Advanced Non–Small-Cell Lung Cancer: Results of West Japan Oncology Group (WJOG) Study 3906L

Introduction: Smoking status is one of the prognostic factors in advanced non–small-cell lung cancer (NSCLC). Currently, adenocarcinoma (Ad) histology is considered a predictive factor in advanced NSCLC. We investigated the correlation between histology or smoking status and survival of NSCLC patients receiving chemotherapy. Methods: We retrospectively reviewed clinical data from stage IIIB or IV NSCLC patients who started first-line chemotherapy at affiliated institutions of West Japan Oncology Group from 2004 to 2005. We also collected information on pack-years of cigarette smoking and years since cessation. Overall survival was compared using log-rank test, and Cox regression analysis was used to identify independent prognostic factors. Results: In total, 2542 consecutive patients were enrolled at 40 institutions. Of those, 71 were excluded because of unknown smoking history. The median overall survival of nonsmoking Ad patients (593 days) was longer than that of smoking Ad, nonsmoking non-Ad, and smoking non-Ad patients (384, 374, and 319 days, respectively; p < 0.001). In Cox regression with sex, age, stage, performance, and treatment as covariates, we found significant interaction (p = 0.039) between histology (Ad/non-Ad) and smoking status (smoker/nonsmoker); smoking conferred a hazard ratio of 1.34 (95% confidence interval, 1.15–1.55) in Ad, but only 0.99 (0.75–1.31) in non-Ad. Higher pack-years and shorter period since cessation were significantly associated with poorer survival in Ad (p < 0.001), but not in non-Ad (p ≥ 0.434). Conclusion: Ad histology is associated with better prognosis, and only smoking status had a prognostic impact in Ad.

A Case of Large-Cell Neuroendocrine Carcinoma Harboring an EML4-ALK Rearrangement with Resistance to the ALK Inhibitor Crizotinib

Journal of Thoracic Oncology ® • Volume 9, Number 6, June 2014 CASE REPORT A 43-year-old never-smoking woman presented with a palpable mass in the left breast. Chest radiography and computed tomography revealed a 5-cm solitary tumor in the left upper lung field (Fig. 1A, B) and multiple mediastinal lymph node enlargements in addition to the breast tumor. Contrast-enhanced brain magnetic resonance imaging revealed multiple, asymptomatic metastases in the brain (Fig. 1C) and a skin metastasis in the scalp. Bone metastasis in the pelvis and hepatic metastasis were also observed. The resected breast sections revealed malignant neoplasia organized into either solid nests or trabeculae of tumor cells with necrotic foci and rosette-like structures (Fig. 2A). Tumor cells showed moderately abundant cytoplasm, pleomorphic and vesicular nuclei, and mitosis (up to 20 mitoses/2 mm). Immunohistochemical analysis showed that the tumor cells were diffusely and strongly positive for cytokeratin (CK) 7, pan-CK, and neuroendocrine markers (chromogranin, synaptophysin [Fig. 2B], and CD56) and negative for thyroid transcription factor-1, estrogen receptor, progesterone receptor, CK5/6, and CK20. Breast tumor specimen analysis before treatment indicated a malignant neoplasm with neuroendocrine structure that was positive for neuroendocrine markers, leading to a diagnosis of a large-cell neuroendocrine carcinoma (LCNEC) with suspected metastasis. Transbronchial biopsy of the lung tumor before treatment showed pathological and immunohistochemical findings similar to the findings for breast tumor. Tumor cells from the lung, breast, and skin were diffusely and strongly positive for anaplastic lymphoma kinase (ALK) by immunohistochemistry using rabbit monoclonal antibody (D5F3; Cell Signaling Technology, Danvers, MA) (Fig. 2C). Fluorescence in situ hybridization analysis with break-apart probes for the ALK gene indicated the presence of an ALK rearrangement in the breast (Fig. 2D) and lung tumors and skin metastasis. Multiplex reverse transcriptase– polymerase chain reaction revealed amplification of echinoderm microtubule–associated protein-like 4 (EML4)-ALK variant 2 (E20; A20) in the breast tumor. Clinically, the tumors were diagnosed as primary lung carcinoma with metastases, including metastasis to the breast. The patient was treated with crizotinib, the first clinically available ALK tyrosine kinase inhibitor, and the lung tumors remained stable with treatment. Six weeks later, enhanced brain magnetic resonance imaging revealed marked increase in the size of the right cerebellar and left temporal lesions (Fig. 1D) and progression of the skin metastasis, indicating both resistance of the tumors to crizotinib and progressive disease.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer.

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

PURPOSE We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib. METHODS We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy. RESULTS A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p=0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p=0.04). CONCLUSIONS Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.

Early Pharmacodynamic Assessment Using 18F-Fluorodeoxyglucose Positron-Emission Tomography on Molecular Targeted Therapy and Cytotoxic Chemotherapy for Clinical Outcome Prediction

Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Molecular analysis of human papillomavirus in never-smokers with non-small cell lung cancer

The causes of lung cancer in never-smokers remain unclear. The potential contribution of human papillomavirus (HPV) to the carcinogenesis of non-small cell lung cancer (NSCLC) has been reported. In 2008, a prospective registry of never-smokers with NSCLC was established at the Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan. Never-smokers with NSCLC were consecutively enrolled onto the registry. Of these patients, 114 with large tumor specimens, the majority of which were surgical tissues, were selected. In total, 23 of the most clinically relevant HPV types were assayed using polymerase chain reaction amplification of the viral genome. Following exclusion of samples with suboptimal quality, DNA was extracted from 96 formalin-fixed paraffin-embedded samples. These 96 cases consisted of 82 females (85.4%) and 14 males (14.6%), with a median age of 67 years (range, 29–83). Almost all cases (93.8%) were of the adenocarcinoma histological subtype. Despite confirmation of the quality and amount of DNA, HPV type 6 was detected in only one case (1.1%). Furthermore, no other samples examined were positive for any other HPV types. The results therefore suggest that HPV does not play a major role as the driving oncogenic event in never-smokers with NSCLC.