Kyoichi Okishio

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.

Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer

We designed a phase II study of weekly irinotecan (CPT-11) and carboplatin for refractory or relapsed small cell lung cancer (SCLC) and assessed the response rate, survival, and toxicity. Twenty-nine patients with refractory or relapsed SCLC were entered onto the trial. The median time off chemotherapy was 3.5 months (range: 0.8-12.9). Patients were treated at 4-week intervals using CPT-11 (50 mg/m(2) intravenously on days 1, 8 and 15) plus carboplatin (AUC = 2 mg/ml min, intravenously on days 1, 8, 15). All patients were assessable for toxicity and survival; 28 patients were assessable for response. There were nine partial responses (PRs). Overall response rate was 31.0% (95% CI: 15.3-50.8%). The median time to progression was 3.5 months. Median survival time was 6.1 months. Major toxicity was myelosuppression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 52 and 21% of patients, respectively. Grade 3-4 diarrhea was observed in 7%. There was one treatment-related death due to febrile neutropenia and sepsis. This combination of CPT-11 and carboplatin seems to be active second-line regimen with acceptable toxicity against small cell lung cancer.

Prospective Assessment of Continuation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Pemetrexed

Introduction: Patients with epidermal growth factor receptor (EGFR) mutation positive non–small-cell lung cancer exhibited marked response to gefitinib or erlotinib. In most cases, however, the patients showed disease progression after EGFR-tyrosine kinase inhibitor (TKI) treatment. We evaluated the efficacy and safety of pemetrexed in combination with EGFR-TKI in patients with disease progression. Methods: Patients with EGFR-mutant stage IIIB or IV non–small-cell lung cancer that progressed during gefitinib or erlotinib therapy were administered pemetrexed with the continuation of EGFR-TKI treatment. Pemetrexed was administered on day 1 at a dose of 500 mg/m2, and EGFR-TKI was sequentially administered on days 2 to 16. This treatment was repeated every 3 weeks until disease progression. The primary endpoint was disease control rate. Results: Twenty-seven patients were enrolled in this study. The median number of treatment cycles was six. Overall response rate was 25.9% (95% confidence interval, 9.4%–42.4%) and disease control rate was 77.8% (95% confidence interval, 62.1%–93.5%). Grade 3/4 hematological toxicities were neutropenia (22.2%), leukopenia (14.8%), and anemia (7.4%). Grade 4 nonhematological toxicities were not observed. Major grade 3 nonhematological toxicities were anorexia (14.8%), infection (14.8%), and fatigue (11.1%). The median progression-free survival was 7.0 months, and median survival time was 11.4 months. No treatment-related deaths occurred. Conclusions: Pemetrexed in combination with erlotinib or gefitinib after disease progression shows favorable response and acceptable toxicity.

An accelerated increase of plasma adrenomedullin in acute asthma

A novel vasorelaxant peptide, adrenomedullin (AM), has been isolated from the acid extract of human pheochromocytoma. We have recently shown that AM inhibits histamine- and acetylcholine-induced bronchoconstriction in anesthetized guinea pigs in vivo, and this bronchodilatory effect is long-lasting. Here, we measured plasma AM concentrations in nine patients with an acute attack of bronchial asthma. The results were compared with values in 30 age-matched normal control subjects and seven age-matched stable asthmatic patients. The mean AM concentrations of patients with an acute asthma attack (98 +/- 22 pg/mL) were clearly higher than those of normal control subjects (18 +/- 2 pg/mL) and stable asthmatic patients (21 +/- 3 pg/mL). Reverse-phase high-performance liquid chromatography (HPLC) showed that the major component of plasma immunoreactive AM in patients with an asthma attack and in normal subjects equally corresponded to authentic human AM(1-52). Our results suggest that plasma AM is markedly increased in many of the patients during an acute attack of bronchial asthma, but it is not observed in stable asthmatic patients. Although this report is preliminary, the observed increase of circulating AM during an acute asthma attack may represent a compensatory mechanism against the bronchoconstriction, probably through its bronchodilatory action.

Intrapleural Administration of Cisplatin and Etoposide to Treat Malignant Pleural Effusions in Patients with Non-Small Cell Lung Cancer

Background: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). Methods: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. Results: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 µg/ml) and etoposide (182.4 µg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, β-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (β-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). Conclusion: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.

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.

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.

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.

A Weekly Combination of Carboplatin and Irinotecan for Previously Untreated Extensive Disease Small-cell Lung Cancer, Results of a Minimum Follow-up of 3 Years: A Multi-center Phase II Trial JMTO LC02-02

OBJECTIVE We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease small-cell lung cancer. METHODS Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m(2)) were administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if >45 responses were observed in the 55 patients. RESULTS Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6-87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8-18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9-7.4). CONCLUSIONS This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.