J. Paul Marcoux

EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. Experimental Design: We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions:EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.

A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.

Efficacy of Beclomethasone Nasal Solution, Flunisolide, and Cromolyn in Relieving Symptoms of Ragweed Allergy

Although three effective topical treatments for allergic rhinitis are available, little information to assist the clinician in choosing among them has been reported. Therefore, we conducted a randomized clinical trial to compare beclomethasone nasal solution, flunisolide, and cromolyn with placebo in 120 patients with hay fever during the ragweed season of 1984. We found that all three agents were superior to placebo (P less than 0.001) and that the glucocorticoids were more effective than cromolyn (P less than 0.001). Surprisingly, we also found that these intranasal treatments considerably reduced the symptoms of seasonal asthma. Further study of this therapeutic advantage is needed.

Cetuximab Monotherapy in Patients with Advanced Non-small Cell Lung Cancer After Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Introduction: Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non-small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI). Methods: Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m2 on day 1 and then 250 mg/m2 weekly until disease progression or unacceptable toxicity. The primary end point was response rate. Results: Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6–5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2–19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case. Conclusions: Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses.

Anti–PD-1 Inhibitor–Related Pneumonitis in Non–Small Cell Lung Cancer

Use of immune checkpoint inhibitors is increasing. Some patients with NSCLC treated with nivolumab develop a radiographic cryptogenic organizing pneumonia (COP) pattern of PD-1 inhibitor–related pneumonitis. Recognition of the radiographic pattern is needed for prompt diagnosis and management. The recent approval of two PD-1 inhibitors for the treatment of non–small cell lung cancer (NSCLC) has rapidly led to the widespread use of these agents in oncology practices. Pneumonitis has been recognized as a potentially life-threatening adverse event among NSCLC patients treated with PD-1 inhibitors; however, the detailed clinical and radiographic manifestations of this entity remain to be described. We report on two cases of anti–PD-1 pneumonitis in advanced NSCLC patients treated with nivolumab after its FDA approval. Both patients presented with ground-glass and reticular opacities and consolidations in a peripheral distribution on CT, demonstrating a radiographic pattern of cryptogenic organizing pneumonia. Consolidations were extensive and rapidly developed within 8 weeks of therapy in both cases. Both patients were treated with corticosteroids with subsequent improvement of respiratory symptoms and radiographic findings. One patient experienced recurrent pneumonitis after completing corticosteroid taper, or a “pneumonitis flare,” in the absence of nivolumab retreatment, with subsequent improvement upon corticosteroid readministration. With the increasing use of immune checkpoint inhibitors in a growing number of tumor types, awareness of the radiographic and clinical manifestations of PD-1 inhibitor–related pneumonitis will be critical for the prompt diagnosis and management of this potentially serious adverse event. Cancer Immunol Res; 4(4); 289–93. ©2016 AACR.

Evaluation of IgE tests in an allergy practice

Abstract We measured serum IgE in 264 patients seen in the course of an allergy practice during the summer of 1970. IgE values were elevated in 21 per cent of patients who had idiopathic asthma and 10 per cent of patients who had idiopathic rhinitis. The elevated IgE was of no immediate clinical help in this idiopathic group because we were unable to detect hidden allergenic factors on further review of the history and skin tests. The finding of such an elevation, however, will prompt us to a continuing search for an allergic etiology or other condition associated with elevation of IgE. In patients who had hypersensitivity to stinging insects, IgE was elevated in 9 of 29 (31 per cent), and in patients with asthma and aspirin intolerance it was elevated in one of 5. Results in small numbers of patients with several other conditions including cold urticaria, chronic urticaria, and drug allergy are also presented.

Asthma symptoms and airway hyperresponsiveness are lower during treatment with nedocromil sodium than during treatment with regular inhaled albuterol

In a double-blind, double-dummy, multicenter study, 212 patients with asthma whose symptoms were not controlled by as-needed use of inhaled bronchodilators were randomized to receive either 4 mg of nedocromil sodium or 180 micrograms of albuterol four times daily for 12 weeks. Asthma symptom scores (daytime asthma, nighttime asthma, morning chest tightness, and cough) and peak expiratory flow rate were recorded daily on diary cards. Bronchial hyperresponsiveness was assessed by changes in diurnal variation in peak expiratory flow rate and by methacholine inhalation challenge. Statistically significant differences were found between groups favoring nedocromil sodium for relief of day and nighttime asthma and morning chest tightness. Patients treated with nedocromil sodium also had significantly lower diurnal variation in peak expiratory flow rate compared with patients treated with albuterol. Compared with patients treated with albuterol, patients treated with nedocromil sodium showed a greater improvement in cough and a decreased sensitivity to methacholine challenge. Patients in both groups reduced their as-needed albuterol use. Regular treatment with nedocromil sodium therefore led to greater asthma symptom control and reduced bronchial responsiveness compared with regular treatment with albuterol. The study also showed that more frequent use of a beta 2-agonist (for symptom relief or not) did not improve asthma control. Both drugs were well tolerated.

Conversion from twice- to once-daily extended-release theophylline treatment in patients with reversible airway obstruction.

This multicenter, randomized, investigator-blinded, parallel group study compared the effects of converting patients from a q12h extended-release theophylline preparation (Theo-Dur) to a q24h extended-release product (Uni-Dur). Patients (n = 133) first received open-label Theo-Dur treatment with dosage titrated to achieve peak serum theophylline concentrations of 10-20 micrograms/ml. Patients then were randomized to continue Theo-Dur (n = 64) or to convert to Uni-Dur (n = 60) with peak serum theophylline concentrations maintained in the desired range. Pulmonary function tests were performed during the open-label and blinded periods; patients maintained diaries and performed peak flow measurements before each dose of study treatment. Adverse events were recorded throughout the study. Respiratory status during blinded treatment was rated as the same or improved compared with open-label treatment by > 87% of evaluable patients and physicians, regardless of treatment group. There were no significant differences in mean peak serum theophylline concentrations at baseline, at the final evaluation, or at any point during the study. Few dosage adjustments were necessary (5/52, Uni-Dur; 9/57, Theo-Dur). There were no significant changes in pulmonary function test results or patient diary entries between the open-label and blinded periods. Headache and nausea were the most commonly reported adverse events. In conclusion, converting patients from twice- to once-daily theophylline treatment resulted in no significant changes in any measures of pulmonary function, and there were no significant differences between the groups during the blinded treatment period.

Case report of tracheobronchial squamous cell carcinoma treated with radiation therapy and concurrent chemotherapy

a Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts b Harvard Medical School, Boston, Massachusetts c Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts d Department of Pulmonary Medicine, Newton-Wellesley Hospital, Newton, Massachusetts e Division of Thoracic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts