Phase II Trial of Dasatinib for Patients with Acquired Resistance to Treatment with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Erlotinib or Gefitinib

Introduction:Dual inhibition of SRC- and EGFR-dependent pathways may overcome acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for patients with lung adenocarcinoma with EGFR mutations. The SRC inhibitor dasatinib demonstrates antitumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.Methods:We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based on evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.Results:Twenty-one patients were enrolled, 9 under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% confidence interval: 0–18%). The median time to progression was 0.5 months (range, 0.2–1.8 months) in patients treated with dasatinib and 0.9 months (range, 0.4–5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.Conclusions:Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib

Distinct Clinical Course of EGFR-Mutant Resected Lung Cancers: Results of Testing of 1118 Surgical Specimens and Effects of Adjuvant Gefitinib and Erlotinib

Background:EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I–III lung cancers is unclear.Methods:At our institution, resection specimens from patients with stage I–III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded.Results:In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34–0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87–1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26–0.72, p = 0.001), and a trend toward improved OS.Conclusions:Patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer

The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non–small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy

Economic and social changes among distressed family caregivers of lung cancer patients

Although costs of lung cancer care have been documented, economic and social changes among lung cancer patients’ family caregivers have yet to be fully examined. In addition, research has not focused on caregivers with greater need for support services. This study examined various economic and social changes among distressed family caregivers of lung cancer patients during the initial months of cancer care in the United States

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer

ASCO published a guideline on use of chemotherapy in advanced stage non–small-cell lung cancer in 1997. The latest update covers treatment with chemotherapy and biologic agents and reviews literature from 2002 to 2009

2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer

ASCO produced the 2011 Focused Update based on phase III randomized clinical trials published on maintenance chemotherapy, addressing one question from the 2009 Guideline Update on chemotherapy for stage IV NSCLC: what is the optimal duration of first-line chemotherapy for stage IV NSCLC