METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = 0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated amino transferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)

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Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR

Summary Background Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor ( EGFR ) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m 2 , intravenously) plus docetaxel (60 mg/m 2 , intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9·2 months (95% CI 8·0–13·9) versus 6·3 months (5·8–7·8; HR 0·489, 95% CI 0·336–0·710, log-rank p Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel. Funding West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70364-X.pdf

Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial

The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.

Epidermal growth factor receptor mutations in lung cancer

Lung cancer is the leading cause of cancer-related mortality not only in the United States but also around the world. In North America, lung cancer has become more predominant among former than current smokers. Yet in some countries, such as China, which has experienced a dramatic increase in the cigarette smoking rate during the past 2 decades, a peak in lung cancer incidence is still expected. Approximately two-thirds of adult Chinese men are smokers, representing one-third of all smokers worldwide. Non-small cell lung cancer accounts for 85% of all lung cancer cases in the United States. After the initial diagnosis, accurate staging of non-small cell lung cancer using computed tomography or positron emission tomography is crucial for determining appropriate therapy. When feasible, surgical resection remains the single most consistent and successful option for cure. However, close to 70% of patients with lung cancer present with locally advanced or metastatic disease at the time of diagnosis. Chemotherapy is beneficial for patients with metastatic disease, and the administration of concurrent chemotherapy and radiation is indicated for stage III lung cancer. The introduction of angiogenesis, epidermal growth factor receptor inhibitors, and other new anticancer agents is changing the present and future of this disease and will certainly increase the number of lung cancer survivors. We identified studies for this review by searching the MEDLINE and PubMed databases for English-language articles published from January 1, 1980, through January 31, 2008. Key terms used for this search included non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, bronchioalveolar cell carcinoma, large cell carcinoma, lung cancer epidemiology, genetics, survivorship, surgery, radiation therapy, chemotherapy, targeted therapy, bevacizumab, erlotinib, and epidermal growth factor receptor.

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Non-Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship

Purpose
This study evaluated overall survival (OS) of patients with advanced non-squamous NSCLC following treatment with the specific endothelin A receptor antagonist, zibotentan in combination with pemetrexed compared with pemetrexed monotherapy.

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A phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer

Kristine Pemberton

Papers

A phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer