In our institution we have completed a Phase I/II investigator-initiated trial of dose-escalated hypofractionated RT given concurrently with Gefitinib (Iressa) with Gefitinib continued after RT completion until progression or toxicity. Three RT dose levels are applied: 4.2 Gy in 10 fractions to 42 Gy; 4.2 Gy in 12 fractions 50.4 Gy and 4.2 Gy in 15 fractions to 63 Gy. Eligible pts are those with either Stage III or IV NSCLC who needed thoracic RT and could not receive chemotherapy. No selection by the EGFR receptor status has been applied. A total of 12 patients have been enrolled. Main toxicities were pulmonary (1 grade 2 pneumonitis; 1 grade 3 infectious pneumonia; 1 grade 4 pneumonitis). There was 1 grade 3 abdominal pain. One patient (with thoracic tumor controlled) died due to the late radiation-esophageal toxicity (tracheo-esophageal fistula in a setting of pre-existing esophageal diverticula) at 12 months from RT. Only one patient experienced local progression of the irradiated tumor, which is very encouraging and may support the hypothesis of the radiosensitizing effect of the EGFR inhibitors. As of now, median survival time for all 12 enrolled patients is 9 months (range: 1-26 mo) from the time of initiating Gefitinib, which is an encouraging result in mostly pretreated patients, many with metastatic disease (Werner-Wasik et al, oral presentation, First ESMO/IASLC European Meeting on Lung Cancer, Geneva, Switzerland, April 2008).