ISEL: A Phase III survival study comparing gefitinib (IRESSA) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced non-small cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens

Reviewer: James M. Metz, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 6, 2005

Presenter: N. Thatcher
Presenter's Affiliation: Christie Hospital, Manchester, UK
Type of Session: Plenary


Gefitinib (IRESSA) is an oral medication that acts as a small molecule inhibitor of EGFR. There have been two Phase II trials demonstrating 250 mg/day has activity in pretreated patients with advanced NSCLC, however a survival advantage has not been shown in the population as a whole. This study was conducted to determine the impact of gefitinib on survival as monotherapy in patients with advanced NSCLC previously treated with chemotherapy.

Materials and Methods

  • Histologically or cytologically proven locally advanced or metastatic NSCLC
  • All patients received 1 or 2 prior chemotherapy regimens and had progression of disease within 90 days of their most recent treatment
  • Patients were randomized to gefitinib 250 mg/day plus BSC versus placebo plus BSC in a 2:1 ratio
  • Primary endpoint was OS and secondary endpoints included time to treatment failure (TTF), objective response (OR), quality of life, and toxicity


  • 1692 patients entered the study and were randomized to gefitinib (n=1129) or placebo (n=563)
  • The arms were well balanced demographically and the median follow-up is 7 months
  • Median survival was 5.6 months (gefitinib) versus 5.1 months (placebo) p=0.11 in the entire population regardless of histology
  • Median survival was 6.3 months (gefitinib) versus 5.4 months (placebo) p=0.07 in patients with adenocarcinoma
  • 1 year survival was 27% (gefitinib) versus 21% (placebo) p=ns
  • 1 year survival was 30% (gefitinib) versus 18% (placeble) p=ns in the adenocarcinoma subgroup
  • OR was 8% vs 1% in favor of gefitinib
  • Subgroup analysis showed improved survival in never-smokers in favor of gefitinib (median survival 8.9 versus 6.1 months; p=0.01) and improved survival in Asian patients with gefitinib (9.5 versus 5.5 months; p=0.01)
  • Toxicity was somewhat higher in the gefitinib arm for rash (37% versus 10%) and diarrhea (27% versus 9%) and primarily grade I and II
  • The incidence of interstitial lung disease was 1% and equal in both arms
  • Survival analysis by EGFR expression is inconclusive

Author's Conclusions

  • Gefitinib (IRESSA) was well tolerated in this group of pretreated advanced NSCLC patients
  • There was not a statistically significant improvement in survival with gefitinib
  • Analysis of a number of biomarkers is ongoing

Clinical/Scientific Implications

Taken as a whole, this trial is disappointing and does not show improvement in survival with gefitinib in this population.  Unfortunately the biomarker analysis of EGFR was inconclusive.  This may in part be due to the fact that tissue was not available for analysis in many of the patients, particularly the Asian and non-smoking patients.  Some patients do respond to gefitinib therapy, however, thus far markers predicting response to gefitinib have been elusive.  This is in contrast to erlotinib which has shown improved survival and has been tied to the expression of EGFR.  Further analysis of the biomarkers from the ISEL study are eagerly awaited.  Because the population as a whole does not show a survival advantage with gefitinib, this agent should be considered in Asian patients and never smokers but broad utilization is not warranted at this time.  Further clinical trials to identify the specific patient populations that benefit from gefitinib are warranted.