TOPICAL: Randomized phase III trial of erlotinib compared with placebo in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC) and unsuitable for first-line chemotherapy

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 7, 2010

Presenter: S. Lee, University College Hospital/UCL Cancer Institute, London, United Kingdom


  • Patients with poor performance status (PS) represent 30-50% of those presenting with advanced (Stage IIIB/IV) NSCLC, and are under-studied.
  • These patients are often not candidates for standard first line chemotherapy (platinum-based doublet chemotherapy), and there is no established first line alternative that is less toxic.
    • They are often managed with best supportive care (BSC) and palliative external beam radiation, as indicated.
  • The class of tyrosine kinase inhibitors, including the EGFR inhibitors erlotinib and gefitinib, are less toxic than standard first line chemotherapy, and would be expected to be better tolerated in this subset of patients;
    • Gefitinib has a demonstrable benefit as first line treatment in selected non-smokers with adenocarcinoma, who carry mutations in EGFR (Mok, NEJM, 2009); however,
    • The use of these drugs as first line treatment in unselected NSCLC patients has not been studied previously.
    • Despite this, they are frequently employed clinically. While well-tolerated, they are also extremely expensive, and this use may not be justified without supporting data.
  • The authors set out to determine whether there is a role for the EGFR inhibitor erlotinib in chemo-naïve, poor PS, advanced NSCLC patients, not selected based on EGFR mutation status, and launched a Phase III trial, the results of which are presented here.


  • Inclusion criteria: Chemo-naïve Stage IIIB/IV NSCLC patients with an ECOG performance status (PS) of 2 or 3, or a PS of 0 or 1, but unfit for platinum chemotherapy, and with a life expectancy greater than or equal to 8 weeks.
  • Patients were randomized to:
    • Erlotinib (150 mg/d) plus BSC (n = 350) or
    • Placebo plus BSC (n = 320).
  • Primary endpoint was overall survival (OS)
  • Secondary endpoints included progression-free survival (PFS), response rate, toxicity, and analysis of molecular biomarkers with respect to outcomes.
  • The trial was powered to detect an increase in 1-year OS from 10% to 17.5%, requiring 664 patients.
  • Intention to treat analysis was performed.


  • Between 2005 and 2009, 670 patients were randomized to either erlotinib (350) or placebo (320), from 78 UK centers.
  • Patient characteristics:
    • Age: median age was 77 yrs (range 42-91)
    • Gender: 61% male, 39% female
    • Histology: 38% adenocarcinoma, 39% squamous histology, 5% large cell, 18% other.
    • Performance status: The percentage of patients with ECOG PS score of 0/1, 2 and 3 were 16%, 55% and 29%, respectively.
    • Stage: 35% stage IIIB and 65% stage IV disease.
  • Baseline patient characteristics were well balanced between the groups.
  • At the time of analysis, 559 patients had died. Median follow-up was 3.5 mos.
  • Overall survival analysis:
    • Hazard ratio (HR; erlotinib vs placebo) for OS was 0.98 [95% CI 0.82-1.15; p = 0.77].
  • Progression free survival analysis:
    • Overall PFS HR was 0.85 (p = 0.038).
  • Subgroup analyses (by gender, histology, the combination of these two, and EGFR mutation status):
    • Significant longer OS and PFS with erlotinib were observed for females only: HR of 0.74 [p = 0.025] and 0.64 [0.49-0.83, p = < 0.001] respectively.
      • Median OS among women increased from 4.3 to 5.3 months;
      • PFS at 1 year among women increased from 5% to 15%.
    • PFS HR for adenocarcinoma versus non-adenocarcinoma was 0.74 [0.57-0.97, p = 0.03].
    • PFS HR with additional of erlotinib according to gender and histology were:
      • 0.68 [0.46-0.99, p = 0.046] females with adenocarcinoma;
      • 0.62 [0.43-0.89, p = 0.01] females with non-adenocarcinoma;
      • 0.85 [0.59-1.22, P=0.37] males with adenocarcinoma; and
      • 1.14 [0.89-1.45, p = 0.31] males with non-adenocarcinoma.
    • There was a PFS benefit in women treated with erlotinib regardless of histology, smoking status, or performance status.
  • The EGFR mutation rate in the patients analyzed so far is 3.5% (11/311 patients); this rate is relatively low, as one might expect in this elderly, heavily smoking population.
    • Even among wild type EGFR females there was a PFS benefit, with a HR of 0.58. There was no benefit among wild-type EGFR males.
  • Toxicity: increased Grade 3/4 rash and diarrhea were observed in patients receiving erlotinib.

Authors' Conclusions

  • This Phase III trial investigated a realistic group of poor performance status patients with advanced NSCLC, with over 50% of patients over the age of 77.
  • Overall, erlotinib did not improve OS in this unselected group of advanced NSCLC patients.
  • However, erlotinib did significantly improve the OS and PFS of females in this study, with a 26% relative decrease in the observed death rate in women who received erlotinib.
  • Furthermore, erlotinib significantly improved the PFS of all patients in the study, although this effect was largely driven by the improved outcomes in females.
  • Therefore, the authors conclude that erlotinib should be considered first line therapy for poor performance status women with advanced NSCLC.
  • The authors acknowledge that the mechanism underlying the improved outcomes in women is unclear.
  • They note that quality of life analysis and additional genetic analysis (including KRAS mutation status) will be presented later.

Clinical Implications

  • This Phase III trial failed to demonstrate an overall survival benefit in this unselected group of poor performance status patients with advanced NSCLC, and therefore erlotinib should not be routinely used as first line therapy in these patients.
  • However, it did demonstrate an overall survival and PFS benefit among female patients, and this benefit appeared to be independent of EGFR mutation status, performance status, smoking status, or histology.
    • Therefore, it would be reasonable to consider erlotinib as first line therapy for female patients with advanced NSCLC who are not candidates for conventional first line chemotherapy.
  • It is intriguing that the benefit with erlotinib was only observed in females, and that it appeared to be independent of EGFR mutation status. This suggests that there may be an alternate genetic pathway that erlotinib is targeting, which remains to be elucidated.
  • The drug was well tolerated in this group of elderly, poor performance status patients.
  • Criticisms and future directions:
    • This study included some patients with a PS of 0-1 who were not candidates for cisplatin chemotherapy; these patients may be better served with an alternative first line regimen such as Carbo/Taxol.
      • Future studies may compare erlotinib with Carbo/Taxol in poor PS women with newly diagnosed advanced NSCLC.
    • The EGFR mutation status analysis has only been performed on a subset of patients (311 of 670 patients); therefore, this data is preliminary and may yield different answers once the analysis is complete.
    • Furthermore, the analysis of additional genetic markers (for example, KRAS and other mutations in EGFR) is pending at this time.
  • In sum, this is an intriguing study that is likely to change practice in the management of poor performance status women with newly diagnosed advanced NSCLC, although it raises intriguing questions about the mechanism underlying this selective benefit.