COMMENTARY

EGFR Mutation Status and TKI Use in NSCLC: The Final Word

Maurie Markman, MD

Disclosures

September 12, 2012

First-Line Erlotinib Followed by Second-Line Cisplatin-Gemcitabine Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The TORCH Randomized Trial

Gridelli C, Ciardiello F, Gallo C, et al
J Clin Oncol. 2012;30:3002-3011

Summary

This phase 3 randomized trial compared single-agent erlotinib followed by cisplatin-gemcitabine at documented progression vs the same regimens given in the reverse sequence to examine the utility of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), such as erlotinib, as primary therapy for patients with advanced non-small cell lung cancer (NSCLC) who are unselected for the presence or absence of an activating EGFR mutation. Individuals eligible for entry into the trial were required to have a performance status of 0 or 1; patients who had received adjuvant chemotherapy previously were not excluded if the regimen did not include gemcitabine and if at least a year had passed since the completion of the treatment.

A total of 760 patients had been enrolled when the Independent Data Monitoring Committee stopped the study. A protocol-defined interim analysis revealed inferior overall survival with the experimental regimen of erlotinib followed by cisplatin-gemcitabine (median, 8.7 months vs 11.6 months; hazard ratio, 1.24). The median progression-free survival also favored the regimen of chemotherapy followed by erlotinib (8.9 months vs 6.4 months; hazard ratio, 1.21). Of note, approximately 42% of the patients who had been randomly assigned to the experimental arm and showed documented progression never received second-line chemotherapy, mostly because of worsening conditions or death.

EGFR mutation status was known in only 36% of the entire population; fewer than 15% in either study arm were mutation-positive.

Viewpoint

Previously reported phase 3 trial data have provided strong support for the clinical utility of administering an EGFR TKI as primary treatment in patients with advanced NSCLC and an activating EGFR mutation.[1,2] Conversely, although previous evidence suggests the lack of utility of this approach in the absence of a documented EGFR mutation, a favorable impact on survival has been observed with EGFR TKI therapy given in the second line in patients who are unselected for mutation status.[3] This finding has raised the question of whether front-line EGFR TKI should also be considered for a wider patient population that includes those unselected for mutation status. The issue is particularly relevant because this class of targeted agents is generally perceived to have a more favorable toxicity profile compared with platinum-based chemotherapy.

The striking negative results of the current trial provide a clear and rather definitive answer to this question. In the absence of a documented activating EGFR mutation, combination cytotoxic chemotherapy should remain the standard of care for patients with advanced NSCLC.

Furthermore, these data appropriately highlight and emphasize the importance of molecular testing at the time of initial diagnosis of NSCLC because the treatment plan, in most cases, will be informed by the presence or absence of an activating EGFR mutation.

Abstract

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....