Role of Erlotinib in EGFR Wild-Type Lung Cancer 


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I welcomed Matthew Stenger’s Journal Spotlight on the TAILOR trial in the August 15 issue of The ASCO Post (“Docetaxel Superior to Erlotinib in Second-Line Treatment of Advanced Non–Small Cell Lung Cancer With Wild-Type EGFR”). The trial was recently published online in Lancet Oncology,1 and addresses important questions about the role of erlotinib (Tarceva) in second-line therapy for non–small cell lung cancer (NSCLC).

An epidermal growth factor receptor (EFGR) tyrosine kinase inhibitor, erlotinib was first approved by the U.S. Food and Drug Administration (FDA) as an anticancer therapy in 2004. This approval was based on the BR.21 randomized trial, wherein patients with NSCLC in whom first- or second-line chemotherapy had failed were allocated to receive either erlotinib or placebo. Patients were enrolled in this trial at a time when we did not yet appreciate the existence of EGFR mutations and their associated sensitivity to EGFR kinase inhibitors.

In the 9 years since the discovery of EGFR mutations, science and medicine has advanced. We now routinely test for EGFR mutations and treat patients with EGFR tyrosine kinase inhibitors instead of chemotherapy when an EGFR mutation is identified. In fact, erlotinib was just recently approved by the FDA for the treatment of first-line EGFR mutant NSCLC.

EGFR Wild-Type

Given the increased use of erlotinib in EGFR mutant NSCLC patients, the question of its benefits in patients who do not have EGFR mutations has gained increasing attention. A retrospective analysis of the BR.21 study suggested that even among patients without an EGFR mutation, there was still a benefit of receiving erlotinib compared to placebo.2 However, most NSCLC patients with a good performance status, who have failed first-line therapy, who seek the opinion of an oncologist want to know their best therapeutic option, not whether the proposed treatment is superior to no treatment.

The TAILOR trial addresses this question specifically for EGFR wild-type patients. The data from the trial demonstrate that docetaxel is more effective than erlotinib in EGFR wild-type. Patients treated with docetaxel had a significantly higher response rate and progression-free survival and a numerically longer overall survival than those assigned to receive erlotinib.

Study Implications

What are the implications of this study? Certainly if the only molecular genotyping test that has been performed is an EGFR mutation test, then patients with EGFR wild-type NSCLC should preferentially receive doctaxel as their second-line therapy. Whether the same findings would apply to other chemotherapies is unknown. However, it is important to recognize that NSCLC patients are no longer divided into EGFR mutant or wild-type groups.

In fact, tumors that do not harbor EGFR mutations may harbor other genomic alterations such as rearrangements in ALK, RET, or ROS1 or mutations in BRAF or ERRB2—many of which are alterations for which there are either approved targeted therapies (crizotinib [Xalkori] for ALK rearrangements) or agents in clinical development. Hence, it is far more critical to extend molecular genotyping to go beyond EGFR mutation testing, to find the most effective therapy for our patients based on their tumor’s genomic profile.

Do the results of the TAILOR trial suggest that patients not harboring an EGFR mutation will never benefit from erlotinib? Three percent of patients had a partial response to erlotinib, and it is possible that there are determinants other than EGFR mutations of erlotinib efficacy that have yet to be fully validated. Potential biomarkers include EGFR amplification and/or presence of EGFR ligands. However, given the low response rate, these are likely to exist in only a minority of EGFR wild-type NSCLC patients. Future studies will be needed to identify this subset of EGFR wild-type NSCLC patients and to determine the effectiveness of erlotinib compared to docetaxel. ■

Pasi A. Jänne, MD, PhD, is Director, Lowe Center for Thoracic Oncology, Scientific Director, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

References

1. Garassino MC, Martelli O, Broggini M, et al: Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small cell lung cancer and wild-type EGFR tumours (TAILOR): A randomized controlled trial. Lancet Oncol. July 22, 2013 (early release online).

2. Zhu CQ, da Cunha SG, Ding K, et al: Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 26:4268-4275, 2008.


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