EGFR's Evolution: New Insights Refine Role of Mutation in NSCLC

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

One measure of the maturation of molecular diagnostics in defining optimal management of malignant disease is the fact that new reports that may be of considerable clinical significance tend to generate relatively limited notice. Yet over time, our use of these tools will more critically define the clinical situations where specific targeted therapeutics are indicated, and will suggest new opportunities for favorably impacting outcomes.

Consider, for example, the continuing unfolding story of the influence of epidermal growth factor receptor (EGFR) mutations in the management of non-small cell lung cancer (NSCLC). It was less than a decade ago that the initial reports appeared noting that the presence of a sensitizing mutation in EGFR helped to define a population of patients with NSCLC who had a realistic opportunity to benefit clinically from the administration of a small-molecule tyrosine kinase inhibitor directed to this receptor.^1,2

This observation was quickly followed by reports demonstrating the relatively high objective response rates associated with the delivery of this class of agents, where the cancers were documented to contain such mutations. Subsequent paradigm-changing randomized phase III trials revealed the superiority associated with EGFR inhibitors over standard chemotherapy employed as first-line therapy in metastatic NSCLC known to contain sensitizing EGFR mutations.^3,4 For example, in a recently reported phase III trial conducted in a European patient population, initial treatment with erlotinib substantially improved progression-free survival (median 9.7 months vs 5.2 months; HR = 0.37, P < .0001) compared with treatment with cytotoxic chemotherapy.⁴

Perhaps not surprisingly, such impressive and clinically meaningful results have led some to suggest that it might be reasonable to treat all patients who present with advanced or metastatic NSCLC with an EGFR inhibitor—without examination of the tumor’s EGFR mutation status—and only deliver standard cytotoxic chemotherapy at the time of subsequent disease progression.

However, a recently reported phase III trial has clearly revealed the general inadvisability of this approach.⁵ Patients with advanced NSCLC, unselected for their EGFR mutation status, were randomized to receive erlotinib followed by platinum-based chemotherapy at the time of disease progression or standard chemotherapy followed by the EGFR inhibitor at progression. In this trial, the patients who received erlotinib as initial treatment experienced a statistically significant inferior survival compared with individuals administered primary chemotherapy (median 8.7 months vs 11.6 months).

Thus, while erlotinib has been shown to produce outcomes deemed “statistically equivalent” to chemotherapy when employed as a second-line treatment option in NSCLC,⁶ the body of clinical evidence suggests that documenting the existence of a sensitizing EGFR mutation and subsequently preferentially delivering an EGFR inhibitor in the presence of such an abnormality, with chemotherapy being administered in its absence, would be a far more rational therapeutic strategy.

Finally, a provocative retrospective analysis involving more than 150 patients with NSCLC whose tumors possessed a sensitizing EGFR mutation has suggested that initial treatment with an EGFR inhibitor may be associated with a lower rate of central nervous system progression compared with the use of upfront cytotoxic chemotherapy.⁷ If confirmed by other investigators, these data suggest the delivery of this class of drugs may be able to prevent or at least substantially delay the development of a particularly ominous complication of the malignancy.

In summary, despite all we have learned about the importance of sensitizing EGFR mutations in defining the management of advanced NSCLC, our education regarding the relevance of this molecular target in optimizing clinical outcomes continues.

References

1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. [published online ahead of print April 29, 2004]. N Engl J Med. 2004;350(21):2129-2139. doi:10.1056/NEJMoa040938.
2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy [published online ahead of print April 29, 2004]. Science. 2004; 304(5676):1497-1500. doi: 10.1126/ science.1099314.
3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma [published online ahead of print August 19, 2009]. N Engl J Med. 2009; 361(10):947-957. doi: 10.1056/NEJMoa0810699.
4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial [published online ahead of print]. Lancet Oncol. 2012;13(3):239-246. doi: 10.1016/S1470- 2045(11)70393-X.
5. Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by secondline cisplatin-gemcitabine chemotherapy in advanced non-small cell lung cancer: the TORCH randomized trial [published online ahead of print July 9, 2012]. J Clin Oncol. 2012;30(24):3002-3011. doi: 10.1200/JCO.2011.41.2056.
6. Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study [published online ahead of print January 24, 2012]. Lancet Oncol. 2012;13(3):300-308. doi: 10.1016/S1470- 2045(11)70385-0.
7. Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations [published online ahead of print June 25, 2012]. Clin Cancer Res. 2012;18(16):4406-4414. doi: 10.1158/1078-0432.CCR-12-0357.