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Response of Intracranial Metastases to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: It May All Depend on EGFR Mutations

Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

To the Editor:

We read with great interest the case description by Fekrazad and colleagues¹ in the Journal. They describe a nonsmoking Native American woman with brain metastases from a lung adenocarcinoma who had a marked response to monotherapy with erlotinib at 150 mg/d. Although they do not provide these data, it is very likely that the patient had an activating epidermal growth factor receptor (EGFR) mutation, based on her clinical characteristics and response to the oral tyrosine kinase inhibitor (TKI) erlotinib.²

In the recently reported phase II trials of gefitinib 250 mg/d³ and erlotinib 150 mg/d^4,5 for patients with the L858R and exon 19 deletion EGFR mutations, patients with CNS metastases were included. The overall response rate in these and other prospective trials of gefitinib and erlotinib exceed or equal 75% for all sites.^3-6 In both instances, it seems that patients with intracranial metastases also have a similar high level of tumor responses in their CNS.^3,4 The Spanish Lung Cancer Group^4,5 followed the CNS response of seven chemotherapy-naïvepatients with an EGFR mutation given erlotinib 150 mg/d (available as part of the 2006 ASCO Annual Meeting's slide presentation of their abstract⁴). They reported four patients with a complete response and three with a partial response to this EGFR inhibitor: a 100% response rate of brain metastases. These results are astounding, and indicate that in a molecularly selected population with brain metastases, both gefitinib and erlotinib can achieve high response rates in a metastatic site that historically has not been sensitive to systemic chemotherapeutic agents used in non–small-cell lung cancer. Despite the striking efficacy of these EGFR inhibitors, secondary resistance is common and the brain may actually be the first site of loss of response to EGFR TKIs.⁷ Others have speculated that over time the effective dose of gefitinib in the CNS may wean to levels that are subtherapeutic to inhibit EGFR mutations.⁷

We look forward to mature results of prospective trials that evaluate the clinical benefit of EGFR TKIs in patients who have EGFR mutations with brain metastases. It is not inconceivable to think that in this patient population, oral TKIs may replace or supplement radiation therapy for management of brain metastases.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Fekrazad MH, Ravindranathan M, Jones DV Jr: Response of intracranial metastases to erlotinib therapy. J Clin Oncol 25:5024-5026, 2007[Free Full Text]

2. Sequist LV, Bell DW, Lynch TJ, et al: Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 25:587-595, 2007[Abstract/Free Full Text]

3. Inoue A, Suzuki T, Fukuhara T, et al: Prospective phase II study of gefitinib for chemotherapy naïve patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340-3346, 2006[Abstract/Free Full Text]

4. Paz-Ares L, Sanchez JM, Garcia-Velasco A, et al: A prospective phase II trial of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). J Clin Oncol 24:369s, 2006 (suppl; abstr 7020)

5. Rosell R, Taron M, Sanchez JJ, et al: Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol 3:277-283, 2007[CrossRef][Medline]

6. Costa DB, Kobayashi S, Tenen DG, et al: Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer 58:95-103, 2007[CrossRef][Medline]

7. Jackman DM, Holmes AJ, Lindeman N, et al: Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol 24:4517-4520, 2006[Free Full Text]

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• Response of Intracranial Metastases to Erlotinib Therapy
  M. Houman Fekrazad, Meera Ravindranathan, and Dennie V. Jones, Jr
  JCO 2007 25: 5024-5026 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Costa, D. B. Articles by Kobayashi, S. Search for Related Content PubMed PubMed Citation Articles by Costa, D. B. Articles by Kobayashi, S. Related Articles Related Article Social Bookmarking                            What's this?