Cancer Therapy: Clinical Phase II Trial of Temozolomide in Patients with Relapsed Sensitive or Refractory Small Cell Lung Cancer, with Assessment of Methylguanine-DNA Methyltransferase as a Potential Biomarker M. Catherine Pietanza 1 , Kyuichi Kadota 2 , Kety Huberman 3 , Camelia S. Sima 4 , John J. Fiore 1 , Dyana K. Sumner 1 , William D. Travis 2 , Adriana Heguy 3 , Michelle S. Ginsberg 5 , Andrei I. Holodny 5 , Timothy A. Chan 6 , Naiyer A. Rizvi 1 , Christopher G. Azzoli 1 , Gregory J. Riely 1 , Mark G. Kris 1 , and Lee M. Krug 1 Abstract Purpose: This phase II study was conducted to assess the efficacy of temozolomide in patients with relapsed small cell lung cancer (SCLC). Experimental Design: Patients with disease progression after one or two prior chemotherapy regimens received temozolomide at 75 mg/m 2 /d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate [ORR; complete response (CR) plus partial response (PR)], which was evaluated separately in sensitive and refractory cohorts. In the available tissue, we assessed O 6 -methylguanine-DNA methyltrans- ferase (MGMT) promoter methylation status by PCR and MGMT expression by immunohistochemistry. Results: Sixty-four patients were accrued: 48 patients in the sensitive cohort and 16 in the refractory group. One CR and 10 PRs were noted in sensitive patients [ORR, 23%; 95% confidence interval (CI), 12%– 37%]. Two PRs were seen in the refractory cohort (ORR, 13%; 95% CI, 2%–38%). As second- and third-line treatment, the ORR was 22% (95% CI, 9%–40%) and 19% (95% CI, 7%–36%), respectively. Among patients with target brain lesions, 38% had a CR or PR (95% CI, 14%–68%). Grade 3 thrombocytopenia and neutropenia were observed in nine patients (14%). A greater number of cases with methylated MGMT had a response compared to those with unmethylated MGMT (38% vs. 7%; P ¼ 0.08). Conclusion: Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC. Clin Cancer Res; 18(4); 1138–45. Ó2012 AACR. Introduction Temozolomide is a nonclassic oral alkylating agent, which produces O 6 -alkylguanine (O 6 -AG) lesions on DNA. The DNA repair protein O 6 -AG DNA alkyltransferase, which is encoded by the O 6 -methylguanine-DNA methyltransfer- ase (MGMT) gene, removes alkyl groups from the O 6 position of guanine. Left unrepaired, chemotherapy- induced lesions trigger cytotoxicity and apoptosis. High levels of MGMT activity in cancer cells blunt the therapeutic effects of alkylating agents and thus can be an important determinant of treatment failure (1, 2). Epigenetic silencing of MGMT via hypermethylation of specific CpG islands of its promoter leads to loss of MGMT activity and improved sensitivity to alkylating agents (1, 2). Temozolomide is used in patients with glioblastoma multiforme and in refractory astrocytoma. In the phase III study of temozolo- mide in glioma, MGMT promoter methylation status was analyzed retrospectively and found to be an independent favorable prognostic factor (3). A recent large Radiation Thoracic Oncology Group study has confirmed these find- ings and has shown that MGMT promoter methylation is associated with response to temozolomide in glioma (4). There is strong rationale to study temozolomide in patients with small cell lung cancer (SCLC). Alkylating agents have single-agent efficacy in SCLC (5). Temozolomide crosses the blood–brain barrier and brain metastases are common in this disease (6). SCLC has aberrantly methylated MGMT (2, 7). Finally, anecdotal responses to temozolomide have Authors' Affiliations: 1 Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, 2 Department of Pathology, 3 Geoffrey Beene Translational Oncology, Sloan-Kettering Institute, Departments of 4 Epidemiology and Biostatistics, 5 Radiology, and 6 Radiation Oncology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). This study was presented, in part, at the 13 th World Conference on Lung Cancer, July 31 to August 4, 2009, San Francisco, CA, and the Chicago Multidisciplinary Symposium in Thoracic Oncology, December 9 to 11, 2010, Chicago, IL. Corresponding Author: M. Catherine Pietanza, Thoracic Oncology Ser- vice, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, NY 10065. Phone: 646-888-4203; Fax: 646-888-4262; E-mail: pietanzm@mskcc.org doi: 10.1158/1078-0432.CCR-11-2059 Ó2012 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 18(4) February 15, 2012 1138 on June 2, 2020. © 2012 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst January 6, 2012; DOI: 10.1158/1078-0432.CCR-11-2059