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.

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 methyltransferase (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 = 0.08).

CONCLUSION:

Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC.

• Authors: M Catherine Pietanza, Kyuichi Kadota, Kety Huberman, Camelia S Sima, John J Fiore, Dyana K Sumner, William D Travis, Adriana Heguy, Michelle S Ginsberg, Andrei I Holodny, Timothy A Chan, Naiyer A Rizvi, Christopher G Azzoli, Gregory J Riely, Mark G Kris, Lee M Krug
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 4 Pg. 1138-45 (Feb 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22228633 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents, Alkylating
• Biomarkers, Tumor
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents, Alkylating (adverse effects, therapeutic use)
• Biomarkers, Tumor (genetics)
• DNA Methylation
• Dacarbazine (adverse effects, analogs & derivatives, therapeutic use)
• Female
• Humans
• Lung Neoplasms (drug therapy, genetics, mortality)
• Male
• Middle Aged
• O(6)-Methylguanine-DNA Methyltransferase (genetics)
• Promoter Regions, Genetic
• Recurrence
• Small Cell Lung Carcinoma (drug therapy, genetics, mortality)
• Survival Analysis
• Temozolomide
• Treatment Outcome