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Cancer Discov. 2019 Oct;9(10):1372-1387. doi: 10.1158/2159-8290.CD-19-0582. Epub 2019 Aug 15.

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer.

Author information

1
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. afarago@mgh.harvard.edu bjdrapkin@partners.org.
2
Dana-Farber Cancer Center, Boston, Massachusetts.
3
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
4
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
5
Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
6
Howard Hughes Medical Institute, Bethesda, Maryland.
7
Harvard Medical School, Boston, Massachusetts.

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy in which inhibitors of PARP have modest single-agent activity. We performed a phase I/II trial of combination olaparib tablets and temozolomide (OT) in patients with previously treated SCLC. We established a recommended phase II dose of olaparib 200 mg orally twice daily with temozolomide 75 mg/m2 daily, both on days 1 to 7 of a 21-day cycle, and expanded to a total of 50 patients. The confirmed overall response rate was 41.7% (20/48 evaluable); median progression-free survival was 4.2 months [95% confidence interval (CI), 2.8-5.7]; and median overall survival was 8.5 months (95% CI, 5.1-11.3). Patient-derived xenografts (PDX) from trial patients recapitulated clinical OT responses, enabling a 32-PDX coclinical trial. This revealed a correlation between low basal expression of inflammatory-response genes and cross-resistance to both OT and standard first-line chemotherapy (etoposide/platinum). These results demonstrate a promising new therapeutic strategy in SCLC and uncover a molecular signature of those tumors most likely to respond. SIGNIFICANCE: We demonstrate substantial clinical activity of combination olaparib/temozolomide in relapsed SCLC, revealing a promising new therapeutic strategy for this highly recalcitrant malignancy. Through an integrated coclinical trial in PDXs, we then identify a molecular signature predictive of response to OT, and describe the common molecular features of cross-resistant SCLC.See related commentary by Pacheco and Byers, p. 1340.This article is highlighted in the In This Issue feature, p. 1325.

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