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- W2969185256 abstract "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" @default.
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- W2969185256 date "2019-10-01" @default.
- W2969185256 modified "2023-10-18" @default.
- W2969185256 title "Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer" @default.
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- W2969185256 doi "https://doi.org/10.1158/2159-8290.cd-19-0582" @default.
- W2969185256 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7319046" @default.
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