Details

Autor(en) / Beteiligte

• Farago, Anna F
• Yeap, Beow Y
• Stanzione, Marcello
• Hung, Yin P
• Heist, Rebecca S
• Marcoux, J Paul
• Zhong, Jun
• Rangachari, Deepa
• Barbie, David A
• Phat, Sarah
• Myers, David T
• Morris, Robert
• Kem, Marina
• Dubash, Taronish D
• Kennedy, Elizabeth A
• Digumarthy, Subba R
• Sequist, Lecia V
• Hata, Aaron N
• Maheswaran, Shyamala
• Haber, Daniel A
• Lawrence, Michael S
• Shaw, Alice T
• Mino-Kenudson, Mari
• Dyson, Nicholas J
• Drapkin, Benjamin J

Titel

Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer

Ist Teil von

• Cancer discovery, 2019-10, Vol.9 (10), p.1372-1387

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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/m 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. . .