Combination Olaparib and Temozolomide in Relapsed Small-Cell Lung Cancer

• Published in: Cancer discovery 2019-10, Vol.9 (10), p.1372-1387
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-19-0582

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. . .