Combination olaparib and temozolomide in relapsed small-cell lung cancer

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

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1372-1387
Number of pages16
JournalCancer discovery
Volume9
Issue number10
DOIs
StatePublished - Oct 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Farago, A. F., Yeap, B. Y., Stanzione, M., Hung, Y. P., Heist, R. S., Marcoux, J. P., Zhong, J., Rangachari, D., Barbie, D. A., Phat, S., Myers, D. T., Morris, R., Kem, M., Dubash, T. D., Kennedy, E. A., Digumarthy, S. R., Sequist, L. V., Hata, A. N., Maheswaran, S., ... Drapkin, B. J. (2019). Combination olaparib and temozolomide in relapsed small-cell lung cancer. Cancer discovery, 9(10), 1372-1387. https://doi.org/10.1158/2159-8290.CD-19-0582