@article{a84b6d786a75487bb0161a32ed6d5614,
title = "Combination olaparib and temozolomide in relapsed small-cell lung cancer",
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.",
author = "Farago, {Anna F.} and Yeap, {Beow Y.} and Marcello Stanzione and Hung, {Yin P.} and Heist, {Rebecca S.} and Marcoux, {J. Paul} and Jun Zhong and Deepa Rangachari and Barbie, {David A.} and Sarah Phat and Myers, {David T.} and Robert Morris and Marina Kem and Dubash, {Taronish D.} and Kennedy, {Elizabeth A.} and Digumarthy, {Subba R.} and Sequist, {Lecia V.} and Hata, {Aaron N.} and Shyamala Maheswaran and Haber, {Daniel A.} and Lawrence, {Michael S.} and Shaw, {Alice T.} and Mari Mino-Kenudson and Dyson, {Nicholas J.} and Drapkin, {Benjamin J.}",
note = "Funding Information: and National Foundation for Cancer Research (to D.A. Haber), and a research agreement through the Novartis-MGH Alliance. Funding Information: We are grateful to the patients and families who participated in these research studies. We thank the members of the MGH thoracic oncology group and other MGH Cancer Center staff for assistance with recruitment of patients and collection of samples, and Edwin Choy for his guidance around initial protocol design. We thank I. Sanidas, A. Guarner-Peralta, B. Krishnan, P. Rumde, V. Kamesan, J. Grinnell, and current and former members of the Dyson and Farago research groups; and L. Zou, R. Corcoran, and C. Benes for critical discussions and scientific input. We thank Jeffrey Engelman for his vision and guidance in launching this project. This work has been supported by AstraZeneca (ISS22810111, to A.F. Farago), NCI grant U01CA220323-A1 (to N.J. Dyson and A.F. Farago) and U24CA213274 (to A.F. Farago), the V Foundation translational grant no. T2016-003 (to N.J. Dyson), NIH career development award K12CA087723 (to A.F. Farago), career development awards from Uniting Against Lung Cancer (to A.F. Farago) and the Lung Cancer Research Foundation (to B.J. Drapkin), the ASCO Young Investigator Award (to B.J. Drapkin), the research fellowship grant from the Deutsche Forschungsgemeinschaft (to M. Stanzione), NIH RO1 CA1299933 (to D.A. Haber), the Howard Hughes Medical Institute and National Foundation for Cancer Research (to D.A. Haber), and a research agreement through the Novartis-MGH Alliance. Funding Information: We are grateful to the patients and families who participated in these research studies. We thank the members of the MGH thoracic oncology group and other MGH Cancer Center staff for assistance with recruitment of patients and collection of samples, and Edwin Choy for his guidance around initial protocol design. We thank I. Sanidas, A. Guarner-Peralta, B. Krishnan, P. Rumde, V. Kamesan, J. Grinnell, and current and former members of the Dyson and Farago research groups; and L. Zou, R. Corcoran, and C. Benes for critical discussions and scientific input. We thank Jeffrey Engelman for his vision and guidance in launching this project. This work has been supported by AstraZeneca (ISS22810111, to A.F. Farago), NCI grant U01CA220323-A1 (to N.J. Dyson and A.F. Farago) and U24CA213274 (to A.F. Farago), the V Foundation translational grant no. T2016-003 (to N.J. Dyson), NIH career development award K12CA087723 (to A.F. Farago), career development awards from Uniting Against Lung Cancer (to A.F. Farago) and the Lung Cancer Research Foundation (to B.J. Drapkin), the ASCO Young Investigator Award (to B.J. Drapkin), the research fellowship grant from the Deutsche Forschungsgemeinschaft (to M. Stanzione), NIH RO1 CA1299933 (to D.A. Haber), the Howard Hughes Medical Institute Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
month = oct,
doi = "10.1158/2159-8290.CD-19-0582",
language = "English (US)",
volume = "9",
pages = "1372--1387",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}