Abstract CT198: Expansion of Phase I/II study of olaparib and temozolomide in patients with relapsed small cell lung cancer (SCLC) and co-clinical trial in patient-derived xenografts (PDXs) for biomarker discovery
Authors: Farago Anna F. , Yeap Beow , Hung Yin P. , Stanzione Marcello , Zhong Jun , Phat Sarah , Myers David T. , Morris Robert , Kem Marina , Rangachari Deepa , Barbie David , Digumarthy Subba R. , Sequist Lecia V. , Hata Aaron N. , Mino-Kenudson Mari , Shaw Alice T. , Dyson Nicholas , Drapkin Benjamin J. 
Published: August 2019

Abstract
Background: SCLC is an aggressive high-grade neuroendocrine malignancy. While SCLC is often highly sensitive to first line etoposide/platinum (EP), response rates to second line cytotoxic chemotherapy range ~10-30%. Inhibition of poly(ADP-ribose) polymerase (PARP) by olaparib (O) has shown activity in SCLC in preclinical studies, and may synergize with the alkylating agent temozolomide (T). We previously reported a confirmed objective response rate (ORR) of 34.5% among an initial 30-patient SCLC cohort treated with combination OT in a Phase I/II trial (Farago et al., ASCO 2018). Here we provide analysis after further expansion to a total of 50 patients (pts).
Methods: Eligibility criteria included histologically/cytologically confirmed incurable SCLC which had progressed following ≥ 1 platinum-based chemotherapy. O (tablet formulation) and T were administered orally on days 1-7 of 21-day cycles, with a recommended phase 2 dose (RP2D) of O 200 mg BID and T 75 mg/m2 QD. Response assessments were performed every 6 weeks. The primary endpoint was objective response rate (ORR). PDXs were generated from a subset of patients prior to OT and at progression, and OT and EP activity were assessed in vivo in a panel of 32 PDXs in a co-clinical trial. Whole transcriptome expression analysis using RNA sequencing was performed in 31 models to identify candidate biomarkers of sensitivity and resistance, and lead candidates were further interrogated using immunoblotting and immunohistochemistry.
Results: Among 50 enrolled pts, the median (m) age was 63 (range 39-85), m number of prior therapies was 2 (range 1-7), 40% were male, and 72% were platinum sensitive. The confirmed ORR was 41.7%. After a m follow up of 7.1 months (mo) among 22 surviving patients, the m progression-free survival (PFS) was 4.2 mo, m overall survival (OS) was 8.5 mo, and m duration of response (DoR) was 4.3 mo. The ORR among platinum-sensitive and platinum-resistant pts was 47.1% and 28.6%, respectively, with no significant differences in mPFS, mOS or mDOR. The most common grade 3/4 treatment related adverse events were neutropenia (38%), anemia (28%) and thrombocytopenia (26%). Among 41 pts treated at the RP2D, dose reductions occurred in 44% overall and 64% of those who received at least 3 cycles. OT activity was further assessed in SCLC PDXs. The efficacy of OT in PDXs derived from 4 patients on the trial mirrored that seen in the patients. Across a panel of 32 PDXs, sensitivity to OT only modestly correlated with sensitivity to EP (Pearson r=0.50 for best response and r=0.48 for time to progression). Candidate biomarkers for sensitivity and resistance to OT were identified in PDX models and validated in patient samples, and will be presented.
Conclusions: OT is shows promising clinical activity in relapsed SCLC. A co-clinical trial in PDXs provides a powerful platform for assessment of cross-resistance to other therapies and identification of clinically relevant biomarkers. Clinical trials identifier NCT02446704.
Citation Format: Anna F. Farago, Beow Yeap, Yin P. Hung, Marcello Stanzione, Jun Zhong, Sarah Phat, David T. Myers, Robert Morris, Marina Kem, Deepa Rangachari, David Barbie, Subba R. Digumarthy, Lecia V. Sequist, Aaron N. Hata, Mari Mino-Kenudson, Alice T. Shaw, Nicholas Dyson, Benjamin J. Drapkin. Expansion of Phase I/II study of olaparib and temozolomide in patients with relapsed small cell lung cancer (SCLC) and co-clinical trial in patient-derived xenografts (PDXs) for biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT198.