Abstract 3081: Precision medicine for patients with advanced small cell lung cancer treated with novel therapeutic agents in a phase I clinical trials unit
Authors: Lim Joline S. , Harris Samuel J. , Ameratunga Malaka , Sundar Raghav , Ang Joo Ern , Collins Dearbhaile , Chénard-Poirier Maxime , Garces Alvaro I. , Kaye Stan B. , Lopez Juanita , Banerji Udai , Bono Johann S. de , Yap Timothy A. 
Published: July 2017

Introduction Small cell lung cancer (SCLC) is aggressive and relapse is inevitable. Novel therapies in the context of phase I (Ph1) clinical trials should be considered in this setting. Next generation sequencing (NGS) identifying putative driver mutations may aid therapy allocation in such trial settings.

Methods Retrospective analysis of characteristics and clinical outcomes of patients (pts) with advanced SCLC referred to the Phase I Clinical Trials Drug Development Unit at the Royal Marsden Hospital between 1992 and 2016, using electronic patient records

Results 85 pts with advanced SCLC were included, of which 45 pts were allocated to ≥1 trial each (48 allocations). Of these, 21 (46.7%) pts started ≥1 trial, with a total of 24 trials commenced. Of the 64 pts who were unable to commence trials, 43 (67.2%) had rapid disease progression, 11 (17.2%) sought other therapies, 5 (7.8%) declined Ph1 trials, and 5 pts did not enrol for other reasons. Pts had a median of 2 previous lines of treatment (range:1-3). 13 pts had tumor molecular profiling with high coverage targeted NGS, yielding 22 distinct mutations; Aberrations in DNA damage repair (DDR) pathway were most common: TP53 (53.8%), FANC (30.8%), ATM (15.4%), ATR, BARD1 and CHEK2 (7.7% each). All pts found to have ≥1 DDR pathway mutation had platinum sensitive disease (disease progression ≥90 days from last platinum dose) in first line setting. Other mutations found include ALK, APC, AR, AXIN1, DDB2, ERBB2, mTOR, PI3K, NOTCH, NTRK17, PDGFR, RB1, RET, STK11, FKT3 and VGFR2. Pts were most commonly treated with novel inhibitors against PARP (n=9), PI3K/AKT (n=3), PD-1 (n=2) and BCL (n=2). Therapies were generally well tolerated with no dose limiting toxicities observed. Of 9 pts who received PARP inhibitors, 1 achieved a RECIST partial response (PR) and remained on trial for 16 weeks; 4 achieved RECIST stable disease (SD) for a median of 17 weeks (range:10.9-31.1 weeks). 1 exceptional responder whose tumor harbored multiple somatic aberrations (TP53, FANCF, AR, ERBB2, NOTCH2) was enrolled on 3 sequential phase I trials - she achieved durable RECIST SD on a PARP inhibitor (31.1 weeks), RECIST PR with a PD-1 inhibitor (38.7 weeks), and durable RECIST SD with carboplatin/ATR inhibitor (27.9 weeks). Platinum sensitivity in the first line setting predicted for improved disease control (RECIST PR/SD 73.3% vs 0%, p&lt;0.05) and longer duration on trial (14 vs 4 weeks, p&lt;0.05).

Discussion Novel therapeutic agents within the context of a dedicated Ph1 trials unit were well tolerated and led to preliminary signals of antitumor activity. Targeted NGS may aid in the identification of pts with putative gene aberrations, potentially predicting for response to novel therapies. Ph1 trials should be considered earlier in the pt's disease course to maximize their prospects of trial enrolment.

Citation Format: Joline S. Lim, Samuel J. Harris, Malaka Ameratunga, Raghav Sundar, Joo Ern Ang, Dearbhaile Collins, Maxime Chénard-Poirier, Alvaro I. Garces, Stan B. Kaye, Juanita Lopez, Udai Banerji, Johann S. de Bono, Timothy A. Yap. Precision medicine for patients with advanced small cell lung cancer treated with novel therapeutic agents in a phase I clinical trials unit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2017-3081