Background: About 35% of all NSCLC presents with locally advanced disease and chemo-radiation results in 5-year OS of only ~31%. PEM-platinum combination is approved in stage IV NSCLC and has similar efficacy to platinum-etoposide in stage 3 NSCLC and a favorable toxicity profile (Proclaim trial). TRC102 is an oral small molecule inhibitor of BER. TRC102 potentiates the cytotoxicity of antimetabolites and alkylators and reverses chemotherapy resistance by rapidly and covalently binding to chemotherapy-induced abasic sites in DNA. TRC102 increased radio-sensitization by PEM of NSCLC cell lines and H1299 and A549 xenografts. Methods: Between 11/2015 and 5/2019, 15 patients were enrolled in a 3+ 3 design: 12 with stage III and 3 with oligometastatic stage IV NS-NSCLC. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D) of TRC102 in combination with PEM, cisplatin and radiotherapy. Secondary objectives were to assess toxicity, tumor response and PFS at 6 months. Based on pre-clinical data, PEM-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated on day 21 and day 23 of the second cycle. After completion of radiotherapy, two additional cycles of PEM-cisplatin were given. Toxicities were assessed by NCI CTACAE version 4 and 5. Results: Median patient age was 69 years (45-79) and median follow up was 16.6 months (3.1-38.6). There were no DLTs or grade 5 toxicity. Hematologic and GI toxicities were the most common adverse events (Table) and radiation pneumonitis was not seen. The RP2D of TRC102 was 200 mg when given with cisplatin/radiotherapy and PEM. Of 15 evaluable patients, 3 had CR (20%) and 12 had PR (80%). The 2-year PFS rate was 49%. Conclusions: PEM-TRC102 combined with cisplatin/radiotherapy in non-squamous NSCLC was safe and well tolerated, and did not cause safety signals beyond those expected from CRT. Preliminary response data and PFS in this cohort was encouraging. A phase 2 trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen is warranted. Clinical trial information: NCT02535325