Adding Base Excision Repair Inhibitor TRC102 to standard Pemetrexed-Platinum-Radiation in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Results of a phase I trial.

Background: TRC102, a small molecule base excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a Phase I clinical trial combining pemetrexed and TRC102 with cisplatin-radiation in stage III NS-NSCLC. Methods: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the DLT and MTD of TRC102 in combination with pemetrexed, cisplatin and radiotherapy. Secondary objectives were to assess toxicity, tumor response and PFS at 6 months. Based on our pre-clinical experiments, pemetrexed-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, 2 additional cycles of pemetrexed-cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5. Results: The median age was 69 years (45-79) with the median follow up of 25.7 months (range: 7.9, 47.4). No DLTs and no grade 5 toxicity were seen. Hematologic and GI toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, 3 had CR (20%) and 12 had PR (80%). The 6-month PFS was 80% and 2- year OS was 83%. Conclusion: Pemetrexed-TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is chosen to be 200 mg TRC102 along with cisplatin-pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A Phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen is warranted.