2012 - A Phase 2 Randomized Study of the BER Inhibitor TRC102 in Combination with Standard Pemetrexed-Platinum-Radiation in Stage III Non-Squamous Non-Small Cell Lung Cancer (NCI 10512)

T. Biswas¹, D. Bruno², R. Dawar³, S. K. Jabbour⁴, J. Malhotra⁵, T. Burns⁶, N. Ohri⁷, T. Lycan⁸, S. Gore⁹, and A. Dowlati¹⁰; ¹Metro Health, Case Western Reserve University, Cleveland, OH, ²Department of Medical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, ³University of Miami, Miami, FL, ⁴Rutgers Cancer Institute of New Jersey, Department of Radiation Oncology, New Brunswick, NJ, ⁵City of Hope, Irvine, CA, ⁶UPMC Hillman Cancer Center, Pittsburgh, PA, ⁷Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, ⁸Department of Internal Medicine, Section of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, ⁹National Cancer Institute, Bethesda, MD, ¹⁰Department of Medical Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH

Purpose/Objective(s): Lung cancer is the leading cause of cancer related death both in the United States and Globally. Recently, addition of Immune Check point inhibitor Durvalumab following completion of chemo-radiation has shown significant improvement in both overall survival and progression free survival (PFS) at 5 years. However, still about 67% of the patients have progression of disease indication new strategies are required to improve the outcome further. Pemetrexed is a third generation antifolate chemotherapy that inhibits Thymidylate synthase and other enzymes in nucleotide synthesis pathway to cause cytotoxicity. Base Excision repair (BER) pathway gets activated via uracil DNA N-glycosylase enzyme (UNG) by creating AP sites which is believed to be an important mechanism to introduce resistance to Pemetrexed cytotoxicity. TRC102 is a small molecule inhibitor that inhibits BER pathway by blocking AP sites and restores cytotoxicity of pemetrexed. We published our Phase I study of combining TRC102 with Pemetrexed-Cisplatin (Pem-Cis) and Thoracic RT (TRT) in stage III and oligometastatic stage IV adenocarcinoma. There was no DLT of the combination and with promising efficacy with response and with 6 months PFS. Based on this result, CTEP approved a phase II randomized trial (NCI #10512) to compare the experimental combination with standard of care Cis-Pem-TRT arm in stage III Adenocarcinoma of lung followed by consolidative durvalumab for 1 year. Materials/

Methods: The LOI was approved by CTEP in 9/2021 with approval of the protocol in 5/2022 maintaining OWEG timeline. The study opened through ETCTN network in 8/2022. The study is a phase II randomized study (1:1) with the phase I combination as the experimental arm. The study drug TRC102 will be provided by CTEP. The primary objective is to improve 1-ar PFS from 56% with current SOC to 75% with the proposed combination. The secondary objectives are to determine OS with the experimental arm and to assess incidence of grade 3 or higher pneumonitis and other toxicities. The primary analysis will be performed using a stratified log-rank test (with the strata being the same as the randomization strata) with a one-sided significance level of 0.10.
Results: The 12-month PFS of NSCLC under chemo-radiation therapy followed by durvalumab (standard care) is about 56%. The target hazard ratio is 2.0, corresponding to a 12-month PFS of 75% for the proposed combination therapy with TRC102.
Conclusion: The study will collect pre-treatment biopsy specimen to test for UNG expression. The hypothesis is high level of UNG in the tumor causes resistance to Pem and addition of TRC102 will improve the efficacy of Pem. NCT05198830.