Background: TRC102 binds to abasic sites in DNA, inhibiting the base excision repair (BER) pathway, which is implicated in resistance to alkylating agents. Preclinical xenograft studies in mice demonstrated a synergistic anti-tumor effect when TRC102 was combined with alkylating agents. TRC102 given in combination with temozolomide in a phase 1 trial demonstrated acceptable toxicity and antitumor activity in patients (pts) with colorectal cancer (CRC), non-small cell lung cancer (NSCLC, squamous cell carcinoma) and granulosa cell ovarian cancer (Oncotarget 2020). Pharmacodynamic (PD) analysis revealed treatment-induced induction of nuclear Rad51 signal, indicating DNA damage repair (DDR) response and tumor biopsy data indicated MGMT methylation correlated with tumor response in CRC (Cancer Cell, 2020). Here we report data from a phase II expansion cohort of this combination in pts with NSCLC. Methods: We conducted a single arm open label trial in a pt cohort with advanced NSCLS, who had received at least one line of therapy in the metastatic setting. Pts who received immunotherapy (ICI) and/or molecularly targeted therapy were eligible. Pts received 125 mg TRC102 (100 mg for BSA < 1.6) and 150 mg/m2 TMZ given orally daily for days 1-5 of 28-day cycle (C). Restaging CT scans were carried out after every 2 C and evaluated using RECIST 1.1. Blood from all pts was analyzed for circulating tumor cells (CTCs) at baseline and the beginning of each C. A two-stage design was employed, with at least 2 objective responses needed among the first 16 pts treated on study in order to proceed to the second stage. Results: Sixteen pts with NSCLC (12 adenocarcinoma, 4 squamous) were enrolled between 11/2016 and 6/2021; 12 men and 4 women, median age of 69 yrs (range 33-80), 1 Hispanic, 3 Asian, 2 Black/African American, and 10 Caucasian. Pts received a median of 3 prior lines of therapy (range 1-7), including ICI in all but 1 pt. Twelve pts were evaluable for response. Three pts experienced clinical progression before completing C 2, and 1 pt withdrew consent before completing C 2. Median number of Cs received by pts was 3 (range 1-14); 9 pts experience stable disease (SD) as best response lasting median of 12 wks (range 8-56 wks), and 4 pts experienced prolonged SD lasting greater than 6 Cs (24 wks). Treatment-related grade 3 adverse events reported include lymphopenia (4) and anemia (1). No grade 4 or 5 events were noted. Conclusion: TRC102 in combination with temozolomide was well tolerated with notable efficacy. Although no objective tumor responses were observed in this heavily pretreated population, 9 of 15 pts experienced SD, lasting ≥ 24 wks in 4 pts. Given the limited options for NSCLC treatment following ICI and TKI treatment, this regimen merits further evaluation. Analysis of CTCs is ongoing, as well as additional biomarker evaluation in other treatment cohorts. Funded by NCI Contract No. HHSN261200800001E

Citation Format: Mohamad A. Salkeni, Geraldine O’Sullivan Coyne, Jennifer Zlott, Naoko Takebe, Ning Ma, Larry Rubinstein, Richard Piekarz, Jared Foster, Brandon Miller, Ralph Parchment, Abdul R. Naqash, Andrea Voth, James Doroshow, Alice Chen. Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with advanced non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P049.