Abstract CT118: A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive & refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer

Abstract Background: Preclinical CRC models reveal KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019). MDSCs also accelerate metastases by ‘priming’ the premetastatic niche via promoting egress of tumors cells into the circulation, inhibiting killing by immune cells and promoting extravasation into the tissues (Veglia et al. Nature 2021). SX-682 is a novel oral small-molecule inhibitor of CXCR1/2 chemokine receptors involved in MDSC-recruitment to TME. This proof-of-concept study investigates whether a CXCR1/2 antagonist in combination with anti-PD-1 therapy can overcome de novo immunotherapy resistance in MSS RAS mutated mCRC and eradicate micrometastatic disease in ctDNA positive CRC post definitive therapy. Methods: STOPTRAFFIC-1 is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 plus nivolumab for patients (pts) with RAS mutated MSS mCRC or ctDNA positive CRC. Key eligibility criteria - Arm A: pts with MSS mCRC with progression or intolerance to 2 prior lines of therapy, ECOG 0/1; Arm B: ctDNA positive post completion of definitive therapy (adjuvant chemotherapy for stage III or metastasectomy for stage IV CRC). Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg PO twice daily) in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29. Adverse events per CTCAE v5.0. RECIST assessments every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to Cohort 5 is completed with expansion arms to open February 2023. Dose expansion is a Simon's optimal two-stage design for Arm A. Efficacy will be assessed in the first 15 pts with a requirement of 2 responses in order to enroll 14 additional pts (N=29). Pre- and on-treatment tissue biopsies will be collected. Arm B will enroll 15 pts with positive ctDNA post definitive therapy. Pts will be screened with CLIA certified ctDNA test for minimal residual disease (MRD) and if positive, enrolled for treatment for up to 6 months (m). Pts will undergo radiographic evaluation at 3 and 6m and then every 3-6m for at least 3 years. The primary objectives are to determine safety profile, recommended phase 2 dose, clinical activity & 6m ctDNA clearance rate in CRC pts with MRD following 6m of SX-682 + Nivolumab on Arm B. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140. Citation Format: Benny Johnson, Cara Haymaker, Van K. Morris, Arvind Dasari, Victoria Serpas Higbie, John Paul Shen, Christine Parseghian, Maria Pia Morelli, Ryan Huey, Michael S. Lee, Jason Willis, Kanwal P. Raghav, Ying Yuan, John Zebala, Ronald A. DePinho, Scott Kopetz, Michael Overman. A phase I/II trial of a CXCR1/2 inhibitor in combination with anti-PD-1 for circulating tumor DNA (ctDNA) positive & refractoryRAS-mutated microsatellite stable (MSS) colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT118.