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Background: Standard treatment of localized muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC); however, only 40-50% respond to NAC and approx. 50% experience relapse. Evaluation of treatment efficacy and early detection of relapse are therefore major clinical challenges. Methods: We present a clinical update of a previously described cohort of 68 patients who received NAC prior to RC (NAC cohort; Christensen et al. JCO 2019; median follow-up (FU) of 58 months) together with evaluation of a retrospectively collected cohort of 120 patients who did not receive NAC (no-NAC cohort; median FU of 71 months). Circulating tumor DNA (ctDNA) was analyzed before NAC (NAC cohort, n=63), prior to RC (NAC cohort, n=67; no-NAC cohort, n=115) and after RC (NAC cohort, n=66; no-NAC cohort, n=37) using Signatera™. RNA-seq was performed on 176 tumors. Results: Updated clinical FU for the NAC cohort showed that ctDNA-positive patients had significantly worse recurrence-free survival (RFS) compared to ctDNA-negative patients (before NAC: HR=16, 95%CI=3.6-70.5, p=0.0002; during surveillance after RC: HR=27.6, 95%CI=7.9-96.9, p Conclusion: Presence of ctDNA was associated with worse prognosis for both NAC and no-NAC treated patients. Transcriptomic analysis of primary tumors showed that anti-tumor immune responses may be associated with a particularly good outcome whereas EMT may be promoting more aggressive disease. Citation Format: Sia Viborg Lindskrog, George Laliotis, Karin Birkenkamp-Demtröder, Iver Nordentoft, Philippe Lamy, Elshaddai Z. White, Natalia Pajak, Tine G. Andreasen, Punashi Dutta, Meenakshi Malhotra, Shruti Sharma, Mark Calhoun, Adam ElNaggar, Minetta C. Liu, Mads Agerbæk, Jørgen B. Jensen, Lars Dyrskjøt. Utility of circulating tumor DNA and transcriptomic profiling in predicting outcome in muscle invasive bladder cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5600.

Background: A high unmet medical need exists for the treatment of patients who are unresponsive to or relapse following treatment with checkpoint inhibitors. Therefore, novel checkpoint inhibitors that can demonstrate clinical activity in this patient population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis. In nonclinical experiments using in vitro and animal models we have demonstrated that inhibition of PVRIG leads to enhanced activation of T and NK cells, and that knockout of PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with advanced solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Dose-limiting toxicities will be assessed within 21 days in cycle 1 of administration of COM701. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Single subject dose cohorts in initial 4 dose cohorts and 3+3 study design for subsequent cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission no DLTs have been reported in the initial 4 dose cohorts. Enrollment in cohort 5 is ongoing. Citation Format: Dan Vaena, Amita Patnaik, Erika Hamilton, Judy Olweny, John Hunter, Adeboye Henry Adewoye, Adam ElNaggar, Drew Rasco. Phase I study of COM701 (a novel checkpoint inhibitor of PVRIG) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT168.