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Background: CD200R1 was identified as a promising immuno-oncology (IO) target from the 23andMe database. Pleiotropic causal variants with opposing effect on risks for cancer and immune diseases, referred to as an IO signature, were observed in 3 components of the CD200R1 pathway. 23ME-00610 is a first-in-class monoclonal antibody that potently inhibits the CD200R1 immune checkpoint (KD less than 0.1 nM). The dose escalation portion of the first-in-human, Phase 1/2a study of 23ME-00610 (NCT05199272) has been completed and we are reporting data for the first time. Methods: Eligible patients were alteast 18 years with histologically diagnosed locally advanced (unresectable), or metastatic carcinoma or sarcoma who have progressed on standard therapies with ECOG 0 or 1. Key exclusion criteria included active autoimmune disease requiring immunosuppressive therapy and Grade 3 or above immune-mediated toxicity related to prior immunotherapy that led to discontinuation. Dose escalation consisted of accelerated titration (2 and 6 mg) followed by a 3+3 design (20, 60, 200, 600 and 1400 mg). Up to 12 participants were included in a PKPD backfill cohort at the recommended phase 2 dose (RP2D) or a previously evaluated dose level. Participants received 23ME-00610 intravenously every 3 weeks (Q3W) infused over 30 minutes. The primary objectives of Phase 1 were determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and tolerability. Key secondary and exploratory objectives included pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of 23ME-00610. Results: Between January 5th, 2022 and November 28, 2022, 21 participants (11/10 male/female; age range: 21-80 years) were enrolled and received ≥ 1 dose of 23ME-00610 across the 2 to 1400 mg cohorts (median duration of exposure: 50 days; range:1-231 days). No dose limiting toxicities, treatment related serious adverse events (TRSAEs) or AEs leading to discontinuation were observed. 14/21 (67%) participants experienced atleast 1 TRAE; the majority were Grade 1 or 2. The most commonly reported TRAEs occurring in atleast 2 participants across all dose levels were headache, fatigue, nausea and pruritis. There was 1 Grade 3 TRAE of increased blood creatinine phosphokinase. Investigator-assessed immune-related AEs including hypothyroidism, pruritis, fatigue and chills were observed at doses 60 mg and above. The PK of 23ME-00610 were dose-proportional at doses 60 mg and above, with a median terminal half-life of ~12 days at 1400 mg. Peripheral saturation of CD200R1 was observed at doses 60 mg and above, as measured by receptor occupancy on T cells and neutrophils, and levels of free soluble CD200R1. Analysis of additional PD data, including cytokines, is ongoing. Conclusion: 23ME-00610 demonstrated an acceptable safety and tolerability profile, with favorable PK and peripheral CD200R1 saturation. Increased immune-related AEs were observed at higher, pharmacologically relevant dose levels. Based on Phase 1 data, 1400 mg 23ME-00610 Q3W will be evaluated in Phase 2a. Citation Format: Shivaani Kummar, Albiruni ABDUL RAZAK, Scott Laurie, Sariah Kell, Dylan Glatt, Sophia R. Majeed, Drew Rasco. First-in-class anti-CD200R1 antibody 23ME-00610 in patients with advanced solid malignancies: Phase 1 results [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 CT174.

Introduction: Analyses of circulating tumor DNA (ctDNA) have shown promise in capturing tumor burden dynamics during immune checkpoint blockade (ICB), with the potential to allow patients with primary resistance to be rapidly identified and redirected to alternative therapies. Methods: BR.36 is an international multicenter, open label, biomarker-directed, phase II trial of molecular response-adaptive immuno-chemotherapy for patients with treatment-naïve non-small cell lung cancer-NSCLC (NCT04093167). The trial consists of two stages; stage 1 was a single-arm study to validate the ctDNA approach, with stage 2 focusing on ctDNA guided treatment selection. Key eligibility criteria included EGFR and ALK mutation negative, ICB and chemotherapy-naïve metastatic NSCLC with PD-L1 expression ≥1%. Primary objectives were to ascertain ctDNA molecular response, determine its timing and concordance with radiologic RECIST/iRECIST response. Secondary objectives included the evaluation of time to ctDNA molecular response and its correlation with progression-free (PFS) and overall survival (OS). Liquid biopsy analyses utilized a validated tumor-agnostic white blood cell (WBC) DNA-informed 33-gene panel approach. Ultra-sensitive error-correction ctDNA next-generation sequencing (NGS) was performed at baseline/cycle 1 (C1D1), cycle 2 (C2D1) and cycle 3 (C3D1) of pembrolizumab (200mg IV q3 weeks). The maximum variant allele fraction (maxVAF) of tumor-derived variants was tracked from the pre-treatment to on-therapy timepoints. Results: Activated October 17, 2019, stage 1 completed accrual of 50 patients on April 5, 2022; data lock date was September 20, 2022. Most patients were ever-smokers (98%), had no prior systemic therapy (92%), stage IV NSCLC (98%), adenocarcinoma (76%) with PD-L1 tumor proportion score of ≥ 50% (96%); cohort consisted of 82% white, 52% female, 56% age>65 and 76% ECOG PS 1 participants. Median follow-up was 13.5 months (range 2.5-23.0). Best overall response rate (ORR) by RECIST was 32% with a median duration of 10.1 months. Matched WBC DNA analyses allowed for effective removal of germline and clonal hematopoiesis variants, followed by evaluation of ctDNA response. MaxVAF clearance signified molecular response (mR), while maxVAF persistence indicated molecular disease progression (mPD). Among 35 evaluable patients (77.8%), 15 were classified in the mR category, with an evaluable mR rate of 43% (90% CI: 0.29-0.58). The median time to molecular response was 2.1 months (90% CI: 1.5-2.6). The sensitivity of ctDNA molecular response for RECIST and iRECIST response was 82% (90% CI: 52%-97%) and 83% (90% CI: 56%-97%), with a specificity of 75% (90% CI: 56.5%-88.5%) and 78% (90% CI: 60%-91%) respectively. Patients with mR attained longer PFS (5.03 vs 2.6 months,) and OS (not reached vs 7.23 months); ctDNA response also provided prognostic information for patients with RECIST stable disease. Conclusions: ctDNA molecular responses were concordant with radiologic response assessments, but importantly better predicted PFS and OS for patients with stable disease or better. These findings are now incorporated into the interventional second stage of the trial. Citation Format: Valsamo K. Anagnostou, Cheryl Ho, Garth Nicholas, Rosalyn Anne Juergens, Adrian Sacher, Andrea Fung, Paul Wheatley-Price, Scott Laurie, Benjamin Levy, Julie Brahmer, Archana Balan, Noushin Niknafs, Egor Avrutin, Liting Zhu, Mark Sausen, Penelope Bradbury, Jill O'Donnell-Tormey, Pierre-Olivier Gaudreau, Keyue Ding, Janet Dancey. A ctDNA-directed, multi-center phase II study of molecular response adaptive immuno-chemotherapy in patients with non-small cell lung cancer: Analysis of Stage 1 of CCTG BR.36 [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 CT212.