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3025 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for pts with unresectable or metastatic HER2+ BC with ≥2 prior anti-HER2–based therapies. T-DXd showed improved progression-free survival vs trastuzumab emtansine (T-DM1) as an earlier-line treatment (tx) for pts with HER2+ metastatic BC in the phase 3 DESTINY-Breast03 trial (Cortes J, et al. Ann Oncol. 2021;32:S1283-S1346. Abstract LBA1). Preliminary antitumor activity of T-DXd was shown in heavily pretreated pts with HER2-low advanced/metastatic BC in the phase 1 DS8201-A-J101 trial (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). We report preliminary results from the dose-finding phase of 2 trials investigating T-DXd combination tx in HER2+ or HER2-low metastatic BC. Methods: DB-07 (phase 1b/2; NCT04538742) and DB-08 (phase 1b; NCT04556773) are 2-part, modular, open-label, multicenter trials of T-DXd combined with other anticancer tx in pts with advanced/metastatic BC that is HER2+ (DB-07) or HER2 low (DB-08). Part 1 of each study is an ongoing dose-finding phase; pts must have ≥1 prior tx for metastatic BC. Part 2 of each study is a dose-expansion phase; pts must have no (DB-07) or ≤1 (DB-08) prior tx for metastatic BC. We report preliminary results from the T-DXd + pertuzumab module of DB-07 part 1 (data cutoff: Oct 15, 2021) and T-DXd + anastrozole and T-DXd + fulvestrant modules of DB-08 part 1 (data cutoff: Sep 27, 2021); pts in the DB-08 modules must be hormone receptor positive. The part 1 primary objective was to assess safety and tolerability and determine the recommended phase 2 dose (RP2D) according to the modified toxicity probability interval-2 algorithm. Pts were followed up beyond the 21-day dose-limiting toxicity (DLT) period (28 days for T-DXd + fulvestrant) for safety events. Results: In DB-07, 7 pts were enrolled and received T-DXd 5.4 mg/kg + pertuzumab 420 mg (loading dose: 840 mg) every 3 wk (q3w; not evaluable for DLTs, n = 1). In DB-08, 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + anastrozole 1 mg daily (not evaluable for DLTs, n = 1); another 6 pts were enrolled and received T-DXd 5.4 mg/kg q3w + fulvestrant 500 mg every 4 wk (loading dose: 500 mg cycle 1 days 1 and 15). For all 3 modules, no DLTs were reported in any DLT-evaluable pts; the dose levels used in part 1 were approved to be the RP2Ds for use in the dose-expansion part of each corresponding module. No deaths on study or cases of interstitial lung disease/pneumonitis were reported to date. Conclusions: The RP2Ds for the T-DXd combinations were the standard doses for BC of each individual drug. These studies are ongoing, with additional T-DXd combinations being evaluated and further follow-up underway. Clinical trial information: NCT04538742; NCT04556773.

Background CD73, an ecto-5’-nucleotidase involved in ATP metabolism, converts AMP into adenosine. ATP could induce production of interferon-beta1, which induces cellular resistance to viral infection and triggers apoptosis of virus-infected cells.2 In COVID-19, SARS-CoV-2 causes severe respiratory syndrome by effectively inhibiting interferon activity,3 4 leading to impaired anti-viral response. Moreover, lung injury seen in severe COVID-19 patients might be caused by excess adenosine.5 Inhibition of CD73 is believed to increase extracellular ATP, thereby countering COVID-19. Furthermore, independent of its inhibitory effects on CD73, preclinical results from other anti-CD73 mAb suggested CD73 blockade activates lymphocytes, induced antibody production from B cells and enhanced lymphocyte trafficking,6 thereby, stimulated the production of anti-SARS-CoV-2 antibodies leading to the rapid clearance of the virus.7 We developed AK119, a humanized monoclonal antibody targeting CD73, as an immunotherapy agent for the treatment of COVID-19. Methods Evaluation of AK119 activity to bind to the CD73 antigen was performed by using ELISA, Fortebio, and FACS assay. The activity of AK119 to inhibit enzymatic activity of CD73 was evaluated by cell-based enzyme assay; and the activity of AK119 to induce internalization of CD73 and enhance CD69 and CD83 expression on B cell were performed by using FACS assays. We also investigated the potential of AK119 to promote immunoglobulin production from human B cells. Results AK119 could effectively bind to human CD73 with high affinity, which is comparable or superior to 10.3AA, a leading anti-CD73 antibody, in protein-based assays. AK119 inhibited CD73 enzymatic activity on MDA-MB-231 cells (IC50_AK119, 27.60 nM; IC50_10.3AA, 15.99 nM) and U87-MG cells (IC50_AK119, 0.2448 nM; IC50_10.3AA, 0.0691 nM), with a higher maximal inhibition rates of 108.26% in MDA-MB-231 cells and 96.24% in U87-MG cells compared with 10.3AA (77.02% and 75.77%, respectively). AK119 effectively induced CD73 internalization in MDA-MB-231 cells and U87-MG cells, and the internalization rate of CD73 was 60.75% and 82.39%, respectively; for 10.3AA, the internalization rate was 50.53% and 73.65%, respectively. Moreover, AK119 could stimulate approximately 4–5 fold up-regulation of CD69 (figure 1A) and CD83 (figure 1B) that are markers of B cell activation; and, AK119 significantly promoted IgG production from B cells. Conclusions In summary, in comparison to a leading CD73 antibody currently in clinical trial, AK119 demonstrated more complete CD73 inhibition; and more dramatic B cell activation and antibody production. Thus, A119 presented desirable preclinical bioactivities. The safety and pharmacokinetics of single ascending doses of AK119 will be evaluated in healthy volunteers in an upcoming Phase 1, First-in-Human study (NCT04516564). Trial Registration NCT04516564 References Zhang C, He H, Wang L, et al. Virus-Triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. J Immunol 2017;199:1372–1381. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014;32:513–545. Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718–724. Yuen CK, Lam JY, Wong WM, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect 2020;9:1418–1428. Hoogendijk AJ, Pinhancos SS, van der Poll T, Wieland CW. AMP-activated protein kinase activation by 5-aminoimidazole-4-carbox-amide-1-β-D-ribofuranoside (AICAR) reduces lipoteichoic acid-induced lung inflammation. J Biol Chem 2013;288:7047–7052. Luke, Jason J., et al. Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers. J Clin Oncol 2019;37: suppl 2505–2505. Corvus Pharmaceuticals, Inc. Corvus Pharmaceuticals Provides Business Update and Reports Second Quarter 2020 Financial Results. 30 July 2020. [https://corvuspharma.gcs-web.com/news-releases/news-release-details/corvus-pharmaceuticals-provides-business-update-and-reports-4].