Background: Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease characterized by hemolysis mediated by autoantibodies directed against red blood cells (RBC). AIHA is classified as either warm (60-70%), or cold agglutinin disease (CAD, 20-25%), depending upon the temperature at which the autoantibodies show maximum binding. Warm AIHA is mediated by warm reactive autoantibodies, which are usually of the immunoglobulin G class (IgG). Almost 90% of CAD is medicated by monoclonal antibodies of IgM class. The diagnosis of wAIHA or CAD is based on the presence of hemolytic anemia, signs of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. Complement plays an important role in warm antibody AIHA. When erythrocytes are heavily coated with immunoglobulin, the amount of antigen-antibody complex can be sufficient for binding complement protein complex C1, thereby activating the classical complement pathway. CAD is almost entirely a complement-dependent disorder. Cold antibodies (IgM) temporarily bind to the RBC membrane, activate complement, and deposit complement factor C3 on the cell surface. These C3-coated RBCs are cleared slowly by the macrophages of the liver through extravascular hemolysis. Less frequently, the complete complement cascade is activated on the cell surface, resulting in the insertion of membrane attack complex C5b to C9 and intravascular hemolysis. Therefore, treatment with inhibitors of complement cascade may halt or at least attenuate acute complement mediated hemolysis in AIHA patients and improve recovery of RBC destruction. Aims: This Phase 2, open-label study is being conducted in the US and Italy to assess the safety, tolerability, efficacy, and PK of multiple subcutaneous (SC) doses of APL-2 administered daily in subjects with wAIHA or CAD. Methods: Patients with primary AIHA are eligible. Patients are required to have hemoglobin (Hb) levels <11 g/L, signs and symptoms of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. The study will recruit 12 subjects with wAIHA and 12 subjects with CAD. APL-2 270 mg/d or 360 mg/d will be administered for 48 weeks. Efficacy is assessed by change from baseline in Hb, transfusion requirements, reticulocytes, lactate dehydrogenase (LDH), haptoglobin, bilirubin, and FACIT fatigue score. Endpoints will be assessed at Weeks 8, 12, 44, and 48. Results: 2 subjects with CAD (Subject 1: 270 mg/d; Subject 2: 360 mg/d) have been treated for at least 8 weeks and up to 12 weeks; 2 subjects with wAIHA (Subject 3: 270 mg/d; Subject 4: 360 mg/d) have been treated for at least 4 weeks. Subject 1 screened with Hb (NR 13.5 g/dL-17.5g/dL) of 10.0 g/dL and reported an increase to 13.0 g/dL at Week 12, with reticulocyte (NR 30-100 10^9/L) reduction from 99.6 10^9/L at Week 2 to 56.34 10^9/L at Week 8 (screening/baseline values not available). Subject 2 had baseline Hb of 7.9 g/dL and reported an increase to 13.6 g/dL at Week 8, with reticulocyte reduction from 154.34 10^9/L at baseline to 67 10^9/L at Week 8. Subject 3 had baseline Hb of 8.0 g/dL and reported an increase to 11.2 g/dL at Week 4, with reticulocyte reduction from 223.44 10^9/L at baseline to 27.12 10^9/L at Week 4. Subject 4 did not show signs of haematological improvement by Week 4, and the principal investigator decided to discontinue the subject at Day 42. Subject 1 had LDH levels within the normal range (100-200 I/U) at screening and remained normal through the study. Subjects 2 reported a baseline LDH of 339 I/U with a reduction to within NR to 107 I/U at Week 8. Subject 3 reported a baseline LDH of 235 I/U, which was also reduced to within NR at Week 4 to 123 I/U. Subject 1 had consistent indirect bilirubin (NR 0.2-0.7 mg/dL) through the study with a baseline value of 1.5 mg/dL and a Week 12 value of 1.4 mg/dL. Subject 2 had a reduction in indirect bilirubin with a baseline value of 1.3 mg/dL and a Week 8 value of 0.5 mg/dL.To date, APL-2 has generally been well-tolerated. No significant infections have been observed. Summary/Conclusions: Interim results demonstrate that systemic inhibition of C3 with APL-2 has demonstrated positive trends in haematological parameters in patients with wAIHA and CAD as early as Week 4. To date, APL-2 has been safe and well tolerated. The study is ongoing and will enroll up to 12 subjects with wAIHA and 12 subjects with CAD. Disclosures Grossi: Apellis Pharmaceuticals: Employment, Equity Ownership. Gertz:spectrum: Consultancy, Honoraria; Medscape: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Apellis: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; janssen: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; celgene: Consultancy; Abbvie: Consultancy; annexon: Consultancy. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Stout:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Jotte has received honoraria, served on a speakers' bureau, and received travel accommodations from Bristol-Myers Squibb and Roche/Genentech. Dr. Nemunaitis is an employee of Gradalis with stock and ownership interests and patents, royalties, and other intellectual properties; has received honoraria from AstraZeneca, served as a consultant with Symvivo, served on the speakers' bureau for AstraZeneca; and provided expert testimony for Foundation Medicine. Dr. Schneider has received honoraria from Foundation Medicine and has stock and/or other ownership interests in Arvinas, Bristol-Myers Squibb, GlaxoSmithKline, Mirati Therapeutics, Novartis Pharma SAS, and Pfizer Pharmaceuticals Israel. Dr. Goldschmidt has served on a speakers' bureau for Bristol-Myers Squibb and served as a consultant for Amgen. Dr. Berz has received honoraria from AstraZeneca, Genentech, Sun Pharma, and Tempus and served on the speakers' bureau for AstraZeneca, Biocept, Boehringer Ingelheim, Caris Life Sciences, Genentech, Natera, Novartis, Sun Pharma, and Tempus. Dr. Seneviratne has served as a consultant and on the speakers' bureau for and received travel accommodations from Novartis Pharmaceuticals UK Ltd. Dr. Socoteanu is an employee of Texas Oncology and has received institutional research funding from AstraZeneca, Bristol-Myers Squibb, Genentech, Eli Lilly and Company, Merck, and Seattle Genetics. Dr. Konduri has served as a consultant for and received travel accommodations from AstraZeneca, Boehr, and Takeda. Drs. Xia, Wang, Hozak, Gueorguieva, Ferry, and Chao are employees of Eli Lilly and Company with stock and ownership interests. Dr. Gandhi was employed by Eli Lilly and Company with stock and ownership interests during the conduct of the study and received consulting fees from Verseau Therapeutics. Dr. Rybkin has served as a consultant for AstraZeneca. The remaining authors declare no conflict of interest.

TPS9129 Background: Despite significant advances in chemotherapy and immunotherapy for advanced NSCLC, the majority of pts ultimately develop progressive disease associated with poor outcomes. KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cell growth and proliferation. KRASG12C mutations occur in 14% of NSCLC (adenocarcinoma), and mutations in KRAS are associated with a poor prognosis. Although KRAS has historically been undruggable, recent research into the development of agents that specifically bind mutant KRAS has led to the development of direct inhibitors of KRASG12C. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to and locks KRASG12C in its inactive state. Adagrasib was optimized for favorable pharmacokinetic (PK) properties, including oral bioavailability, long half-life (̃24 h), and extensive tissue distribution. Initial results have demonstrated encouraging antitumor activity and tolerability of adagrasib monotherapy in pts with NSCLC harboring a KRASG12C mutation. Methods: KRYSTAL-12 is a multicenter, randomized Phase 3 study evaluating the efficacy of adagrasib (600 mg BID) vs docetaxel in pts with advanced NSCLC harboring a KRASG12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study is designed to demonstrate improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS). Secondary endpoints include safety, objective response rate (ORR) per RECIST 1.1, duration of response (DOR), plasma PK parameters of adagrasib, and patient-reported outcomes (PROs). The study will also explore correlations between gene alterations (at baseline and upon development of treatment resistance) and efficacy. Approximately 450 patients will be randomized in a 2:1 ratio to receive adagrasib or docetaxel and will be stratified by region (United States/Canada vs other countries) and sequential vs concurrent administration of prior platinum-based chemotherapy and anti–PD-1/PD-L1 antibody. The planned sample size is sufficiently powered for the hypothesized treatment effect of the endpoints. Pts will receive study treatment until disease progression, unacceptable adverse events, investigator decision to terminate treatment, or patient withdrawal. This study is currently enrolling and will be open at sites in the United States, Europe, and Asia. Clinical trial information: NCT04685135.

cyclophosphamide on D-1. On D0 the CAR groups received 1.5-2x10 6 CAR T cells with aPDL1 continuing until W12. Mice were bled every two weeks starting D+7 from CAR T cells to assess CLL load, CAR/T cell subsets and groups were culled together when they got sick or peripheral blood (PB) CLL>70%. Results: Compared to WT CAR T cells, AT CAR T cells proliferate less in culture, skew towards CD8 cells, exhibit significantly lower transduction efficiencies in CD8 cells and have higher expression of PD1 + in both CD4 and CD8 cells. All mice treated with CAR T cells cleared their CLL and normal B cells at D+7, and those mice treated with WT CAR T cells all remained in remission until W18, whereas 50-60% of mice treated with AT CAR T cells slowly relapsed from D+21. Spleen weights in WT CAR treated mice were equivalent to age matched controls whilst AT CAR treated mice had variable size by W18. The addition of aPDL1 to AT CAR T cells did not alter their performance from AT CAR T cells alone in any parameter examined. CAR T cell expansion in all groups was greatest at D+7 and the majority of CAR + cells were CD8 + and PD1 + . PD1 + expression was significantly higher in AT compared to WT CAR T cells at D+7. Summary/Conclusion: CD19+ relapse post CAR T cells is determined byT cell fitness as WT CAR T cells can prevent relapse and can normalise PD1+ expression and spleen size. CAR T cells derived from CLL T cells are less able to prevent CD19+ relapse and this is not improved using concurrent aPDL1, which also seems to have limited activity in treatment alone of AT TCL1 CLL. Ongoing studies using CAR plus immunotherapy and BTK inhibitor combinations are addressing which steps are necessary to optimize CAR T cell fitness.

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