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Abstract Background Randomized, controlled trials found 7 days of antibiotics to be as effective as 14 days for the treatment of uncomplicated Gram-negative bacteremia. The routine use of repeat blood cultures for these uncomplicated infections is low yield and not recommended. A review of the management of these infections at Denver Health found the median duration of therapy was 10 days and nearly two-thirds of patients had blood cultures repeated. A multifaceted intervention was implemented to reduce duration of therapy and use of repeat blood cultures. The purpose of this study was to evaluate the impact of the intervention. Methods This retrospective cohort study took place from 1/2019 - 12/2019 (pre-intervention) and 10/2022 - 9/2023 (post-intervention). 3 interventions were implemented including a) development and dissemination of a guideline for the management of uncomplicated Gram-negative bacteremia which recommends 7 days of therapy and against repeat blood cultures for most patients b) clinical decision support to discourage repeat blood cultures c) prospective review of positive blood cultures with provider feedback performed by an infectious diseases pharmacist. All patients over 18 years of age with a positive blood culture with a Gram-negative organism were included. The primary outcome was duration of therapy pre-and post-intervention. The secondary outcome was proportion of patients with repeat blood cultures. Results Patient demographics were similar between groups. Urinary tract and E. coli were the most common source and pathogen, respectively. Most patients completed therapy with an oral agent; either a fluoroquinolone or cephalosporin. Cefdinir decreased and cephalexin increased based on institutional guidance. The median duration of therapy decreased from 10 to 7 days (p< .01) and fewer patients had repeat blood cultures (60% vs 31%, p< .01). There were fewer cases of C. difficile in the post-intervention group, otherwise no differences in safety outcomes. Conclusion Implementation of a guideline for the management of uncomplicated Gram-negative bacteremia, clinical decision support, and review of positive blood cultures with provider feedback performed by an infectious diseases pharmacist reduced duration of therapy and the use of repeat blood cultures. Disclosures All Authors: No reported disclosures

BackgroundAbequolixron is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. The binding of ApoE to its receptor LRP8 robustly inhibits angiogenesis and depletes myeloid-derived suppressor cells (MDSCs), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPIs) and chemotherapy, providing a rationale for combination therapy with abequolixron. In prior escalation and expansion cohorts of this Phase 1b clinical trial, abequolixron resulted in antitumor activity across multiple tumor types when administered either as a single agent or in combination with CPIs and/or chemotherapy. In these cohorts, MDSC depletion with concomitant CD8 T cell response was observed.MethodsSubjects with non-squamous NSCLC who had progression of disease after receiving CPI and platinum-based chemotherapy and/or targeted agents were treated with abequolixron (120 mg BID for 5/7 days continuously) and docetaxel (35 mg/m2 weekly x 3 on a 28-day cycle). Efficacy endpoints were overall response rate and progression-free survival per RECIST 1.1.ResultsAs of 16May2024, 21 subjects were enrolled and treated with abequolixron plus docetaxel, with treatment ongoing in 5 subjects (table 1).ConclusionsThe combination of abequolixron and docetaxel was well tolerated and resulted in promising preliminary efficacy in second/third-line NSCLC. A Phase 2 randomized trial in subjects with recurrent advanced/metastatic NSCLC with disease progression after CPI and platinum-based therapy is planned.Trial RegistrationNCT02922764. 657 Table 1Study results ApoE genotype biomarker data will be presented at the meeting

e14587 Background: PSMA, a transmembrane protein highly expressed on the surface of prostate cancer cells, is a validated target in prostate cancer; however, achieving a favorable therapeutic index has been challenging for PSMA-directed T-cell engagers (TCE’s). AMG 340, a PSMA-targeted TCE with a novel low-affinity CD3 binding domain specifically engineered to mitigate cytokine release syndrome (CRS) toxicity and maintain efficacy was investigated in a phase 1, open-label, dose-escalation study (NCT04740034). Methods: Patients (pts) with mCRPC who had received ≥2 prior lines of therapy were treated with AMG 340 monotherapy (1.5–800 mg intravenously every 3 weeks [Q3W]) during dose escalation. The primary outcome measures were dose-limiting toxicities, treatment-emergent adverse events (TEAEs), and pharmacokinetic profile. Secondary outcomes included prostate antigen specific (PSA) response and objective response per response evaluation criteria in solid tumors (RECIST). Results: As of September 6, 2023, a total of 42 pts (mean ± SD age, 68.5±7.8 years) received AMG 340 step up dosing across 11 cohorts. At doses up to 800 mg Q3W, AMG 340 had a manageable side effect profile. Any grade TEAEs reported in ≥30% of pts included CRS (52%), nausea (52%), vomiting (52%), fatigue (48%), diarrhea (38%), increased aspartate aminotransferase (36%), increased alanine aminotransferase (33%), and hypocalcemia (31%). Treatment-related toxicities included CRS (52%; Grade 1, 26%; Grade 2, 24%; Grade ≥3, 2%) and thrombocytopenia (24%; Grade 2, 10%; Grade ≥3, 14%). Step dosing was implemented at doses >40 mg and successfully mitigated CRS incidence and severity after the first dose. The maximal tolerated dose was not reached, as increasing the dose beyond 800 mg was predicted to minimally increase the potential AMG 340 activity. Exposure increased in an approximately dose-proportional manner with no evidence of clinically significant anti-drug antibodies. AMG 340 demonstrated evidence for pharmacodynamic engagement as shown by cytokine induction. Of the 41 PSA evaluable pts, PSA responses were seen across dose levels (PSA50, n=4), but were not dose dependent. Eight of 42 pts remained on treatment after 6 months. Among 27 RECIST evaluable pts, no RECIST responses were observed (n=14 stable disease, n=0 partial or complete response). Conclusions: Despite reaching high doses, no dose response was observed, and AMG 340 did not generate sufficient clinical activity to warrant further exploration. However, AMG 340 demonstrated manageable CRS toxicity showing that decreased CD3-binding strength mitigates CRS, the main toxicity of TCEs. Clinical studies are ongoing evaluating the PSMA protein as a molecular target for prostate cancer. Clinical trial information: NCT04740034 .

TPS3191 Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). While several approved nonselective PARPi have provided robust anti-tumor activity, they are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1 but spare PARP2 may improve the risk-benefit profile for this class of therapies by retaining anti-tumor activity while avoiding PARP2-related toxicities. IMP1734 (EIK1003) is a potent PARP1-selective inhibitor that inhibits tumor growth in nonclinical models and may widen the therapeutic index in tumors where non-selective PARPi have demonstrated efficacy. Methods: Study EIK1003-001 (IMP1734-101) is a global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of IMP1734 in participants with advanced solid tumors. The study has 3 parts: Part 1 (FIH; Dose Escalation), Part 2 (Dose Optimization), and Part 3 (Dose Expansion at the recommended dose for expansion [RDE]). Part 1 of this study is currently enrolling and consists of dose escalation of IMP1734 in study participants with advanced/recurrent/metastatic ovarian, breast, or prostate cancer with suspected deleterious/deleterious mutations in a pre-specified panel of homologous recombination repair (HRR) genes (n = 70). Eligible participants must be ≥ 18 years of age, have histologically or cytologically confirmed tumors as indicated in each study part, and at least 1 RECIST v1.1-measurable lesion and/or pre-specified serum tumor-specific marker. All participants must have a deleterious or suspected deleterious mutation in select HRR genes. Primary endpoints include safety and tolerability (evaluation of dose-limiting toxicities and determining the maximum tolerated dose, maximum achievable dose, and RDE). Secondary endpoints include evaluation of the pharmacokinetic parameters of IMP1734 and measures of efficacy, including overall response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints include analysis of pharmacodynamic biomarkers, serial ctDNA measurements, and patient quality-of-life measures. This study opened on 11 Dec 2023. Clinical trial information: NCT06253130 .

This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12months. After 2years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2years. Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.