Citations

e20012 Background: PM 2.5, particulate matter with a diameter of 2.5 micrometers or less, is a major contributor to lung cancer and associated mortality. Epidemiological studies reveal a concerning trend, with each 10 micrograms per cubic meter increase in PM 2.5 associated with a 15% higher risk of lung cancer and a 13% increase in mortality rates, underscoring the significant burden it imposes on public health systems globally. We aimed to evaluate the odds of association between environmental exposure to PM 2.5 and the risk of lung cancer and associated mortality. Methods: We performed a systematic review and umbrella meta-analysis using studies containing quantitative data on PM 2.5 and lung cancer. We used PRISMA guidelines and the MOOSE protocol using PubMed and MeSH terms like PM 2.5, non-small cell cancer, lung cancer, pollutants, particulate matter 2.5, and environmental factors. We had excluded non-full-length articles, non-meta-analysis studies, and non-human studies. RavMan 5.4 was used, and generic inverse variance methods with mixed effect models were applied to identify a pooled risk ratio with a 95% confidence interval. Forest plots were obtained, and sensitivity analysis was performed based on funnel plots and I2 (heterogeneity) values. Results: Of the 245,529 articles evaluated for the quality of the data, 99 met the inclusion and exclusion criteria. Out of 99, we used six articles to derive the quantitative data. In umbrella meta-analysis, PM 2.5 exposure was associated with a 1.16 times higher risk (95%CI: 1.1-1.22, p<0.00001, I2=0%) of lung cancer and a 1.22 times higher risk of non-lung cancers (95%CI: 1.15-1.30, p<0.00001, I2=0%). PM 2.5 was associated with non-significant higher mortality (RR: 1.06, 95%CI: 0.99-1.13, p=0.09, I2=97%) with leave-on-out analysis (excluding Chen et al.) significant association between mortality and PM 2.5 (RR: 1.08, 95%CI: 1.06-1.10, p<0.00001, I2=0%). Conclusions: Our umbrella meta-analysis shows a significant risk of lung cancer and mortality from PM 2.5 exposure. Further investigation and increased consciousness are necessary to mitigate the risk of lung cancer associated with this pollutant.

7516 Background: Immune effector cell hemophagocytic lymphohistiocytosis IEC-HS is a complication of CAR T cell therapy (CART). This study aims to look at the outcomes of CART patients who develop IEC-HS. Methods: Patients who developed IEC-HS after receiving CART and patients who developed IEC-HS without (nonCART) between December 2020 and March 2022 were included. Results: The 20 CART patients were older than the 25 nonCART patients. Peak ferritin, fibrinogen, CRP, serum creatinine and transaminases were similar between the 2 group. CART patients had lower white blood cell count and platelets and bilirubin than the nonCART patients. CART patients were more like to have markedly elevated IL-6 levels (> 315 mg/ml), higher IL-18, higher MCP-1, and suppressed IL-1β and GMCSF than nonCART patients (Table). Treatment of IEC-HS included tocilizumab (n = 19), anakinra (n = 18) siltuximab (n = 4) and basiliximab (n = 4), dexamethasone (n = 18) methylprednisolone (n = 6), etoposide (n = 1) and ruxolitinib (n = 1). A significant response defined by a 90% reduction or normalization of the cytokine was observed with IL-10 and IFN-ϒ in 92.3% and 84.6% of the CART patients respectively. An intermediate response was noted with TNF, IL-6, MCP-1 and MIP-1 in 38.4%, 30.8% and 61.6% and 38.5% of the patients respectively. No patient had a significant response in IL-2Rα or IL-1β and only 7.7% had a significant response in IL-18. Of the 5 patients who had a MIP-1 response, 4 were on basiliximab +/- high flow continuous venovenous hemofiltration and the only patient that had an IL-18 response was on both modalities. The 100-day mortality after IEC-HS in the CART patients was 40% and was associated with higher peak and lower best ferritin but not the percentage reduction (Table). Higher TNF (90.3 pg/ml vs 37.2 pg/ml, p = 0.05), markedly elevated levels of IL-6 (92% vs 50%, p = 0.03) and IL-10 (33% vs 0%) and an IL-6 response (44.4% vs 0%) were associated with survival at day 100. IL-6 responders had lower peak ferritin vs IL-6 nonresponders (14066 mcg/L vs 45051 mcg/L, p = 0.08). Enterococcus faecium bacteremia developed in 75% of the nonsurvivors vs 16.6% of the 100-day survivors (p = 0.009). Survivors cleared the enterococcus bacteremia within days while nonsurvivors had protracted bacteremia. Conclusions: IEC-HS is devastating complication of CART. Anti-cytokine therapy can reduce some cytokines and ferritin but overimmunosuppression may lead infectious complication, in particular with E. faecium. Better biomarkers are needed to finetune immunosuppressive therapy in order to avoid over-immunosuppression. [Table: see text]

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

TPS5125 Background: B7-H3 is a member of the B7 superfamily, which includes PD-L1 (B7-H1) and PD-L2 (B7-DC). Enoblituzumab is a humanized Fc-optimized B7-H3–targeting antibody that induces antibody-dependent cellular cytotoxicity (ADCC). A recent investigator-initiated trial demonstrated that enoblituzumab therapy, used in the neoadjuvant prostate cancer setting, is feasible, safe, may enhance short-term clinical outcomes, and appears to stimulate intratumoral immune activation including CD8+ T cell infiltration and peripheral expansion of tumor-infiltrating T-cell clones that correlated with undetectable PSA at 1-year post-prostatectomy. To assess the impact of enoblituzumab on recurrence-free survival following prostatectomy, a phase 2, randomized, neoadjuvant clinical trial in high-risk localized prostate cancer patients has been started. We hypothesize that targeting B7-H3 with enoblituzumab will delay or prevent recurrence following prostatectomy compared to standard of care (SOC) . Methods: The HEAT trial is an investigator-initiated, multi-center, randomized, phase 2 study that is presently enrolling (NCT06014255). Eligible patients will undergo a pre-treatment prostate biopsy and conventional imaging (CT and bone scan) as well as PSMA-PET. Patients who have clinical stage cT1c-T3b, cN0 cM0 disease by conventional imaging (N1 by PSMA allowed with up to 3 LNs each ≤1 cm) will be eligible as long as concurrent hormonal or radiation therapy is not given. Prostate biopsy, within 3 months of enrollment, needs to show at least 3 positive cores containing at least 1 core with at least 50% disease involvement with Gleason ≥4+3=7 disease (with at least 1 additional high-risk feature such as PSA>20 ng/ml or cT3) or a Gleason sum ≥8. Patients will receive enoblituzumab at a dose of 15mg/kg IV biweekly for 6 doses (12 weeks) on the treatment arm, followed by prostatectomy, or will be scheduled for prostatectomy directly within 4-8 weeks on the SOC arm. 219 patients will be randomized (2:1) to treatment versus SOC. Pre-treatment, on-treatment, and post-treatment biomarkers of response and resistance will be collected. Patients will be followed according to standard institutional practices, but will require PSA evaluations every 3 (±1) months during year 1 and every 6 (±2) months during years 2-5. In both arms, salvage or adjuvant therapy will occur after biochemical or radiographic progression. The primary endpoint is recurrence-free survival (RFS) defined as any metastasis events, local pelvic visceral or lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (including salvage or adjuvant therapy), or death for any cause, whichever occurs first. Secondary endpoints include additional clinical and immunologic correlates. Clinical trial information: NCT06014255 .

TPS5108 Background: Penile cancer is a devastating malignancy that affects just over 2000 patients per year in the United States and approximately 40,000 worldwide. Metastatic or unresectable penile cancer is rapidly fatal in most cases and there are few effective systemic therapy options.1 There is an urgent need for alternatives to chemotherapy such as immunotherapy or targeted therapy. Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4 protein on the tumor cell surface and having efficacy in treatment of metastatic urothelial carcinoma.2 Recent studies have demonstrated frequent and strong expression of nectin-4 in penile squamous cell carcinoma (PSCC).3,4 In this setting, Mayo Clinic is leading a phase II trial of EV for advanced PSCC, currently in progress. Methods: This single arm, open-label, two-stage, phase II trial evaluates best overall response rate (BRR) to EV in patients with PSCC regional lymph node involvement or distant metastatic (M1) disease. Participants may have had any prior systemic therapy or be treatment naïve. Previously untreated patients must be ineligible for or have refused surgery or radiotherapy, have N2-N3 disease and are ineligible for or have refused neoadjuvant chemotherapy, or have clinical evidence of M1 disease. Participants will receive treatment with EV until disease progression, withdrawal, death, or limiting toxicity. Participants will receive EV 1.25 mg/kg intravenous on days 1, 8, and 15 of a 28-day cycle, with tumor assessment performed at 8-week intervals. The primary endpoint is the combined BRR of partial and complete responses (whether confirmed or unconfirmed) according to RECIST 1.1. Secondary endpoints are confirmed response rate, duration of response, progression-free survival, overall survival, adverse events, and BRR in HPV related and unrelated subgroups. Stage 1 will consist of 15 participants, and if there are 2 or more responses will proceed to Stage 2 with an additional 10 participants. The trial opened to enrollment in December 2023, and is active at Mayo Clinic sites in Minnesota, Arizona, and Florida. Clinical trial information: Funding and drug supplied by Astellas Pharma Global Development, Inc./Seagen Inc. NCT06104618. 1. Chahoud J, et al., Curr Opin Urol. 2022 Jan 1;32(1):8-16. 2. Powles T, et al. N Engl J Med. 2021 Mar 25;384(12):1125-1135. 3. Tekin B, et al. Hum Pathol. 2023 Dec;142:42-50. 4. Grass GD, et al. Eur Urol Open Sci. 2023 Jan 10;49:1-5. Clinical trial information: NCT06104618 .

2071 Background: Brigimadlin (BI 907828) is a potent small molecule inhibitor of the p53-MDM2 pathway currently in a phase 0/1 clinical trial in combination with radiotherapy in newly diagnosed MGMTunmethylated glioblastoma (GBM). To inform development of brigimadlin for GBM, we developed a pharmacokinetic (PK)/ pharmacodynamic (PD)/ efficacy model using GBM patient derived xenografts (PDXs). Methods: Brigimadlin PK parameters were evaluated in FVB wild-type and knockout (Mdr1a/b-/-Bcrp1-/-) mice and in athymic nude mice. Drug binding was measured by rapid equilibrium dialysis, and drug levels quantified by LC/MS-MS. Dose-response relationships were evaluated in subcutaneous and orthotopic PDXs across a range of doses. Response to brigimadlin (2 mg/kg weekly) +/- RT (2 Gy x 10 fractions) was evaluated in orthotopic PDXs. Results: Brigimadlin significantly delayed median time to regrowth of GBM108 ( MDM2amplified) subcutaneous tumors (vs. placebo; p<0.05) at dose levels of 0.25 mg/kg (1.3-fold), 0.5 mg/kg (1.5-fold), 1 mg/kg (2.6-fold), and 2 mg/kg (5.3-fold). A single dose of brigimadlin resulted in corresponding intra-tumoral drug levels 24 hours post-dose: 84 nM (0.25 mg/kg), 175 nM (0.5 mg/kg), 398 nM (1 mg/kg) and 924 nM (2 mg/kg) and dose-dependent upregulation of p53 target genes (p21 and PUMA). In contrast, GBM14 ( MDM2non-amplified) showed regrowth delay (1.6-fold) only at 2 mg/kg (p=0.008). Brigimadlin was highly bound (fraction unbound = 0.0006 in brain; 0.0017 in GBM tumor tissue), and CNS distribution was limited by efflux; in wild-type mice Kp,uu_brain = 0.002 ± 0.003; in Mdr1a/b-/-Bcrp1-/- mice Kp,uu = 0.043 ± 0.025. Efficacy of brigimadlin was compared in orthotopic GBM108 PDXs grown in athymic nude mice vs. immuno/efflux-deficient (Rag2-/-Mdr1a-/-Bcrp1-/-) mice. In nude mice, median survival was extended at 2 mg/kg brigimadlin (1.4-fold, p=0.009), with corresponding intra-tumoral drug levels of 29 nM. In efflux deficient mice, median survival was extended (p<0.05) at 0.25 mg/kg (1.5-fold), 0.5 mg/kg (1.5-fold), 1 mg/kg (1.8-fold), and 2 mg/kg (>4-fold). Measurement of intra-tumoral drug levels is in progress. In combination with RT in GBM108, brigimadlin (2 mg/kg x 2 weeks) extended median survival vs. vehicle (66 vs. 50 days; p=0.012) and enhanced median survival following RT (128.5 vs. 82 days; p=0.009). In GBM14, 2 mg/kg brigimadlin (2 mg/kg x 12 weeks) extended median survival (39.5 vs. 32.5 days; p=0.0004) and enhanced survival following RT (97 vs. 81 days; p<0.0001). Conclusions: Efficacy of brigimadlin is dependent on adequate CNS delivery. Studies in subcutaneous PDX demonstrated intra-tumoral total drug levels in the mid-nanomolar range provide meaningful tumor effects in a highly sensitive, MDM2 amplified PDX. In orthotopic PDXs with and without MDM2 amplification, brigimadlin provided further benefit in combination with RT. These data support ongoing clinical evaluation of brigimadlin in GBM.

2012 Background: Navtemadlin (nvtm) is a potent, selective, orally available small molecule inhibitor of murine double minute 2 homologue (MDM2), which has completed a Ph 0 surgical window of opportunity study in glioblastoma, IDH-wildtype (GBM; Lee SNO 2022). To optimally interpret the clinical data, an extensive evaluation of nvtm PK, PD, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to nvtm +/- radiotherapy (RT) was characterized in vitro and in vivo across a panel of GBM PDXs with various TP53 and MDM2 alterations. Efficacy, PK, and PD were evaluated in flank or orthotopic PDX models. p53 pathway activation was evaluated by qPCR, Western blot, and IHC. Nvtm brain penetration was evaluated in immunodeficient abcb1a/b-/- (P-glycoprotein; P-gp), abcg2-/- (BCRP), or double-knockout mice. Binding was assessed by rapid equilibrium dialysis, and nvtm concentrations by LC/MS-MS and MALDI-MSI. Results: Nvtm decreased in vitro viability of TP53WT GBM PDX explant cultures with IC50s <100 nM, but was ineffective in TP53-mutant GBM. In flank PDX models, nvtm (100 mg/kg daily for 4 weeks) delayed tumor regrowth by 1.9 to 4.8-fold in TP53 WT PDXs without MDM2amplification (n=9 models), and more markedly by 20.1 to 29.4-fold in MDM2amplified models (n=4; 2 PDXs did not recur). In a flank PDX dose-response study, nvtm delayed the growth of MDM2amplified GBM108 at 25 mg/kg vs. placebo (61 vs. 11 days; p=0.014; mean intra-tumoral nvtm = 590 nM). In contrast, growth of MDM2 non-amplified GBM14 was delayed only at 100 mg/kg (37 vs. 15 days; p=0.082; mean intra-tumoral nvtm = 2990 nM). In both flank models, p53 target gene upregulation was similar between 25 and 100 mg/kg and did not correlate with regrowth. Nvtm was highly bound (fraction unbound = 0.090 in culture media and 0.014 in GBM tissue homogenate). In mice after oral dosing, distribution to CNS was limited by P-gp, with a brain to plasma ratio of 0.009 and unbound ratio of 0.005, whereas BCRP deficiency did not affect CNS distribution. With orthotopic GBM108, nvtm efficacy was evaluated in nude vs. efflux-deficient mice. In nude mice, nvtm was ineffective at doses up to 100 mg/kg; however, in efflux deficient mice, the mean intra-tumoral nvtm level at 25 mg/kg was similar to flank tumors (690 nM) and survival was significantly extended (134 vs. 62 days, p=0.0002) with additional benefit at 100 mg/kg (>300 vs. 62 days, p=0.002). Conclusions: Nvtm showed significant efficacy in TP53 WT GBM flank PDX models but efficacy in orthotopic PDX was highly dependent on CNS penetration. Targeting nvtm levels based on the in vitroIC50 may significantly underestimate the in vivo effective concentration . In vivo studies showed lower intra-tumoral nvtm levels are required to significantly inhibit growth of MDM2amplified compared with non-amplified tumors.

Discovery of effective systemic therapies for patients with advanced penile cancer has been slow to occur. Comprehensive genomic profiling from several studies shed light on the molecular oncogenesis of penile squamous cell carcinoma (PSCC) and differences between HPV-related and unrelated tumors. While these two subsets of PSCC appear distinct in their biology, there are not yet specific treatment strategies recommended on that basis. Cell surface proteins have been identified that may potentially serve as drug targets for monoclonal antibodies or small molecule inhibitors. Here, we review some of the new biological insights regarding PSCC that could lead to improved therapies, as well as the related clinical trials recently completed or in progress. We conclude that antibody-drug conjugates are especially promising, as are the combinations of immune checkpoint inhibitors with other types of drugs.