BACKGROUND:Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited. METHODS:This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. RESULTS:Among 110 pts, median age at ICI initiation was 65 (IQR: 59-75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients. CONCLUSIONS:Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis.

Descriptive graph of all patients tested in this cohort who were found to have new MG diagnoses through testing (11.8%), and the percentage of patients with a clinically significant monoclonal protein test (0.4%). Clinically significant tests were those that led to a new lymphoplasmacytic diagnosis or uncovered MG as the source of the patient's anemia for which they received monoclonal protein testing.

Peripheral neuropathy can be associated with certain monoclonal gammopathies; therefore, monoclonal protein testing is routinely performed in the evaluation of this symptom. However, limited data exist regarding the utility of monoclonal protein testing for this indication. Data suggest those receiving a new monoclonal gammopathy of undetermined significance (MGUS) diagnosis have similar rates of diagnosis-related anxiety when compared to those receiving a myeloma diagnosis (Maatouk et al., Blood Cancer J 9(2), 2019; Adami et al., Eur J Clin Invest 49(3), 2019; Rögnvaldsson et al., Blood Cancer J 11(5):1–13, 2021). To quantify the utility of monoclonal protein testing with respect to early detection of malignancy or determining etiology of peripheral neuropathy. We reviewed records of patients who received monoclonal protein testing for neuropathy as per ICD-10 codes at our institution during 2021 (n=1436). All those with previously diagnosed monoclonal gammopathies were excluded (n=37). Clinical utility was defined as finding a new lymphoplasmacytic neoplasm diagnosis, or if the neuropathy was ultimately attributed to the monoclonal gammopathy identified with testing. Among 1399 patients receiving monoclonal protein testing, 148 (10.6

TPS2698 Background: Chimeric antigen receptor (CAR) T-cell therapies for treating solid tumors are challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using CEA T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities (1,2). A2B530 is an autologous logic-gated, CEA-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (3). The activator recognizes CEA on the surface of both tumor and normal cells while specificity for tumor cells is provided by a blocker that binds HLA-A*02. In patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). HLA-A*02 LOH can be detected using next-generation sequencing (Tempus AI, Inc.). With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH. Methods: EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530 in adult patients. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1–eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study. The key inclusion criteria include histologically confirmed recurrent unresectable, locally advanced, or metastatic cancers associated with CEA expression: non-small cell lung, colorectal, or pancreatic cancers. Patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 and determine the recommended phase 2 dose (RP2D). The dose-escalation portion is based on the Bayesian optimal interval design. The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530. Phase 2 will assess overall response rate per RECIST v1.1. As of January 29, 2024, 8 patients have been enrolled on EVEREST-1. A2B530 was successfully manufactured for all patients, and all patients have received A2B530 infusion, with the first patient dosed in May 2023. Dose escalation is ongoing. 1. Parkhurst, et al. Mol Ther. 2022. 2. Tabernero, et al. J Clin Oncol. 2017. 3. Hamburger, et al. Mol Immunol. 2020. 4. Sandberg, et al. Sci Transl Med. 2022. Clinical trial information: NCT05736731 .

TPS2699 Background: Despite the success in hematologic cancers, chimeric antigen receptor (CAR) T-cell therapies are challenging to implement in solid tumors owing to a lack of tumor-specific targets that discriminate cancer from normal cells. MSLN expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (TCGA 2022), making it a potential target for cancer therapy. MSLN-targeted cell approaches, including CAR T-cell and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (1-3). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T-cell therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker binds HLA-A*02 and prevents CAR T-cell activity. Thus, in patients with both germline HLA-A*02 and tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (4). Through this unique discriminatory mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients should have received ≥1 line of prior therapy such as checkpoint inhibitor, molecular targeted, or chemotherapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc.). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. 1. Beatty, et al. Gastroenterology. 2018. 2. Haas, et al. Mol Ther. 2023. 3. Hong, et al. ESMO 2021. Abstract 9590. 4. Hamburger, et al. Mol Immunol. 2020. Clinical trial information: NCT06051695 .

Background:Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes. Objectives:The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs). Methods:A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0. Results:Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively (P < 0.0001), and median OS was 3.0 vs 24.0 months, respectively (P = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3. Conclusions:Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity.

Pleural epithelioid mesothelioma (PEM) is divided into low and high grades based on nuclear atypia, mitoses, and necrosis in the tumor. Assessing mitoses and nuclear atypia tend to be labor-intensive with limited reproducibility. Ki-67 proliferation index was shown to be a prognostic factor in PEM, but its performance has not been directly correlated with tumor grade or mitotic score. This study evaluated the potential of Ki-67 index as a surrogate of tumor grade. We also compared the predictability of mitoses and Ki-67 index for overall survival (OS). Ninety-six PEM samples from 85 patients were identified from the surgical pathology file during 2000-2021 at our institution, and all glass slides were reviewed by 2 pulmonary pathologists to confirm the diagnosis and assign the tumor grade. Digital image analysis (DIA) was done for Ki-67 index. The agreement on tumor grading between 2 reviewers was moderate (kappa value = 0.47). The correlation between mitotic count (average count by 2 reviewers) and Ki-67 index was 0.65. The areas under the curve for predicting tumor grade by mitotic score and Ki-67 index were 0.84 and 0.74 (reviewer 1) and 0.85 and 0.81 (reviewer 2), respectively. High Ki-67 index and mitoses were significantly associated with poor OS (P=0.03 and 0.0005, using 30% and 10/2 mm2 as cutoffs, respectively). In conclusion, Ki-67 index by DIA was associated with tumor grade as well as mitotic count, and its predictability for OS was comparable to that of mitotic score, thus being a potential surrogate for tumor grade.

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

OBJECTIVES:Accurately predicting which patients diagnosed with non-small cell lung cancer (NSCLC) will respond to immunotherapy remains a clinical challenge. This study aims to determine the associations between MYC immunoreactivity, MYC copy number gain (CNG), driver mutations and survival following immunotherapy treatment, to provide insight into whether clinical MYC assessment may have predictive value. MATERIALS AND METHODS:MYC copy number status was determined in 82 patients with NSCLC treated with immunotherapy, and MYC immunohistochemistry (IHC) was performed on 80 of these cases. MYC staining in ≥ 40 % of tumor cells was considered positive. Driver gene alterations, PD-L1 status and survival outcomes were assessed through retrospective chart review. Overall survival (OS) and progression free survival (PFS) were calculated from the date of immunotherapy initiation. RESULTS:Nine (11 %) of 82 cases had MYC CNG and 56 (70 %) of the 80 immunostained cases were positive for MYC. MYC CNG was significantly associated with STK11 mutation (P=0.023), whereas positive MYC IHC was significantly associated with KRAS mutation (P=0.0076) and current/former smoking (P=0.0007). MYC CNG and positive MYC IHC were not significantly associated with each other (P=0.42), or with PD-L1 ≥ 1 % (MYC CNG: P=0.10; MYC IHC: P=0.09). Positive MYC IHC and PD-L1 ≥ 1 % were both significant predictors of OS (MYC: HR 2.7, 95 % CI 1.1-6.4, P=0.026; PD-L1: HR 0.33, 95 % CI 0.15-0.72, P=0.0055). MYC IHC positive/PD-L1 < 1 % cases had the shortest OS (median 230 versus 918 days, P=0.00069) and PFS (median 84 versus 254 days, P=0.0087). MYC CNG was not associated with OS or PFS. CONCLUSION:We find that positive MYC IHC is an independent predictor of shorter OS after immunotherapy treatment, with MYC positive/PD-L1 < 1 % status predictive of particularly poor immunotherapy response. We identify positive MYC IHC as a feature of possible relevance to NSCLC treatment selection and of interest for future therapy development.

Background Screening for monoclonal gammopathy (MG) is often performed in the evaluation of anemia. While certain MGs may be associated with anemia, these are rare conditions. Monoclonal gammopathy of undetermined significance (MGUS; prevalence of 8% among age >50 years) is common, but rarely causes anemia in isolation. Therefore, abnormal results from MG screening may be unrelated to patient symptoms and result in both financial and psychological harm. Limited data exist to guide clinicians regarding the utility of MG testing for anemia. Aims This study aims to describe both the clinical utility of MG screening during the evaluation of anemia and the most common etiologies for anemia in patients whose workup included MG screening. Methods We reviewed medical records of patients who received MG screening to evaluate anemia at Mayo Clinic in 2021. Patients with a previously diagnosed MG were excluded. MG testing included serum protein electrophoresis and free light chain assessments. The following data were extracted: hemoglobin, hematocrit, mean corpuscular volume (MCV), calcium, creatinine, eGFR, and the final hematologic diagnosis related to the monoclonal protein. Clinician documentation was evaluated to determine the attributed etiology of anemia. Results Among the 271 patients with anemia who were screened for MG, 33 (12.2%) were found to have a newly diagnosed MG. Only 2 patients screened for MG were ultimately found to have anemia caused by MG. These included a case of multiple myeloma and one patient with cold agglutinin disease and secondary hemolysis. In all patients screened, their anemia was ultimately thought to be due to iron deficiency (31.7%), B12 deficiency (3.0%), anemia of chronic disease (ACD)/inflammatory anemia (14.4%), chronic kidney disease (CKD) (3.7%), hemolysis (1.5%), hypogonadism (1.9%), idiopathic (21.0%), multifactorial: iron deficiency + ACD/inflammatory (3.0%), multifactorial: nutritional; iron deficiency + B12 deficiency (3.0%), multifactorial: ACD + CKD (5.2%), multifactorial: iron deficiency + CKD (1.8%), multifactorial: not otherwise specified (NOS) (6.6%), medications (0.4%), and other (2.6%). Both patients with newly diagnosed MG associated anemia presented with peripheral neuropathy as their primary symptom. Among these 2 patients diagnosed with dysproteinemia associated anemia, only one (0.4%) was placed on therapy for their MG. Summary/Conclusions In the evaluation of anemia, routine MG screening has low clinical utility. Less than 1 in 100 patients were found to have anemia attributable to MG. Furthermore, only 0.4 in 100 patients received MG-directed therapy. Most patients screened with SPEP for undifferentiated anemia were found to have anemia attributable to common causes including iron/nutritional deficiency, inflammatory processes, and CKD. Most patients with undifferentiated anemia would benefit from an anemia evaluation that focuses on the most common causes up front. Given the cost to healthcare and potential psychological harm to the patient of incidental MG diagnosis, further study is warranted to guide clinicians and limit the ordering of MG testing to individuals who are most likely to derive benefit.

BackgroundImmune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene-driven advanced non-small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated.Methods was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post-protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted.ResultsTwenty-three frontline trials in nononcogene-driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first-line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy.ConclusionThe rate of crossover and postprotocol ICI use was low in frontline trials for first-line NSCLC incorporating ICI. Given the proven survival overall survival of ICI in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration. The rate of crossover and postprotocol immune checkpoint inhibitor (ICI) use was low in ICI monotherapy/dual ICI and chemotherapy/ICI trials for first-line non-small cell lung cancer. Given the proven survival overall survival of immunotherapy in a broad population, there is a need to ensure availability of this life-prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

Background Immunotherapy has shown promise in treating patients with metastatic NSCLC, but response rates vary. This study aims to investigate the relationship between PD-L1 CNV and response to immunotherapy in patients with NSCLC. Methods We conducted a retrospective analysis of patients who received immunotherapy, and were identified to have information on CNV status for PD-L1 through the MayoComplete Solid Tumor Panel (MCSTP) Next Generation Sequencing (NGS) assay. Response to therapy was evaluated using evidence of radiographic progression, date of death or date of last follow-up. Progression-free survival (PFS) and Overall survival (OS) were defined as time interval between data of initiation of immunotherapy to date of radiographic progression and date of death respectively. Results 98 patients were included in the study, most of whom had received immunotherapy as a first-line treatment (77%). The median age was 70.5 years (range: 39–88), and 64% were male. The most common histology was adenocarcinoma (68%), followed by squamous cell carcinoma (16%) and others (16%). We found that PD-L1 CNV was altered in 54% of patients with either heterozygous deletion (34%) or copy number gain (20%). We observed higher median PD-L1% in patients with PD-L1 CNV copy number gain compared to normal/deletions (80% vs 5%,p=0.0172) (table 1). In terms of smoking status, 94% of patients had a history of smoking (84% former smokers, 10% current smokers and 6% never smokers). Most patients had stage IV disease at treatment initiation (68%), and the ECOG performance status was mostly 0 or 1 (78%). The median PFS and OS for the cohort was 5.4 and 23.8 months respectively (table 1). We observed improved response to immunotherapy with higher PDL1 IHC% as has been reported previously. However, we did not find any significant differences in median PFS by presence (7.5 [normal] vs 5.0 months [altered], p=0.28) and type (7.5 [normal] vs 5.5 [deletion] vs 4.4 months [gain], p=0.56) of PD-L1 CNV alteration. Similarly, there were no significant differences in OS by presence (23.8 [normal] vs 26.6 [altered] months, p=0.38) and type (23.7 [normal] vs 26.6 [deletion] vs not reached [gain] months, p=0.51) of PD-L1 CNV alteration (figure 1). Conclusions Our study did not find any significant difference in median PFS and OS between patients with normal PD-L1 CNV and those with altered PD-L1 CNV, including different types of PD-L1 CNV alterations. Our study suggests that PD-L1 CNV status may not be a reliable predictive biomarker for response to immunotherapy in patients with advanced NSCLC.

Background Chimeric antigen receptor (CAR) T-cell therapy has been challenging in solid tumors due to an absence of tumor-specific targets and the resultant on-target, off-tumor toxicity. Tmod, a novel logic-gated CAR T-cell therapy, utilizes a blocking receptor to discriminate tumor from normal cells, thus mitigating on-target, off-tumor toxicity (figure 1).1 2 The blocker recognizes human leukocyte antigen (HLA), an antigen that is subject to LOH.3 4 Among advanced colorectal, pancreatic, and non-small cell lung cancers, HLA LOH occurs in 15.6%, 19.6%, and 23.1% of patients, respectively (Tempus Database).5 However, HLA LOH can only be therapeutically exploited if patients are identifiable through a feasible clinical workflow. BASECAMP-1 is an ongoing prescreening study to: 1) Identify patients with tumor-associated HLA LOH and eligible for Tmod CAR T-cell therapy, and 2) Obtain leukapheresis in preparation for the autologous CAR T-cell therapy trials EVEREST-1 (A2B530 targeting carcinoembryonic antigen; NCT05736731) and EVEREST-2 (A2B694 targeting mesothelin). Methods BASECAMP-1 (NCT04981119) eligibility has 2 parts (figure 2). Patients with metastatic solid tumors or at high risk of relapse will be screened for germline HLA-A*02. Tumor tissue from patients with germline HLA-A*02:01 heterozygosity will be analyzed for somatic tumor HLA-A*02:01 LOH via Tempus next-generation sequencing testing. In addition, patients may be identified via the Tempus AWARE program. AWARE analyzes tissue from patients submitted to Tempus as part of the patient's routine clinical workup. Institutional investigators are then informed of molecular results and can communicate with treating physicians regarding enrollment opportunities. Patients with tumors demonstrating HLA-A*02 LOH may be screened for subsequent leukapheresis, and banked T cells will be available for the EVEREST-1 and EVEREST-2 studies. Results As of June 1, 2023, 664 patients were consented at 9 institutions (figure 3). HLA status was determined for 584 patients; 234 were identified as HLA-A*02:01 heterozygous (40%). LOH results were available for 117 patients; 13 were LOH positive (11%). In addition, the AWARE program has been deployed since January 2022. We have identified 52 patients across sites with study-specific disease types with HLA-A*02:01 LOH; of these, 13 are currently being screened, 23 have been found ineligible, and 16 have consented. This demonstrated the feasibility of leveraging a diagnostic during routine clinical workup to identify rare, molecularly defined patients for personalized clinical studies. Trial Registration NCT04981119 Please note, this trial is a screening/non-interventional clinical trial. References 1. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298- 2. DiAndreth B, Hamburger A, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030. 3. Sandberg ML, Wang X, Martin AD, et al. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. Sci Transl Med. 2022;14:eabm0306. 4. Tokatlian T, Asuelime GE, Mock J-Y, et al. Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells. J Immunother Cancer. 2022;10:e003826. 5. Simeone DM, Hecht R, Patel SP, et al. BASECAMP-1: Leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy. J Clin Oncol. 2022;40(16_Suppl):TPS2676. Ethics Approval This study was approved by site IRBs

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Screening for monoclonal gammopathy (MG) is routinely performed in the evaluation of peripheral neuropathy. While certain MGs may be associated with neuropathy, for example light chain amyloidosis (AL), POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome, and Waldenstrὂm macroglobulinemia (WM), these are rare conditions (<10/million/year combined). In contrast, multiple myeloma (MM; 7/100,000/year) and monoclonal gammopathy of undetermined significance (MGUS; prevalence of 8% among age >50 years) are more common, but rarely cause neuropathy. Therefore, abnormal results from MG screening may be unrelated to patient symptoms and result in financial and psychological harm. Limited data exist to guide clinicians regarding the utility of MG testing for neuropathy. Aims: This study aims to describe the clinical utility of MG screening during the evaluation of neuropathy. Methods: We retrospectively reviewed the charts of patients screened in 2021 for MG as part of the workup for peripheral neuropathy at Mayo Clinic. Patients with a previously diagnosed MG were excluded. MG testing included serum protein electrophoresis and free light chain assessments. In patients with MG, the following data were extracted: hemoglobin, calcium, creatinine, eGFR, and the final hematologic diagnosis related to the monoclonal protein. We followed the patients longitudinally to determine the attributed etiology of peripheral neuropathy. Patients were divided into those with a lymphoplasmacytic neoplasm and those with MGUS alone. Patients diagnosed with MGUS were stratified based upon the etiology of their neuropathy after workup was completed to assess the clinical utility of testing. The routine MG screenings which found a new diagnosis of lymphoplasmacytic neoplasm were deemed to be of clinical utility regardless of neuropathy etiology. Results: Among the 1436 patients with neuropathy who were screened for MG, 150 (10.4%) were found to have a newly diagnosed MG. Of the latter, 148 (98.6%) were MGUS and the other 2 (1.4%) were MM (1) and POEMS (1). Only 12 (0.83%) patients screened for MG were ultimately found to have neuropathy caused by MG. The types of MG felt to be responsible for the neuropathy were MGUS (5 IgM, 4 IgG, and 1 IgM/IgG biclonal), MM (1), and POEMS (1). Common causes of neuropathy in patients with newly diagnosed with MG were; hereditary/genetic conditions (25; 16.6%), diabetes mellitus or hyperglycemia (23;15.3%), mechanical/radiculopathy (13; 8.6%), CIDP (9; 6%), alcohol (8; 5.3%), autoimmune-related (6; 4%), and idiopathic (39; 26%). Among the 2 patients with newly diagnosed lymphoplasmacytic neoplasms, one presented with the Sign of Leser Trelat and lytic bone lesions on imaging. The other patient presented with symptoms consistent with POEMS including edema, hypothyroidism, and sclerotic bone lesions on imaging. Among the 12 patients diagnosed with MG associated neuropathy, 4 (33%) were placed on therapy for their MG. Therapies included lenalidomide, rituximab, and IVIG. Summary/Conclusion: In the evaluation of peripheral neuropathy, routine MG screening has low clinical utility. Less than 1 in 100 patients were found to have a MG associated neuropathy. Furthermore, only 3 in 1000 patients received MG-directed therapy. Given the cost to healthcare and potential psychological harm to the patient of incidental MG diagnosis, further study is warranted to guide clinicians and limit the ordering of MG testing to individuals who are most likely to derive benefit. Keywords: Myeloma, Monoclonal gammopathy, Multiple myeloma, MGUS

Recent FDA reviews of cemiplimab and sintilimab combined with chemotherapy for patients with advanced-stage non-small-cell lung cancer reached discordant outcomes, as cemiplimab was approved and sintilimab was rejected. The applications share many serious faults, including neither serving an unmet need nor enrolling any patients from the USA. We argue that the FDA criteria should be more transparent and consistent; moreover, the historical policy of the FDA to abstain from consideration of the cost of a drug perpetuates a crisis in oncology care and should be re-examined.

Background Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies1; however, implementation of these therapies in solid tumors has been challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities.2 3 EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530, a logic-gated CEA-targeting Tmod CAR T-cell therapy, in adult patients. Tmod CAR T-cell therapy addresses challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (figure 1).4 5 The activator receptor recognizes CEA on the surface of both tumor and normal cells. CEA is normally widely expressed in epithelial cells, particularly of the gastrointestinal (GI) system and can be upregulated in GI and lung tumors. Specificity for tumor cells is provided by a blocker that recognizes human leukocyte antigen (HLA) A*02, which is absent on tumor cells with HLA-A*02 LOH.6 LOH for HLA-A*02 is observed in solid tumor malignancies and can be detected using the Tempus next-generation sequencing testing. With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH. Methods Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1 eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study (figure 2). The key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers that are associated with CEA expression: non-small cell lung (NSCLC), colorectal (CRC), or pancreatic (PANC) cancers. Patients should have received ≥1 line of prior therapy (eg, checkpoint inhibitor, molecular-targeted, or chemotherapy). The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 in patients with NSCLC, CRC, and PANC, and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530. Trial Registration NCT05736731 References 1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640–654. 2. Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19:620–626. 3. Tabernero JT, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(15_Suppl):3002. 4. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310. 5. DiAndreth B, Hamburger A, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030. 6. Sandberg ML, Wang X, Martin AD, et al. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. Sci Transl Med. 2022;14:eabm0306. Ethics Approval This study was approved by site IRBs.

BACKGROUND:Lurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients.METHODS:A retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events.RESULTS:Lurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported.CONCLUSION:This real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.