tbuckley/cabot-search huggingface dataset:
Sex and racial disparities in incidence and survival outcomes in adolescents and young adults (AYA) with lung cancer in the United States.
Authors: Chukwuka Eneh, Stephanie Ogbonda, Ifeanyi Uche, Nosakhare Paul Ilerhunmwuwa
Journal: Journal of Clinical Oncology (2024)

8033 Background: Limited data exists on the impact of race on the incidence and survival of lung cancer among adolescents and young adults (15 – 39 years). We examined the Surveillance, Epidemiology, and End Results Plus Data (SEER) to determine the association of race, sex and other demographic/clinicopathologic factors with incidence trends and survival in AYA. Methods: Lung cancer cases in AYA diagnosed between 2000 and 2020 were extracted from the SEER database. Age-standardized incidence rates per 100,000 persons were obtained, and the annual percentage change (APC) was used to compare incidence trends stratified by various demographics. Relative survival was calculated with the SEER Stat software. Multivariate regression analyses were performed to determine association with mortality. Results: We identified 5129 cases of lung cancer among AYA of which 50.9% (n=2610) were female, 56.6% (n=2904) were Non-Hispanic Whites (NHW), 17% (n=872) were Hispanics, 13.3% (n=684) were Non-Hispanic Blacks (NHBs), 12.5% (n=643) were Non-Hispanic Asian or Pacific Islander (NHAPI) and 0.5% (n=26) were Non-Hispanic American Indian/Alaska Native (NHAIA). Overall age-adjusted incidence rates (AAIR) of lung cancer among AYA decreased (APC, -2.01 [- 2.72 to -1.34)], slightly more in females (APC -2.05 [-2.93 to -1.26)] compared to males (APC, -2.01 [-2.74 to -1.34)]. The greatest decrease was seen in NHWs -2.4 [-3.1 to -1.8)]. There was no significant change in the AAIR among NHBs and Hispanics. NHBs showed the lowest 5-year survival rate (RSR-5: 58.8 [57.3-60.1]) with NHWs showing the highest survival (RSR-5: 77.8 [77.4-78.3]). On multivariable analysis, race was an independent predictor of mortality: Hispanics (HR: 0.78: 95% CI = 0.69 - 0.88) and NHAPI (HR: 0.79: 95% CI = 0.68 - 0.87) compared to NHW, had reduced odds of mortality. There was no association between sex and mortality. Conclusions: There is an overall decline in age-adjusted incidence rates of lung cancer, with more pronounced decline in females and specific racial groups. NHBs exhibited the lowest 5-year survival rate. Additionally, various socioeconomic and histologic factors demonstrated varying impacts on mortality. [Table: see text]
Predicting response of patients with NSCLC to immunotherapy using innate immune fitness (IIF) profiling.
Authors: Robyn Alice Lindley, Nathan E Hall, Jared Mamrot
Journal: Journal of Clinical Oncology (2024)

8038 Background: Aberrant activity of AID/APOBEC deaminase enzymes can cause 'off-target' somatic mutations in cancerous cells. Mutations associated with deaminases and other mechanisms can be quantified using metrics relating to motif usage, strand bias, transitions/transversions, codon context, and amino acid changes. Collectively, these metrics form an Innate Immune Fitness (IIF) profile (US Patent 20200370124). The aim of this project was to conduct IIF profiling on a cohort of Non-Small Cell Lung Cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI), and use the IIF profiles to build and evaluate a predictive model. Methods: Whole exome and progression-free survival (PFS) data was obtained from Rizvi et al. 2015, Hellmann et al. 2018, Miao et al. 2018, Fang et al. 2019, Frigola et al. 2021, and Ravi et al. 2023 (n = 515). IIF profiles were generated using CRIS (v5.0.0; GMDx Genomics Ltd). Patients were classified as a ‘Responder’ (PFS &gt; 12 months or Complete Response; n = 148) or ‘Non-Responder’ (PFS ≤ 12 months; n = 367). Machine learning models were generated using the H2O.ai AutoML platform and evaluated using multiple rounds of cross-validation. Patient response predictions were collated for each patient and a consensus ‘IIF Score’ was calculated. Multivariable analysis of IIF Score, TMB (10mut/Mb) and PD-L1 TPS ( &lt; 1%, 1% - 50%, &gt; 50%) was conducted using a Cox proportional-hazards model. Results: The predictive accuracy of IIF Scores was 76% (Sensitivity = 58%; Specificity = 83% , NPV = 83% , PPV = 58%) with a Hazard Ratio (HR) of 0.39 (0.29-0.53; p &lt; 0.001; corrected for TMB and PD-L1). In comparison, the predictive accuracy of TMB was 67% (Sensitivity = 53%; Specificity = 79% , NPV = 79% , PPV = 44%), HR = 0.77 (0.59-1.00; p = 0.049; corrected for IIF Score and PD-L1). ‘PD-L1 &gt; 50%’ accuracy was 53% and HR = 0.64 (0.44-0.94; p = 0.023; corrected for IIF Score and TMB). The Area Under the Curve (AUC) for IIF Score was significantly higher than TMB (0.77 vs 0.70; DeLong test: p &lt; 0.001). Conclusions: IIF Score was the strongest predictor of patient response to ICI. Despite the inherent limitations of combining data from multiple cohorts, IIF Score outperformed TMB and PD-L1 in predictive accuracy, HR and AUC. With a Negative Predictive Value of 83%, these results support the use of IIF Score as a biomarker for identifying ICI Non-Responders in NSCLC patients. Research Sponsor: GMDx Genomics Ltd.
Can teclistamab be safely administered in the community? A single-center experience.
Authors: Rahim Jiwani, Samantha Maples, Santhosh Sadashiv, Prerna Mewawalla
Journal: Journal of Clinical Oncology (2024)

e19502 Background: Majority of patients with multiple myeloma are treated in community settings. Teclistamab, a highly effective bispecific T-cell engager (BiTE), was approved for the treatment of relapsed refractory multiple myeloma but has the potentially lethal toxicity of cytokine release syndrome (CRS). Due to the risk of CRS, pharmacies/providers must be REMS-certified prior to prescribing treatment. CRS most commonly occurs after the 1 st 3 doses with a median onset time of 2 days. The hospitals most comfortable administering and monitoring for BiTE toxicities are typically transplant/cellular therapy centers. Patients are hospitalized for 48 hours following the administration of first 3 doses. Subsequent outpatient treatment typically continues at these centers as well, limiting patient access to highly effective treatment. Whether teclistamab can safely be given in non-rapid response community infusion centers (CIC) with a less vigorous monitoring schedule is unknown. We established a monitoring guide to expand teclistamab accessibility to 18 (CIC) in our network. Methods: At AHN, a monitoring guide was devised for teclistamab (Table) based on existing safety data regarding the incidence and timing of CRS. Patients would be admitted for the 1 st 3 doses and monitored for 48 hours after each dose. Starting with the 4 th dose, teclistamab administration at CIC with no additional monitoring would be allowed if there were no CRS events with the immediately preceding dose. If the patient experienced a CRS event with the immediately preceding dose, the patient would be monitored for 1 hour until a dose was tolerated with no subsequent CRS events. Nursing and pharmacist education was arranged for all CIC regarding CRS identification and management. All CIC pharmacies were prospectively enrolled in the teclistamab REMS program at the time education was deployed. Prescribing providers were REMS certified as well. Results: Between 1/2023 and 1/2024, a total of 8 patients were treated at 6 CIC within AHN. Of those 6 centers, 3 were non-rapid response CIC. Out of the eight patients treated at local infusion centers, starting with the fourth teclistamab dose, none experienced CRS events. No additional safety occurred, and no patients were subsequently hospitalized for teclistamab toxicities. Conclusions: Teclistamab can be safely administered at CIC, including centers without rapid response capabilities, starting with the 4 th dose after prior ramp-up administration. Post-injection monitoring may be reduced without increased incidence of CRS-related toxicities. Our monitoring guide may serve as a model for the safe administration of teclistamab and other BiTEs in CIC. [Table: see text]
Real-world comparison of adherence to branded 20 mg dexamethasone tablets and generic 4 mg dexamethasone tablets among patients with multiple myeloma.
Authors: Daniel G Worley, Iryna Melnyk, Dawn Johannesen, Jennifer Ellis, Pamela Landsman-Blumberg
Journal: Journal of Clinical Oncology (2024)

e19518 Background: Branded 20 mg dexamethasone tablets (BDex) is the first and only FDA-approved dexamethasone specifically indicated for the treatment of adult patients with multiple myeloma (MM) in combination with other anti-myeloma products. Generic oral dexamethasone is only available at lower dosages (e.g., 4 mg) despite the standard dexamethasone dosage for MM being 20 or 40 mg. The availability of 20 mg tablets would, therefore, reduce pill burden and assumably improve adherence in MM patients. The objective of this analysis was to quantify and compare adherence of BDex and generic 4 mg dexamethasone (GDex) among MM patients using real-world evidence. Methods: Using an open claims database, which included professional, hospital, and pharmacy claims for over 295 million individuals across the United States from 2015 to 2023, BDex and GDex users aged ≥18 years with MM were identified. Baseline summary statistics were generated and chi-squared and t-tests were performed comparing continuous and categorical variables respectively between the treatment cohorts. Treatment adherence was determined using a medication possession ratio for flexible time period (MPRF) given variable numbers of cycles across patients. MPRF was reported as both a continuous and binary measure (≥80%). Differences in MPRF were determined utilizing t-tests. Results: Between September 1, 2020 and June 30, 2023, 43 BDex and 3,775 GDex users meeting all study criteria, including ≥2 prescription claims, were identified. Overall, 30.8% were aged 18-64 years, 54.6% were male, 71.2% were insured through Medicare, and 20.3% were insured commercially. Bortezomib monotherapy, immunomodulatory agent monotherapy, and daratumumab and bortezomib were the most common treatment regimens (17.5%, 11.1%, 7.2%, respectively). Mean MPRF was significantly higher in BDex users compared to GDex overall (97.1% vs 89.5%, p &lt;0.001), among those 18-64 (98.7% vs 89.1%, p &lt;0.001), those with commercial insurance (99.9% vs 90.4%, p&lt;0.001), and those with Medicare (96.1% vs 89.6%, p=0.048). A significantly greater proportion of BDex users were considered adherent compared to GDex patients (95.3% vs 78.4%, p=0.007). This trend was seen across age and payer sub-cohorts, with significant differences seen in those with Medicare (96.0% vs 78.7%, p= 0.035). Conclusions: Adherence to BDex was greater than to GDex in this MM study population overall, and for age group and payer sub-cohorts. Given these findings, physicians may want to consider overall pill burden and regimen complexity when prescribing MM treatment for their patients.
Quantitative systems pharmacology (QSP) model to predict combination activity of CD19-targeted antibody drug conjugate (loncastuximab tesirine) co-dosed with a CD20/CD3 T-cell bispecific (epcoritamab) in patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Joseph P. Boni, Yuezhe Li, A. Katharina Wilkins, Jimena Davis, Tim Knab
Journal: Journal of Clinical Oncology (2024)

e19059 Background: Loncastuximab tesirine-lpy (Lonca) is an antibody-drug conjugate comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin. Epcoritamab-bysp (Epco) is a CD20×CD3 T cell-engaging bispecific antibody (bsAb) that redirects T-cells to eliminate malignant B-cells. Epco and Lonca target different B-cell surface antigens and combining both is expected to have additive or synergistic efficacy. Previously, a novel QSP model for Lonca was developed (Utsey K et al. Clin Pharmacol Drug Dev. 2023;12:123-125) and validated with clinical data from patients with R/R DLBCL (Caimi P et al. Blood. 2022;140:9548-9550). A combination QSP model for Lonca with Epco in R/R DLBCL was described to predict potential anti-tumor synergies in proposed clinical trials. Methods: The model reduced previous Lonca model complexity while maintaining core functionality and was combined with a published QSP model for T-cell bsAbs (Hosseini I et al. Npj Syst Bio Appl. 2020;6(1):1-11) to predict tumor dynamics after Lonca and/or Epco treatment. Assumptions included: 1) Lonca or Epco induce healthy and malignant B-cell killing; 2) tumor comprises malignant B- &amp; T-cells; 3) tumor volume is based on malignant B-cell count; 4) T-cells can enter or leave tumor as with other tissues; 5) CD19-/low CD20+ B-cells account for tumor heterogeneity from cells insensitive to Lonca treatment. Results: Tumor growth inhibition (TGI) was predicted to plateau by Cycle (C) 2 with Epco monotherapy. By end of C3, however, predicted median normalized tumor volume reduction with co-dosing Lonca and Epco was approximately 1 log order greater than Epco alone. Maximum activity of Lonca and Epco therapy was not observed until C4 or later as depth of tumor regression increased with additional treatment cycles. Since patients with DLBCL may present with low T-cell counts (Hutchings et al. Lancet. 2021) the effect of T-cell count at baseline was evaluated. A 50% decrease at baseline from 2000-1000 T-cells/µL significantly reduced antitumor effect with Epco alone but made no difference with Lonca in combination. Conclusions: These results resemble predictions for Lonca in combination with other bsAbs (Lonca plus mosunetuzumab or glofitamab; abstract submitted to AACR 2024). By end of C3, Lonca plus Epco was predicted to promote substantially more TGI than Epco or Lonca alone. While increased doses of Lonca from 90-150 µg/kg in combination had limited additional therapeutic benefit, combination treatment beyond C3 was predicted to increase depth of tumor regression. Response from Lonca and Epco co-dosing was predicted to be less affected by suppressed T-cell counts at baseline compared to Epco alone; a feature that may enhance responsiveness when T-cell level is moderate.
CD19 expression in diffuse large B-cell lymphoma (DLBCL) patient biopsies after treatment with tafasitamab.
Authors: Alla Volgina, Beth Rumberger, Hrefna Johannsdottir, Thomas Stauffer Larsen, Diana Alvarez Arias
Journal: Journal of Clinical Oncology (2024)

e19050 Background: Tafasitamab (tafa) is a CD19-targeting immunotherapy that induces enhanced antibody dependent cellular cytotoxicity and phagocytosis. Tafa received accelerated FDA approval in 2020 for treating relapsed or refractory DLBCL in combination with lenalidomide in patients ineligible for autologous stem cell transplant, based on results from L-MIND, a multicenter, open-label, single-arm, phase 2 trial. FirmMIND (NCT05429268) is an ongoing identical study, further evaluating efficacy and safety of tafa in this setting. Several other CD19 targeting agents are available; however, CD19 antigen loss following treatment with chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has raised concerns over CD19-targeted therapy sequencing. Loss of CD19 has not been observed to date in tafa clinical trials or practice. Methods: To evaluate CD19 expression at screening and after disease progression in firmMIND, we developed an immunohistochemistry (IHC) assay using a mAb that binds to an intracellular epitope of CD19 clone LE-CD19. To validate that CD19 expression is detectable after tafa treatment, we treated cultured SU-DHL-4 or Jurkat cells with tafa at a saturating concentration for 24 hours. After washing out unbound tafa, cells were harvested at specific timepoints. Resulting cell line blocks were assessed for CD19 expression by IHC. We also monitored CD19 trafficking in response to fluorescently labeled tafa by confocal microscopy. Results: By IHC, CD19 expression was comparable between treatment conditions, suggesting the assay can effectively measure CD19 expression in lymphoma biopsy samples post-tafa. Confocal microscopy showed a fraction of tafa-bound CD19 internalized and colocalized with a CD19 intracellular pool labeled with anti-CD19 mAb clone EPR5906; this mAb also detected CD19 that remained localized on the cell surface. The data demonstrated that CD19 persists on tumor cells after tafa treatment at levels that could be bound by other CD19-targeting therapies. As of the January 25, 2024 data cutoff, we received 6 end-of-treatment (EOT) samples from patients in firmMIND. Biopsies were collected 14-26 days after the last tafa dose; 5 of 6 samples were biopsies from lymph nodes or liver and showed ≥80% of tumor cells staining CD19+ on membranes with 3+ intensity by IHC, except 1 that was collected only 6 days after last dose and showed 50% positivity. The sixth biopsy (extranodal subcutaneous lesion) showed no CD19 expression at baseline or EOT. Conclusions: Patient biopsy analysis and preclinical data suggest that following tafa treatment, CD19 antigen is preserved on the surface of tumor cells after short and transient internalization and could be targeted by other CD19 agents, such as CART therapy. This conclusion is supported by sequential treatment with tafa followed by CART in vivo (Sakemura, 2024). Analyses are ongoing to confirm these findings.
Efficacy of venetoclax-dexamethasone (VenDex) v pomalidomide-dexamethasone (PomDex) in patients (Pts) with t(11;14)-positive relapsed/refractory multiple myeloma [t(11;14)+ RRMM]: Phase 3 CANOVA study biomarker subgroup analysis.
Authors: Nizar J. Bahlis, Rakesh Popat, Meral Beksac, Meletios Athanasios Dimopoulos, Moshe E. Gatt, Francesca Gay, Jae-Cheol Jo, Prashant Kapoor, Martin Kortüm, Silvia Ling, Chandramouli Nagarajan, Kenshi Suzuki, Maika Onishi, Monique Dail, Emily Rossi, Xizhi (Adam) Luo, Emma Louise Arriola, Orlando Felix Bueno, Jeremy A. Ross, Maria-Victoria Mateos
Journal: Journal of Clinical Oncology (2024)

7510 Background: The randomized Phase 3 CANOVA study’s (NCT03539744) primary analysis showed multiple numerically improved efficacy endpoints with VenDex v PomDex, but the primary endpoint of mPFS by IRC was not statistically significant. Here, we report correlative biomarker analyses from CANOVA. Methods: CANOVA is a randomized, global, open-label Phase 3 study of VenDex v PomDex in pts with t(11;14)+ RRMM and ≥2 prior lines of therapy (LOTs). The primary endpoint was mPFS by IRC. Key secondary endpoints included ORR, ≥VGPR, mOS, and MRD negativity (&lt;10 -5 ). In post hoc mPFS sensitivity analysis, disease progression, death, and start of next LOT were defined as events. BCL2 gene expression by RNAseq (3.7 log2 FPKM prespecified median cutoff for BCL2 high v BCL2 low ) and chr1q abnormalities by whole-exome sequencing (normal, gain, or amp) were assessed centrally from pretreatment, CD138-enriched BM aspirates. Results: mPFS, post hoc mPFS, and mOS in the VenDex arm were similar by BCL2 status, with numerically higher ORR, ≥VGPR, and MRD negativity rates in the BCL2 high subgroup. In contrast, mPFS and mOS within the PomDex arm were numerically longer in the BCL2 low subgroup, despite equal ORR in both subgroups (Table). Presence of 1q abnormalities was evenly distributed across BCL2 high v BCL2 low subgroups in the VenDex arm (51% v 45%) but not in the PomDex arm (59% v 31%). Normal 1q and gain(1q) subgroups had numerically improved mPFS, mOS, ORR, ≥VGPR, and MRD negativity with VenDex; pts with amp(1q) had poor outcomes regardless of treatment, albeit the sample size was small. Conclusions: Pts with BCL2 high or gain(1q) had numerically improved clinical efficacy with VenDex v PomDex. Clinical benefit was consistent across BCL2 subgroups ( BCL2 high or BCL2 low ) with VenDex but not PomDex. Pts with amp(1q) fared poorly irrespective of treatment arm. Clinical trial information: NCT03539744 . [Table: see text]
A phase I, first-in-human study of ONO-7018 in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia.
Authors: John C. Byrd, Pierluigi Porcu, Thomas Sundermeier, Takashi Nakada, Takeyuki Iwata, Sergio Prados, Leo I. Gordon
Journal: Journal of Clinical Oncology (2024)

TPS7083 Background: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key component of the caspase recruitment domain-containing protein 11 (CARD 11)-B-cell lymphoma/leukemia 10 (BCL 10)-MALT1 signalosome complex, which activates nuclear factor-kappaB (NF-κB) signaling in response to B-cell–receptor or T-cell–receptor stimulation. Activation of NF-κB signaling promotes survival and proliferation of B-cell lymphoma and T-cell lymphoma. ONO-7018 is an oral, potent, and selective MALT1 inhibitor that has demonstrated preclinical efficacy in several lymphoma models (Morishita D, et al. Blood. 2020). Therefore, ONO-7018 has therapeutic potential for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This study aims to determine the maximum tolerated dose (MTD) and to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ONO-7018 as monotherapy in patients with relapsed or refractory NHL or CLL. Methods: This Phase I, first-in-human, open-label, multicenter study will be done in two parts, a dose-escalation phase (part 1) and a dose-expansion phase (part 2). An estimated 54 eligible patients will be enrolled. Patients must be adults with relapsed/refractory NHL or CLL with measurable disease; all acute toxic effects of prior antitumor therapy should be grade ≤1; have Eastern Cooperative Oncology Group performance status 0 to 2; and have adequate bone marrow, renal, and hepatic function. Exclusion criteria include history of other lymphoid malignancy, central nervous system involvement, active autoimmune disease, systemic and active infection, serious or uncontrolled medical disorder, and patient inability to swallow tablets. ONO-7018 will be administered orally. In part 1, patients will be assigned to a dose level cohort (≤4 dose levels: DL1-DL4) using a 3+3 dose-escalation design. In part 2, patients will be given the recommended dose level from part 1, following safety review. The primary endpoints include dose-limiting toxicity, MTD, and treatment-emergent adverse events. Secondary endpoints include pharmacokinetics, objective response rate, duration of response, progression-free survival, and overall survival. The study began February 13, 2023, and is currently recruiting; part 1 is ongoing. Clinical trial information: NCT05515406 .