Real-world Population Research Articles

Interaction between VEGF-A and immune checkpoint targets in triple-negative breast cancer and mechanisms of immune evasion and tumor progression.

1096 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment triple negative breast cancer (TNBC). However, not all patients with TNBC benefit from the addition of ICIs due to factors such as intrinsic and acquired resistance to ICIs, and complex interplay between tumor and immune cells in the tumor microenvironment (TME). Vascular endothelial growth factor (VEGF) promotes angiogenesis and potentially modulates tumor immune evasion. A phase I clinical trial has shown that a bispecific antibody to VEGF-A and PD-L1 produces encouraging tumor responses in advanced TNBC. In this study, we investigated the interaction between VEGF and various immune gene expression signatures including PD-L1 in a real-world breast cancer patient population. Methods: Comprehensive immune profiling, including the RNA-seq based gene expression assessment of 395 immune-associated genes, was performed on 120 formalin-fixed paraffin-embedded breast cancer samples. PD-L1 expression (Combined Positive Score, CPS ≥ 10%) was measured by immunohistochemistry (IHC; 22C3). Clinicopathologic variables were collected. Statistical associations between quantitative biomarkers, including 28 immune checkpoint genes, were calculated using Pearson correlations (r), and comparisons of quantitative biomarkers between groups were performed using the proportions test. For statistical significance, p<0.05 was required. Results: The study cohort included 29 patients (24.2%) with TNBC and 91 (75.2%) with non-TNBC (including ER+/HER2- and HER2+). Most patients had metastatic tumors (n=92, 76.7%) and invasive ductal carcinoma (n=83, 69.2%). Among the TNBC group, 21 patients had PD-L1 positive tumors (72.4%), defined by CPS ≥ 10.In non-TNBC, VEGF has significant, though weak (r<0.35) correlations with the expression of three checkpoint genes: AKT1 (r=0.35, p=0.00063), ICOS (r=0.34, p=0.00099), and TIM3 (r=0.29, p=0.0061). In TNBC, VEGF has significant, strong (r>0.47) correlations with the expression of three other checkpoint genes: PD-1 (r=0.47, p=0.0094), PD-L1 (r=0.57, p=0.0012), and PIK3CA (r=0.6, p=0.00051) However, in TNBC, VEGF gene expression does not have a statistical association with PD-L1 IHC (CPS ≥/< 10 (p=0.9)). Conclusions: Our findings suggest that there is an interplay between angiogenesis and an immunosuppressive tumor immune microenvironment in TNBC to a greater degree than in non-TNBCs. This supports the notion that angiogenesis mediators such as VEGF-A may enhance the expression of immunosuppressive checkpoint molecules, leading to immune evasion and tumor progression. Combination treatments of ICIs, especially anti-PD-1 therapy, with VEGF antibodies may be promising approaches to enhance the immune responses in TNBC, especially in tumors with CPS<10, where the current frontline treatment is cytotoxic chemotherapy.

Comparison of zanubrutinib (zanu) and acalabrutinib (acala) in B-cell malignancies: An adverse event (AE)-based analysis.

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [Table: see text]

Impact of pathogenic germline variants in HRR genes on gastroesophageal cancer in a large real-world Chinese population: A comprehensive study.

10588 Background: Genetic testing in gastroesophageal cancer has been limited to those with hereditary cancer syndromes, restricting understanding of the impact of germline variants in sporadic cancers. Our study expands this by exploring germline and somatic characteristics in a broad Chinese cohort, enhancing risk assessment and guiding treatment strategies in a wider population. Methods: From October 2017 to April 2023, we retrospectively analyzed 2596 Chinese gastroesophageal cancer (GEC) patients, including 2003 with gastric cancer (GC), 196 with gastroesophageal junction cancer (GEJC), and 397 with esophageal cancer (EC). A 520-gene panel including 62 genes associated with cancer predisposition, was employed for genomic profiling of paired tumor and white blood cell samples. The pathogenicity of germline variants was determined according to ACMG guidelines. Results: In this retrospective cohort, the proportion of patients carrying pathogenic/likely pathogenic (P/LP) germline variants was 5.3% in GC, 5.6% in GEJC, and 5.0% in EC, respectively. Notably, genes associated with HRR exhibited the highest rates of P/LP germline mutations in GEC (94, 3.7%), with the majority occurring in non-BRCA HRR genes (77, 3.0%). The top five genes with the highest mutation rates were ATM, PALB2, FANCA, CHEK2, and RAD54L. Compared to the East Asian population without cancer in the genomAD database, a higher proportion of P/LP germline mutations were found in the CDH1(Inf [6.46-Inf], p < 0.001), PALB2 (5.60 [1.61-13.09], p = 0.002), SDHA (8.99 [1.29-99.42], p = 0.012), ATM (2.15 [1.08-4.09], p = 0.02), and CHEK2 (3.83 [1.06-13.32], p = 0.02) genes in GC. Similarly, significant increases in PALB2 (10.36 [2.32-37.28], p = 0.002) and ATM (4.42 [0.86-14.33], p = 0.036) were also observed in EC and GEJC. The HRR P/LP variant group exhibited a higher incidence of biallelic inactivation (loss of wildtype allele) compared to the B/LB variant group (24.7% vs 6.6%, p<0.001). Moreover, the similar trend was observed for the moderately/uncertainly penetrant gene ATM and FANCA (38.5% vs 0.6%, p < 0.001; 42.9% vs 9.8%, p = 0.025), which suggests that ATM and FANCA may be associated with a high risk. The HRR genes ATM(56 vs 61, p = 0.052), CDH1(33 vs 61, p = 0.003), and FANCI(48 vs 61, p = 0.041) with P/LP variants were associated with a younger age of onset. Carriers of HRR P/LP variants had less prevalent somatic TP53 variants in GC and GEC and higher HRD score compared to non-carriers (p=0.005). Conclusions: Our research delineates the germline P/LP variant landscape in Chinese GEC, revealing the significant role of HRR P/LP variants. The presence of P/LP variants in HRR genes in GEC is linked to distinct disease characteristics and progression, underscoring their importance in guiding personalized treatment approaches and risk evaluation.

Characterization of remote symptom alerts generated from patient-reported outcome (PRO) symptom monitoring in a real-world breast cancer population.

e23193 Background: Women with breast cancer experience debilitating symptoms, yet the patient-reported symptom burden among patients on treatment remains largely uncharacterized. This study characterized electronic PRO (ePRO) symptom monitoring data of patients with breast cancer in real-world settings to assess differences in remote symptom alerts by clinical characteristics. Methods: We conducted a retrospective descriptive study of complete case ePRO data reported by patients at twelve US sites using Carevive PROmPT, a remote symptom monitoring platform. Participants consent to share de-identified, aggregate ePRO symptom data and sociodemographic and clinical characteristics from the electronic health record. We characterized PRO-CTCAE symptom data reported by breast cancer patients on active cancer treatment enrolled between 9/2020 and 11/2023. The PRO platform generates an algorithm-based alert if the combination of symptom severity, frequency, and interference is moderate or severe. We used descriptive statistics to characterize symptom severity and number of alerts by baseline patient-report ECOG status, age, cancer stage (Stage I-III vs. IV), and breast cancer subtype. Results: Of 646 patients, 519 (80%) generated alerts during treatment. Population characteristics were: median age 56 years-old (range 26-84), 72% White, 20% Black/African American, 62% Stage I-III, 15% HER2 positive, 47% ER and/or PR positive, HER2 negative,18% triple negative. Patients reported a total of 19,425 symptoms over a median of 12 weeks with 80% compliance rate, of which 39% resulted in alerts. Participants generated a median of 1 alert per week. About 50% of alerts occurred in the first 12 weeks of ePRO completion, with a higher proportion in Week 1-4 across all subgroups (range, 15-38%). On average, ECOG 2 or greater patients generated more alerts per week than ECOG 0-1, (mean 2.1, (SD 1.3) vs. 1.7 (SD 1.0). Younger patients ( < 50 years) generated more alerts compared to those older than 50 years (87% vs. 77%). Patients with early-stage disease reported more alerts than the Stage IV group (81% vs. 78%). In the metastatic setting, triple negative patients reported a median of 3 (range 1-8) moderate/severe symptoms per week; the other subtypes reported a median of 1 (range 1-8). Conclusions: Women on breast cancer treatment reported their symptom experience with high compliance rates in the real-world setting. Nearly 40% of symptom reports generated an alert, with a higher proportion in the first month of treatment. Younger, early-stage, and metastatic triple negative patients with breast cancer reported a higher symptom burden compared to other groups. Future work will investigate symptom experience by sociodemographic and clinical characteristics to further identify patients who may benefit from more intensive symptom reporting and management.

Efficacy of trifluridine/tipiracil in 3rd or 4th line of treatment in patients with advanced or metastatic colorectal cancer: A real-world data analysis with subgroups exploration.

e15576 Background: Patients with unresectable mCRC can achieve long-term overall survival (OS) thanks to modern systemic treatment and subsequent lines of therapy. With effective 1st, 2nd and next lines of therapy, their condition often allows further lines of treatment. Since publication of RECOURSE study, one of the most frequently used drugs in the 3rd or 4th line is trifluridine/tipiracyl (FTD/TPI). There is limited data on optimal selection of patients in order to obtain the greatest therapeutic gain with the least toxicity. The aim of this study was to find and define groups of patients who would benefit most from this treatment in a real-world mCRC patient population. Methods: Consecutive patients with unresectable or metastatic colorectal cancer (mCRC) started treatment with FTD/TPI between 1/Sep/2019 and 31/Dec/2023. Clinical factors including age, gender, primary location of colorectal cancer, BRAF, RAS and MSI-H status, ECOG performance status, baseline CEA level, location of metastases, response to treatment and AEs occurrence were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Jan/2024. Results: 822 medical records of patients with mCRC were analyzed. In total 261 patients treated with FTD/TPI were enrolled. 204 (78%) patients were treated with FTD/TPI in 3rd line (L3) and 57 (22%) in the 4th line (L4). Patients with RASmt were statistically more numerous in the L3 group; no other statistically significant differences in baseline characteristics was found between L3 and L4 groups. Estimated median OS (mOS) was 10.2 and 14.4 months in L3 and L4 group, respectively; no statistical significance was found between them (p = 0.0866; HR = 1.34, Cl 95% 0.9-1.9). Estimated median PFS (mPFS) was 7.4 and 4.6 months in L3 and L4 group, respectively, and statistically significant differences in mPFS was found in the L3 group in comparison to L4 (p = 0.0079; HR = 0.65, Cl 95% 0.5-0.9). Disease progression (PD) was found in 187 (92%) and 50 (88%) patients in the L3 and L4 group, respectively. PD was most common reason for discontinuing therapy. Most frequent serious AEs of grade 3 or higher were diarrhea, neutropenia and weakness. There were no grade 5 AEs and toxicity rarely led to discontinuation of FTD/TPI therapy. 102 (39%) patients were qualified for next line sequential systemic treatment after L3 or L4. Conclusions: Patients with mCRC who were treated with FTD/TPI in the 3rd line had better PFS than patients treated in 4th line, but mOS was statistically non-significantly better in L4 than L3, which requires further analysis. FTD/TPI is an effective therapy in subsequent lines of treatment for mCRC patients with acceptable toxicity.

Real-world immune-related adverse events in patients with early triple negative breast cancer who received pembrolizumab.

1099 Background: The addition of pembrolizumab to chemotherapy (KEYNOTE-522 regimen) in high risk early triple negative breast cancer (TNBC) has improved clinical outcomes. However, this treatment can result in immune-related adverse events (irAEs) involving any organ and in some cases, life-long toxicities or even death. This retrospective study describes real-world patterns of irAEs in patients (pts) with early TNBC who received pembrolizumab at two academic centers. Methods: We evaluated irAEs in pts with stage II-III TNBC from MD Anderson Cancer Center and Lyndon B Johnson diagnosed between January 2018 and May 2023 who received neoadjuvant pembrolizumab plus chemotherapy. We excluded those enrolled on clinical trials. We utilized ASCO irAE and CTCAE v5 guidelines for toxicity grading. Logistic regression assessed the effect of clinical variables on irAEs, adjusting for covariates. Results: We identified 233 pts with a median age of 51 ± 12 years; 62% with stage II and 35% with stage III TNBC; 25% were Hispanic/Latino, 21% non-Hispanic Black and 42% were non-Hispanic White. In total, 80 pts (34%) developed 100 separate irAEs (94 with definite and 6 with possible/probable attribution). The most common irAEs were endocrine (52%) followed by gastrointestinal (23%). Grade ≥ 3 irAE occurred in 26 instances, with the most common being gastrointestinal (13 instances). A fatal irAE occurred in 2 pts where both were colitis. A total of 26 irAEs resulted in hospitalization, 45 required systemic steroids, and 15 required additional immunosuppressive therapy. Most (66) irAEs were unresolved at last follow up, although the majority had improved to grade 1 (37/66) and 32 patients discontinued pembrolizumab early due to irAEs. No clinical factor (race, stage, tumor grade, age, body mass index) was associated with development of an irAE. Conclusions: In this real-world diverse population, we identified a similar rate and severity of irAEs as reported in the KEYNOTE-522 trial. Hospitalizations occurred in 26% of irAEs while most developed persistent immune toxicity. Gastrointestinal irAEs were more common compared to KEYNOTE-522 reported data. Research is needed to better predict and mitigate the burden of irAEs and to improve the long-term survivorship care of pts with early TNBC pts who receive pembrolizumab. [Table: see text]

Treatment rates and reasons for non-treatment in a real-world cohort of patients with pancreatic cancer.

e13554 Background: The proportion of patients who receive treatment for pancreatic ductal adenocarcinoma (PDAC) and reasons for non-treatment in real-world patient populations are poorly understood. Our study aims to determine treatment rates, predictors for non-treatment, and the rationale for declining treatment in a well-defined, diverse, community-based patient population. Methods: We identified all adult patients with PDAC (n = 3852) between 2010 and 2020 through the Kaiser Permanente Northern California Cancer Registry. Patients were stratified by age and tumor characteristics to determine rates of oncologic therapy. Multivariable logistic regression was used to assess how covariates were associated with receiving treatment. A detailed chart review of all patients ≤ 65 years and a random sample of 100 patients > 65 years with non-metastatic disease who did not receive treatment was performed to better understand the reasons for non-treatment. A random sample of 20 patients with metastatic disease who did not receive treatment were also reviewed. Results: Of patients with PDAC, 77.7% of patients with non-metastatic and 56.2% with metastatic disease received any cancer-directed treatment. A multivariate analysis showed no statistically significant differences by race/ethnicity or gender. Increasing age was a significant negative predictor of treatment. Charlson comorbidity index (CCI) did not influence treatment rates in patients with non-metastatic PDAC, but in patients with metastatic disease those with CCI 3+ had a decreased odds of receiving treatment. Of patients ≤ 65 years with non-metastatic disease, 90.3% were seen by an oncologist, and of those patients 89.3% were offered treatment. The primary reason for declining treatment was patient/family preference in 80.8%, followed by PDAC-related frailty in 11.5%, and medical comorbidity/other malignancy in 7.69%. Similarly, of patients > 65 years with non-metastatic disease, the majority were also seen by an oncologist, offered treatment, and declined due to personal preference. The same trends were noted in patients with metastatic PDAC. Conclusions: A significant proportion of patients with PDAC did not receive cancer-directed treatment in a real-world, community-based patient population, and this was more likely for patients with metastatic disease. Race and gender did not influence whether patients received treatment in this fully insured patient population and comorbidity had a small effect. Patients of increasing age, however, were less likely to receive treatment. Most patients who did not initiate treatment did so primarily due to patient/family preference despite being offered cancer-directed therapy by their treatment team. These findings may help guide the development and utilization of patient decision-aids in PDAC to improve goal concordant care that accounts for patients’ preferences and values.

Prognostic impact of BRCA mutation on metastasis-free survival in a localized/locoregional high-risk real-world prostate cancer population.

Prognostic impact of BRCA mutation on metastasis-free survival in a localized/locoregional high-risk real-world prostate cancer population.

The transformative role of digital health platforms: Bridging diversity gaps in cancer care in younger patient populations.

e13503 Background: Digital health platforms are transforming cancer care by offering unprecedented access to treatment options, including clinical trials (CTs). In this study, we analyzed data from the Leal digital health platform to identify demographic and behavioral trends among patients that may have implications for quality care and access to advanced treatments. Methods: Leal is an AI-based platform that matches cancer patients to CTs based on a self-reported medical profile. The profile includes parameters essential for CT matching, including disease status, stage, biomarker/mutational status, treatment history, comorbidities and demographics. The analysis incorporated data from 34,913 Leal Health community members, spanning a range of cancer types and encompassing all disease stages. Results: The digital platform attracted a significantly younger user base, while also reflecting key demographic trends consistent with the broader real-world cancer patient population. Specifically, 45% of the users were under 60 years old, and 20% were under 50, leading to a mean age of 60 years. This is notably younger than the general cancer patient population's mean age at diagnosis of 66 years (p = 0.03). The platform engaged diverse demographics, particularly among younger age groups (p<0.0001). Notably, one-third of users under 40 and over a quarter under 60 belonged to minority groups. African American at younger ages represented about 10% of all signups, bridging a significant disparity for this minority group, even more so within the space of CT search and recruitment where African Americans represent up to 5% of patients. Moreover, younger users exhibited significantly higher disease knowledge (p<0.0001), enhancing their potential for precise matching with advanced treatments. Conclusions: Digital health platforms uniquely attract younger and more diverse demographics, reflecting a broader spectrum of patient needs and experiences while significantly bridging racial disparity in CTs representation. This shift has profound implications for healthcare knowledge and outcomes. Our findings highlight the importance of adopting digital platforms to address the unique needs of the younger patient population.

Assessment of carcinoembryonic antigen-related cell adhesion molecule 5 expression by immunohistochemistry in real-world clinical samples of non-small cell lung cancer.

e20013 Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an emerging target of antibody-drug conjugate therapy for non-small cell lung cancer (NSCLC). High expression of CEACAM5 has been reported in approximately 25% of patients with lung adenocarcinoma (Lefebvre AM, et al. Lung Cancer. 2023; 184:107356). However, CEACAM5 expression has not been systematically examined in a real-world patient population with NSCLC. In this study, we evaluated our experience in the assessment of CEACAM5 expression by immunohistochemistry (IHC) in routinely diagnosed clinical samples. Methods: We assessed the expression of CEACAM5 by IHC on clinical biopsy/resection samples of consecutively diagnosed NSCLC from September 2022 to June 2023 at our institution, using the anti-CEACAM5 clone 769 antibody assay protocol developed for tusamitamab ravtansine clinical trials. Only cases adequate for PD-L1 22C3 and Oncomine Comprehensive Assay v3 NGS assay were included. CEACAM5 expression was scored independently by three pathologists based on the method proposed by Lefebvre et al. Expression levels were categorized as high (≥ 50% tumor cells at ≥ 2+ intensity), moderate (1–49% tumor cells at ≥ 2+ intensity), and negative (0 or 1+ intensity). Interrater reliability was assessed by Kendall’s coefficient of concordance (KCC) and Fleiss’ Kappa. Discordant classification was reviewed with the final classification achieved by consensus. Association with PD-L1 TPS and NGS results was determined by Chi-squared test. Results: This study cohort consisted of 150 consecutively diagnosed NSCLC, including 133 adenocarcinomas and 17 squamous cell carcinomas. The samples were derived from both primary (n = 138) and metastatic sites (n = 12). Both membranous and cytoplasmic CEACAM5 expression was observed in neoplastic cells, but was consistently absent in nonneoplastic cells. The prevalence of consensus high CEACAM5 membranous expression was 21% (n = 32) overall, 20% in primary (n = 28) and 33% (n = 4) in metastatic sites. The level of interrater agreement across all categories was moderate (KCC = 0.77). Interrater agreement between high CEACAM5 expression versus moderate/negative categories combined was also moderate (Kappa = 0.60). Challenging features included the determination of staining intensity and mixed membranous and cytoplasmic staining pattern, and cases near the cut-offs of the defined categories. CEACAM5 expression was not associated with PD-L1 TPS (p = 0.42) or EGFR mutations (p = 0.44). Conclusions: Our data showed that approximately 20% of routinely diagnosed clinical NSCLC samples had high CEACAM5 expression by IHC. The interrater reliability on the determination of high CEACAM5 expression was moderate among the three pathologists. We highlighted the challenging aspects in the evaluation of this biomarker.

Prognostic analysis and outcomes of metastatic pancreatic cancer patients receiving nab-paclitaxel plus gemcitabine as second or later-line treatment.

Pancreatic cancer (PC) first-line therapy often consists of polychemotherapy regimens, but choosing a second-line therapy after disease progression, especially following first-line FOLFIRINOX, remains a clinical challenge. This study presents results from a large, multicenter, retrospective analysis of Italian patients with metastatic PC (mPC) treated with Nab-paclitaxel/Gemcitabine (AG) as second or later line of treatment. Main objective of the study is to identify prognostic factors that could inform treatment decisions. The study included 160 mPC patients treated with AG in 17 Italian institutions. AG was administered according to labelling dose, until disease progression, unacceptable toxicity or patient refusal. Variations in schedules, dose modifications, supportive measures, and response evaluation were determined by individual clinicians' practice. AG was well-tolerated and exhibited promising clinical activity. The overall response rate (ORR) and the disease control rate (DCR) were 22.5% and 45.6%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 6.8 months, respectively. Among the patients who received AG as a second-line therapy (n = 111, 66.9%), median PFS and OS were 4.2 and 7.4 months, respectively. Notably, in the 76 patients (68%) receiving AG after first-line FOLFIRINOX, an ORR of 19.7% and a DCR of 46.0% were observed, resulting in a median PFS of 3.5 and median OS of 5.7 months. The study identified specific clinical or laboratory parameters (LDH, NLR, fasting serum glucose, liver metastases, ECOG PS, and first-line PFS) as independent prognostic factors at multivariate level. These factors were used to create a prognostic nomogram that divided patients into three risk classes, helping to predict second-line OS and PFS. This study represents the largest real-world population of mPC patients treated with AG as a second or later line of therapy. It supports the feasibility of this regimen following first-line FOLFIRINOX, particularly in patients with specific clinical and laboratory characteristics who derived prolonged benefit from first-line therapy.

Improving ethnic and racial diversity within clinical trial populations through community recruitment and inclusion initiatives: Experience from MyTACTIC.

e13679 Background: Clinical trial populations are not typically ethnically diverse, restricting healthcare equity and the generalizability of clinical trial data to real-world populations. Moreover, mostpatients (pts) with cancer in the US receive treatment in the more diverse community setting, where minority groups are usually better represented but with lower trial enrollment rates than academic centers. MyTACTIC (NCT04632992) is a phase II, non-randomized basket trial evaluating targeted therapies in pts with advanced solid tumors with specific biomarkers. Inclusive research practices, including mostly community recruitment, were implemented in MyTACTIC to improve access for patients who may otherwise not have been able to enroll. This retrospective analysis presents their impact on the diversity of the trial population. Methods: Adult pts with advanced solid tumors were enrolled from community cancer clinics (private practices and community hospitals) or large academic centers, into 1 of 15 arms based on biomarker alterations. Inclusive research practices implemented to diversify pt recruitment included: revision of eligibility requirements to be more inclusive for minorities; language simplification and streamlining of study protocol; training activities; free transportation. We compared race and ethnicity data between the study population and trial sites’ catchment area (geographical area of pts around the clinical site). Results: Forty pts, all of White race, were initially enrolled across 14 sites, which prompted additional focus on diversity efforts. The trial was expanded to 45 sites across 21 states: 252 pts were enrolled (83% of White race) (Table). Most (96%) selected sites (n=249 pts) were community clinics. The proportion of pts from racial minorities was generally higher in study centers from ethnically diverse catchment areas. Protocol streamlining and staff training were also beneficial to pt recruitment. Free-ride transportation removed the barrier of access to clinical trial sites. The impact of other initiatives will be presented. Conclusions: Running clinical trials at community oncology sites does not, in itself, equal increased diversity of study populations: other efforts, including but not limited to free transportation and community site selection, are also needed. Here we share some learnings from the MyTACTIC study, based on outcomes from the various inclusive research practices implemented in this trial. Clinical trial information: NCT04632992 . [Table: see text]

Increase in blood pressure in patients with metastatic kidney cancer treated with combination checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.

e24128 Background: The combination therapy of an immune checkpoint inhibitor (ICI) with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) is considered a first line treatment option for patients with metastatic clear cell renal cell carcinoma (ccRCC). TKI-induced hypertension is a well-known potential side effect with VEGFR-TKIs however little is known about the real-world increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with and without underlying hypertension treated with this combination therapy. Methods: A retrospective study was performed that included patients with metastatic ccRCC who were treated at the University of Florida Health Cancer Center between June 2019 and September 2022 who received treatment with the combination of an ICI and VEGFR-TKI. The data collected included history of hypertension, patients use of anti-hypertensive therapy at baseline, SBP and DBP prior to initiation of therapy and at approximately one month after initiation of treatment. Results: We identified a total of 29 patients who met the inclusion criteria for our study. The median age was 68 years old (IQR 61-72) while 25 patients (86%) were male and 4 (14%) were females. There were 27 patients (93%) who were treated with axitinib with pembrolizumab, while 1 (3%) was treated with cabozantinib with nivolumab, and 1 (3%) was treated with lenvatinib with pembrolizumab. Out of the 29 patients, 11 (38%) did not have hypertension prior to therapy while 18 (62%) did have baseline hypertension and were receiving at least one anti-hypertensive treatment. In those patients without baseline hypertension, the median baseline SBP was 113 and the median SBP after one month of treatment was 144 (p = 0.01). Conversely, those patients with baseline hypertension, the median baseline SBP was 122 and median SBP after one month of treatment was 148 (p = 0.003). In those without hypertension at baseline, the mean SBP increase after one month was 27.3% while in those with baseline hypertension the mean increase in SBP of 17.0%. Conclusions: Our study demonstrates that in a real-world population of patients with metastatic ccRCC there is a statistically significant elevation of both SBP and DBP when treated with the combination of an ICI and VEGFR-TKI and that in those patients without baseline hypertension and not on anti-hypertensive therapy at baseline, there is a more pronounced increase in blood pressure. This data should reinforce the need to have close monitoring of SBP and DBP during therapy, regardless of whether the patient has underlying hypertension or not, and may help guide anti-hypertensive therapy during kidney cancer treatment.

Survival benefit of autologous transplant (ASCT) for mantle cell lymphoma (MCL) in the California Cancer Registry (CCR).

e19043 Background: Extended follow up of the prospective Nordic MCL2 cohort shows ASCT in CR1 confers a median OS (mOS) of 12.7 y (Eskelund, BJH 2016). Incorporation of BTK inhibitors in 1L MCL is challenging the role of ASCT in an ongoing prospective trial (TRIANGLE, ASH 2022). The present study aims to evaluate the role of ASCT and the impact of social determinants of health (SDH) in a diverse real-world population of MCL patients. Methods: Adult MCL patients diagnosed from January 1, 2000 to December 31, 2020 in the CCR were identified with ICD-O-3 code 9673. The study was approved by UCLA IRB. OS was estimated using KM statistics, calculated from diagnosis to death/last follow-up. Univariate Cox proportional hazards modeling for lymphoma-specific survival (LSS) was performed for variables of interest; those significant at p ≤ 0.10 were incorporated in a stepwise multivariable regression excluding patients with missing data. Socioeconomic status (SES) variables were reported using census-block group data at diagnosis. Results: 5740 ethnically diverse patients were included (NH Whites, n=4038; NH Black, n=175; Hispanic, n=1057; Asian/Pacific Islanders, n=400). Median age at diagnosis was 69 y (IQR 61–68) and 71% were males. 4096 (71%) and 1346 (23%) patients received chemoimmunotherapy and were treated at an NCI/NCCN center, respectively. With a median follow-up of 33 m (IQR 9–76), mOS of the entire cohort was 4.4 y. ASCT patients (n=652, 11%) had improved mOS compared to non-ASCT (14.2 y vs 3.7 y, respectively p<0.001), and 100-day TRM was 2.5%. In the univariable model for all subjects, age, Charlson Comorbidity Index (CCI), married, chemoimmunotherapy, ASCT, NCI/NCCN center, insurance, period of diagnosis, and community SES, poverty, and education were prognostic for LSS. Race, sex, and rural residence were not associated with LSS. Multivariable analysis of 4148 subjects showed significant predictors of LSS were age ≥ 70 y (HR 1.71, p<0.001), ASCT (HR 0.54, p<0.001), diagnosis after 2013 (HR 0.78, p<0.001), CCI (Ref 0; 1-2 HR 1.22, p<0.001; 3+ HR 1.94, p<0.001), married (HR 0.86, p=0.003), NCI/NCCN treatment center (HR 0.77, p=0.001), higher education (top 40% with high school diploma vs. bottom 20%, HR 0.70, p<0.001), higher overall SES (medium vs. low SES tertile, HR 0.81, p=0.003), and increased community poverty (middle 40% vs. bottom 20%, HR 1.14, p=0.043). Conclusions: Our data represent the largest real-world cohort describing the role of ASCT and SDH in MCL. A minority of patients received ASCT and had improved OS compared to non-ASCT patients. While follow-up of ongoing prospective studies will clarify the role of ASCT using contemporary 1L regimens, the present data suggest ASCT in select patients results in durable response with low TRM. Socially disadvantaged patients should be identified and offered supportive programs early in the disease course to mitigate inferior outcomes.

Sex influence on cancer immunotherapy efficacy and safety in advanced non-small cell lung cancer (NSCLC): A Canadian institution real-world experience.

e20618 Background: Males and females differ in innate and adaptive immune responses. This difference may also be reflected in their response to cancer immunotherapies. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced NSCLC, however the impact of sex on treatment outcomes in these patients remains unclear. The aim of this retrospective cohort study was to evaluate sex-related differences in immunotherapy outcome in a real-world population of NSCLC patients treated with ICIs. Methods: Demographics, clinical, pathological and treatment characteristics were assessed. Treatment-related variables were analyzed to understand the differences in efficacy and safety outcomes including response rates, PFS, OS and all-cause treatment discontinuation (TD) in relation to sex. Results: 152 advanced NSCLC patients receiving first-line immunotherapy, either alone or in conjunction with chemotherapy, were included in the study cohort. Females were younger age, were more likely to be non-smokers, have non-squamous tumors and had a higher prevalence of pre-existing autoimmune diseases compared to males. Disease control (CR/PR/SD) was achieved in 65.8% of patients. Median PFS was 12.0 mo in females and 14.1 mo in males. Median OS for all patients was 15.8 mo; 16.1 and 15.7 mo in females and males respectively. No statistical differences based on gender were observed in PFS and OS (P = 0.767 and P = 0.657). In regression analysis older age and presence of liver metastases were independent poor prognostic factors. Gender was not an independent prognostic factor in PFS and OS. Notably, 44 or 28.9% patients developed symptomatic immune-related adverse events (ir-AEs) that led to TD (Table 1). ir-AE-related TD occurred at a significantly higher rate in females compared with males (Table 1; 38.2% vs 19.7%, RR = 1.90; 95% CI: 1.12 to 3.26; p = 0.018). GI toxicity, including hepatitis and colitis was predominantly observed in females, whereas pneumonitis was the most frequent ir-AE leading to TD in males. Conclusions: Despite no significant differences based on gender were observed in PFS and OS, our study showed that female patients with advanced NSCLC receiving ICIs are at a substantially greater risk of severe symptomatic ir-AEs and TD. This finding indicates that broad-based sex differences in this context could potentially exist and emphasizes the need for further investigations into the role played by gender in immunity and cancer immunotherapy treatment.[Table: see text]

Risk of Gastrointestinal Perforation in Patients With Rheumatic Diseases Exposed to Janus Kinase Inhibitors Versus Adalimumab: A Nationwide Cohort Study.

To compare the risk of gastrointestinal perforation (GIP), a rare but serious adverse event, in patients who a JAK inhibitor (JAKi; tofacitinib, baricitinib, upadacitinib, or filgotinib) versus adalimumab (tumor necrosis factor inhibitor) among a comprehensive real-world population of patients with rheumatic diseases. We conducted a nationwide population-based cohort study of the French national health data system, the exposed group that received a JAKi and the comparison group adalimumab. We included all individuals with a rheumatic disease who had their first dispensation of these treatments from July 2017 to December 2021. The primary endpoint was the occurrence of GIP (end of follow-up May 2022). Weighted hazard ratios (wHRs) were estimated with the inverse probability of treatment weighting method to account for confounding factors. Concomitant administration of systemic glucocorticoids, nonsteroidal anti-inflammatory drugs, and proton-pump inhibitors were time-varying variables. The cohort included 39,758 patients: 12,335 and 27,423 in the groups that received a JAKi and adalimumab (mean age 58.2 and 47.3 years; female 76% and 58%; rheumatoid arthritis 85.3% and 27.3%, and psoriatic arthritis/axial spondyloarthritis 14.7% and 72.7%), respectively. During follow-up, 38 and 42 GIPs occurred in the groups that received a JAKi and adalimumab groups; incidence rates were 2.1 (95% confidence interval [CI] 1.5-2.8) and 1.1 (95% CI 0.8-1.5) per 1,000 person-years, respectively. Rates of GIP did not differ between the groups that received a JAKi and adalimumab: wHR 1.1 (95% CI 0.7-1.9; P = 0.65). Despite the lack of power in some subgroup analyses, results were consistent whatever the subgroup of a type of JAKi received or subgroup with a type of rheumatic disease. In this nationwide cohort study, the rates of GIPs did not differ between groups of patients who received JAKi and adalimumab treatment. These results need to be confirmed in other observational studies.

Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population

Alcohol use disorders are among the top causes of the global burden of disease, yet therapeutic interventions are limited. Reduced desire to drink in patients treated with semaglutide has raised interest regarding its potential therapeutic benefits for alcohol use disorders. In this retrospective cohort study of electronic health records of 83,825 patients with obesity, we show that semaglutide compared with other anti-obesity medications is associated with a 50%-56% lower risk for both the incidence and recurrence of alcohol use disorder for a 12-month follow-up period. Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without type 2 diabetes. Similar findings are replicated in the study population with 598,803 patients with type 2 diabetes. These findings provide evidence of the potential benefit of semaglutide in AUD in real-world populations and call for further randomized clinical trials.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use. The AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals. The database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. "Cardiac disorders" was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308-10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%). This study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN.

Early rhythm control in patients with recently diagnosed atrial fibrillation: findings from the GLORIA-AF Registry Phase III

Abstract Background Early rhythm control (ERC) can improve outcomes in select patients with atrial fibrillation (AF) but real-world data are lacking. Purpose To evaluate the effectiveness of ERC in a real-world cohort of AF patients. Methods From the global, prospective GLORIA-AF Phase III Registry, adult patients with recent diagnosis (< 3 months and < 4.5 months in Latin America) of AF and CHA2DS2-VASc score ≥1 were included. ERC was defined as treatment with an antiarrhythmic drug, catheter ablation, or cardioversion at the baseline. Multivariable logistic regression analysis determined the odds of receiving ERC and an oral anticoagulant [OAC] with results reported as adjusted Odds Ratio (aOR) and 95% Confidence Intervals (95%CI). Risk of major outcomes was determined using multiple Cox regression analyses. The primary outcome was a composite of all-cause death and major adverse cardiovascular events (MACE). Secondary outcomes included all-cause death, thromboembolism and major bleeding. Results were reported as adjusted Hazard Ratio (aHR) and 95%CI. Results 21,051 AF patients (age: 70.2±10.3, 45% female) were included. Of these, 6,932 (32.9%) received ERC, while 14,119 (67.1%) did not. Patients receiving ERC were younger with a higher prevalence of paroxysmal AF (62.8% vs. 53.2%) and heart failure (23.1% vs. 21.4%). They were less likely to have prior stroke/transient ischemic attack (TIA), chronic obstructive pulmonary disease (COPD), and they had a lower mean CHA2DS2-VASc score (3.0±1.5 vs. 3.3±1.5). Age ≥75 [aOR: 0.53; 95%CI (0.0.49-0.57)] and age 65-75 [aOR: 0.76; 95%CI (0.70-0.82)] were associated with lower odds of receiving ERC. Those with prior stroke/TIA [aOR: 0.55; 95%CI (0.50-0.61)] and COPD [aOR: 0.82; 95%CI (0.71-0.94)], as well as patients with more sustained form of AF and patients recruited in North America were less likely to receive ERC. Conversely, female sex, higher symptom burden, hypertension and coronary artery disease were associated with higher odds of receiving ERC (Figure 1). Patients who received ERC were more likely to receive OACs [aOR: 1.36; 95%CI (1.25-1.48)]. Survival curve for the primary outcome according to ERC are shown in Figure 2. During a median follow-up of 3.0 [IQR: 2.9-3.1] years, ERC was associated with lower risk of the primary composite outcome (aHR: 0.88, 95% CI:0.80-0.96, p=0.006); Similar results were observed for the secondary outcomes. Conclusions In a real-world population with recently diagnosed AF, clinical risk factors and characteristics were associated with ERC. Patients who received ERC had a reduced risk of major outcomes. These findings suggest that in real-world patients with AF, ERC may provide beneficial effects on long-term outcome.Odds Ratios to be treated with ERC.Survival curve.

Real-world multicenter registry on a novel focal lattice tip catheter toggling between pulsed electric field and radiofrequency for atrial tachyarrhythmia ablation

Abstract Background Pulsed field ablation (PFA) has emerged as a novel non-thermal energy source for cardiac tissue ablation. A novel focal 9mm lattice tip catheter, namely Sphere-9 (Affera Inc), has recently received regulatory approval; the technology is part of a technology that allows the delivery of either pulsed electric field or radiofrequency energy and incorporates a proprietary 3D electroanatomical mapping system. Purpose To describe the first real-world, multicenter experience with the AfferaTM system. Methods Consecutive AF patients undergoing first-time or redo atrial tachyarrhythmia ablation with the AfferaTM system in two different centres between August and November 2023 were prospectively enrolled. PFA was always used to ablate the posterior left atrium, whereas anterior applications were performed using either radiofrequency energy (RF/PF strategy) or PFA (PF/PF strategy) based on operator's discretion. Data on first-pass pulmonary vein isolation (PVI) and posterior wall isolation (PWI), as well as success rate of extrapulmonary ablation were reported. Primary safety endpoint included any technology-related periprocedural complications. Results 46 patients (mean age: 67±10; 41.3% males, 60.8% non-paroxysmal AF) were included. 5 (10.8%) patients were in atrial flutter (AFlu) at the beginning of the procedure, whereas AF was the rhythm at presentation in 19 (41.3%) others. First-time PVI was performed in 37 (80.4%) patients, 68.4% of whom received concomitant PWI. PVI was performed with PFA-only in 27% of them. First-pass isolation was achieved in 97.3% and 100% of PVI and PWI cases, respectively. Additional lesions included an anterior or posterior mitral line (6 and 15 patients), CTI (4 patients) or substrate ablation in 3 patients. Evidence of first-pass line block was documented in 96.4% of patients. The remaining 9 (19.6%) patients had already undergone a previous ablation; remapping showed 27.7% of PVs requiring reisolation. PWI was performed in 88.9% of them, for the first time (75%) or due to reconnection (25%). Additional lesions included an anterior or posterior mitral line (3 and 3 patients) or CTI in 2 patients. Evidence of first-pass line block was documented in 100% of patients. In 3 AFlu patients, the arrhythmia was mapped and termination was achieved while performing an AML (2 patients) and CTI (1 patient). Procedural duration was 96.5±15.6 min for first time and 97.8±12.6 min for redo procedures. Mean left atrial dwelling and fluoroscopy times were 75.4±17.6 min and 7.36±2.1 min, respectively. No technology-related complications were documented. Conclusions AF ablation with the focal 9-mm lattice tip catheter Sphere-9 confirmed high efficacy and safety in a real-world population.