Citations

Abstract Chimeric antigen receptor T‐cell (CAR‐T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B‐cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR‐T therapy in older patients with RR LBCL in the real‐world setting. Patients aged ≥65 years with RR LBCL, treated with anti‐CD19 CAR‐T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65–89). Best objective and complete response rates were 86% and 62%, respectively. Median follow‐up after infusion was 18.3 months. The median progression‐free survival (PFS) was 6.9 months, with 6‐ and 12‐month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR‐T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR‐T in older patients, including those aged ≥80 years. The age at CAR‐T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR‐T therapy solely based on their chronological age.

1027 Background: Imlunestrant is a next-generation, oral SERD designed to deliver continuous ER-target inhibition. In the first-in-human Phase 1a/b EMBER study (NCT04188548), imlunestrant demonstrated favourable safety, PK, and clinical benefit when administered as monotherapy or with targeted therapy in ER+, HER2- aBC. Here we present clinical data of imlunestrant with HER2 targeted therapy, in patients (pts) with ER+, HER2+ aBC enrolled in EMBER. Methods: Pts were randomized to imlunestrant (400mg po daily) + trastuzumab (H), with or without (±) abemaciclib (Part C) or received maintenance treatment with imlunestrant + H + pertuzumab (P) (Part E), at standard doses in 21-day cycles. Key eligibility (Part C): ≥ 2 prior HER2 directed regimens, no prior CDK4/6i or fulvestrant; (Part E): received 1st line induction taxane chemotherapy (any duration) + H + P, without disease progression and ≤1 prior therapy for aBC. Key endpoints included safety, PK, ORR, CBR and PFS. Results: Overall, 45 pts with ER+/HER2+ aBC received the following combinations: imlunestrant + H (n=18), imlunestrant + H + abemaciclib (n=21; 1 pt received 800 mg imlunestrant), and imlunestrant + H + P (n=6). Baseline characteristics, safety, and preliminary efficacy are presented below (Table). Most TEAEs were grade 1-2. Common TEAEs with imlunestrant + H were fatigue (33%) and nausea (28%); with imlunestrant + H + abemaciclib were diarrhea (100%), neutropenia (57%), fatigue (52%) and nausea (48%); and with imlunestrant + H + P were diarrhea (50%) and arthralgia (50%). Imlunestrant PK was consistent with those previously reported with no drug-drug interactions observed with the combinations. From Part C, sequencing of baseline plasma ctDNA samples (n=37) identified prevalent mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Clinical activity of imlunestrant in this ER+/HER2+ population, while based on small numbers, is promising. Conclusions: Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab was well tolerated, showed no drug-drug interactions, and demonstrated preliminary antitumor activity in pts with ER+/HER2+ aBC. Clinical trial information: NCT04188548 . [Table: see text]

1022 Background: The Bria-IMT regimen is a combination immunotherapy using an allogeneic whole cell cancer vaccine combined with checkpoint inhibitors (CPIs). Intradermally administered irradiated SV-BR-1-GM breast cancer cells secrete GM-CSF and present tumor associated antigens (TAAs) on HLA-I and –II molecules to directly stimulate anti-tumor immunity. Anti-PD1 CPI further stimulates T-cells and synergizes with SV-BR-1-GM. Here we report the results of the phase 1/2 trial (NCT03328026) of Bria-IMT in metastatic/advanced breast cancer evaluating sequencing of SV-BR-1-GM inoculation and CPI. Methods: Analysis of the phase 1 with expansion phase 2 cohort randomized by sequence using SV-BR-1-GM, checkpoint inhibitor (pembrolizumab or retifanlimab), low dose cyclophosphamide (Day –2) and post-dose local pegylated interferon α, with cycles every 3 weeks. In the 1:1 randomized cohort, CPI is either dosed at C1 prior to SV-BR-1-GM (original sequence) or delayed to C2 post-SV-BR-1-GM (alternative sequence). Cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) were monitored as biomarkers. Results: A total of 54 patients were dosed: 11 with pembrolizumab, 44 with retifanlimab (1 patient received pembrolizumab and later retifanlimab). Median age=61 (38-81); Median prior regimen=6 (2-13); 72% ER+/PR+/HER2-; 6% HER2+ and 22% triple negative. Bria-IMT regimen was well tolerated with only 9% drop-out rate due to AE. AEs related to IPs were seen in 74% of patients; the majority (91%) being grade 1-2, and few (1.7%) grade 4 cases including pulmonary embolism, dehydration and increased lipase. Among 30 patients with post-dose CAML/CTC data and evaluable outcome, CAML count <5 associates with disease control (p=0.06, Chi square test). Patients who developed DTH to SV-BR-1-GM had significantly better PFS and higher OS. Patients treated with phase III formulation had an increase in PFS. Quality of life improvement correlates with disease outcome and survival. Among the patients treated with the phase III formulation of SV-BR-1-GM (n=23 with evaluable outcomes), objective response rate (ORR) is 13% and disease control rate (DCR) is 61%, with median PFS and OS are 4.1 and 13.3 months, respectively. In the randomized portion, the original sequence cohort had higher DCR (43% vs 36%) and OS (P=0.08, HR 0.30, 95%CI 0.08-1.17) compared to the alternative sequence cohort. Conclusions: BRIA-IMT has shown a favorable safety profile while providing benefits to heavily treated aMBC patients. Superior outcomes and survival were seen in patients treated with the phase III formulation and regimen now being used in the ongoing Ph3 trial, confirming the improvement in efficacy of the novel regimen. The results from this randomized phase 2 study informed the study design of the ongoing Ph3 trial comparing BRIA-IMT to standard of care physician choice treatments (NCT06072612). Clinical trial information: NCT03328026 .

Abstract Aims This study aimed to evaluate the clinical significance of secondary mitral regurgitation (MR) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We conducted a prospective study enrolling consecutively evaluated patients with HFpEF undergoing invasive haemodynamic exercise testing with simultaneous echocardiography. Compared to HFpEF without MR (n = 145, 79.7%), those with mild or moderate MR (n = 37, 20.3%) were older, more likely to be women, had more left ventricular (LV) systolic dysfunction, and more likely to have left atrial (LA) myopathy reflected by greater burden of atrial fibrillation, more LA dilatation, and poorer LA function. Pulmonary artery (PA) wedge pressure was higher at rest in HFpEF with MR (17 ± 5 mmHg vs. 20 ± 5 mmHg, p = 0.005), but there was no difference with exercise. At rest, only 2 (1.1%) patients had moderate MR, and none developed severe MR. Pulmonary vascular resistance was higher, and right ventricular (RV)-PA coupling was more impaired in patients with HFpEF and MR at rest and exercise. LV and LA myocardial dysfunction remained more severe in patients with MR during stress compared to those without MR, characterized by greater LA dilatation during all stages of exertion, lower LA emptying fraction and compliance, steeper and rightward-shifted LA pressure–volume relationships, and reduced LV longitudinal contractile function. Conclusions Patients with HFpEF and mild or moderate MR have more severe LV systolic dysfunction, LA myopathy, RV-PA uncoupling, and more severe pulmonary vascular disease. Mitral valve incompetence in this setting is a phenotypic marker of more advanced disease but is not a causal factor in development of HFpEF.

e12641 Background: Many promising agents or combinations regimens relevant to breast cancer lack sufficient clinical information for use in the neoadjuvant setting. To enable acceleration of drug development by reducing time and cost of clinical trial planning and conduct, the Phase I initiative PRE-ISPY Program was created. Methods: The PRE-ISPY Program is built within the I-SPY network, with the overall aim to streamline the regulatory pathway and the processes of trial design, contracting, activation, enrollment, execution, data gathering and analysis, as well as reporting of new therapeutic agents or combinations of relevance to breast cancer. Results: The PRE-ISPY trial is an open-label platform phase IB study designed to evaluate compelling single agent or combination regimens with the overall goal of moving promising drug regimens into I-SPY2 Trial and/or into other oncology-based trials in a timely manner. Graduation of a PRE-ISPY regimen to I-SPY2 is not mandatory. The primary objectives in each study Arm are to determine safety and to obtain preliminary efficacy data of the new regimen in patients with metastatic cancer, including a cohort of breast cancer patients. Each Arm may contain a Part 1 (dose finding) and a Part 2 (dose expansion). The new treatment can be tested also in patients with other solid malignancies than breast cancer, in which the treatment may be applicable, as specified in the design of the Arm. A breast cancer specific cohort is required in Part 2. Candidate treatment regimens are selected with advice from the I-SPY2 Agent Selection Working Group. The PRE-ISPY/Phase IB trial has multiple ongoing drug regimen Arms subsequently added as new protocol appendices through amendments to a Master protocol. There is no randomization; participants are enrolled, and treatment selected according to the relevance of therapy to their disease. Prospective companion biomarkers are evaluated. The current arms under study are PRE1: ALX-148 combined with trastuzumab deruxtecan; PRE2: tucatinib combined with zanidatamab; and PRE3: vidutolimod combined with cemiplimab. Selected agents or therapeutic combinations are tested through this protocol in the I-SPY Network Centers that participate in the PRE-ISPY Program. Toxicities are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Clinical responses are evaluated based on RECIST v1.1 criteria. Conclusions: Once safety is established, promising regimens can be rapidly transitioned to I-SPY 2.2 or other phase 2/3 trials. The first patient was enrolled on 2/1/2023. Clinical trial information: NCT05868226 .

Background: The obesity epidemic has led to an increase in the proportion of patients with chronic liver disease due to metabolic associated steatosic liver disease and in the prevalence of obesity in patients with cirrhosis. Metabolic and bariatric surgery (MBS) has been proven to determine weight loss, obesity-related medical problems remission, and liver steatosis, inflammation, and fibrosis improvement. However, cirrhosis and portal hypertension are well-known risk factors for increased morbidity and mortality after surgery. The aim of this study is to evaluate the safety of MBS in patients with compensated advanced chronic liver disease (cALCD) and clinically significant portal hypertension (CSPH). Material and methods: This is an international, multicentric, retrospective study on 63 individuals affected by obesity with cALCD and CSPH who underwent MBS in tertiary referral centers with experts hepatobiliary surgeons between January 2010 and October 2022. The primary endpoint was postoperative mortality at 90 days. The secondary endpoints included postoperative weight loss at last follow-up and postoperative complication rate. In addition, the authors performed subgroup analyses of Child-Pugh (A vs. B) score, MELD (≤9 vs. >9) score, and type of surgery. Results: One patient (1.6%) experienced gastric leakage and mortality. There were three (5%) reported cases of portal vein thrombosis, two (3%) postoperative acute renal failure, and one (1.6%) postoperative encephalopathy. Child-Pugh score A resulted to be a protective factor for intraoperative bleeding requiring transfusion at univariate analysis (OR: 0.73, 95% CI: 0.55–0.97, P=0.046) but not at multivariate analysis. MELD>9 score and the type of surgery did not result to be a risk factor for any postoperative complication. Conclusion: MBS is safe in patients with cALCD and CSPH performed in tertiary bariatric referral centers with hepatobiliary expert surgeons. Larger, prospective studies with longer follow-up periods are needed to confirm these results.

Mutations in isocitrate dehydrogenase (IDH) genes, an early step in the ontogeny of lower-grade gliomas, induce global epigenetic changes characterized by a hypermethylation phenotype and are critical to tumor classification, treatment decision making, and estimation of patient prognosis. The introduction of IDH inhibitors to block the oncogenic neomorphic function of the mutated protein has resulted in new therapeutic options for these patients. To appreciate the implications of these recent IDH inhibitor results, it is important to juxtapose historical outcomes with chemoradiotherapy. Herein, we rationally evaluate recent IDH inhibitor data within historical precedents to guide contemporary decisions regarding the role of observation, maximal safe resection, adjuvant therapies, and the import of patient and tumor variables. The biological underpinnings of the IDH pathway and the mechanisms, impact, and limitations of IDH inhibitors, the actual magnitude of tumor regression and patient benefit, and emergence of resistance pathways are presented to guide future trial development. Management in the current, molecularly defined era will require careful patient selection and risk factor assessment, followed by an open dialog about the results of studies such as INDIGO, as well as mature data from legacy trials, and a discussion about risk-versus-benefit for the choice of treatment, with multidisciplinary decision making as an absolute prerequisite.

e24143 Background: Accurate assessment of glomerular filtration rate (GFR) is crucial to guiding drug eligibility, dose-adjusting systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. To date, there has been a lack of guidance to standardize approaches to GFR estimation in the cancer population based on the available evidence. We aim to present data on the first systematic review (SR) of GFR estimating equations in patients with cancer. Methods: We conducted a SR on behalf of the American Society of Onco-Nephrology (ASON) on the accuracy of equations to estimate GFR in adult patients with cancer, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We required that studies use a reference methodology as comparator involving measured GFR via urinary or plasma clearance of an exogenous filtration marker or carboplatin. Two search strategies focusing on studies using serum creatinine (Cr) and cystatin C (Cys) were developed. Risk of bias and quality assessment was performed for all studies. Results: A total of 39 studies (21,949 patients in total, 19,025 with solid cancers) were included. Studies assessing populations in Europe were most frequent (50%), followed by Asia (27%) and the remaining from Australia/New Zealand and North and South America. Risk of bias and quality assessment allocated 15 studies (38%) as low or very low quality, and 24 (62%) as low-moderate or moderate quality. The most commonly assessed GFR estimating equations included Cockroft-Gault (32 studies), Modification of Diet Renal Disease (MDRD) (24 studies), Chronic Kidney Disese Epidemiology Collaboration Study (CKD-EPI)Cr (22 studies), Wright (13 studies), CKD-EPICys (8 studies), CKD-EPICr-Cys (8 studies), and Jeliffe (8 studies). Given the importance of accurate and timely eGFR assessment and the evidence supporting the performance (i.e., accuracy) of the CKD-EPI incorporating both Cr and Cys, we suggest the use of this equation in patients with cancer (grade 2C). Where Cys is unavailable, CKD-EPICr is the next preferred equation given the supporting data for its performance and widespread availability. Since included studies were moderate quality or lower, the ASON rated the certainty of evidence as low. Also, additional data on clinical outcomes related to the selection of eGFR equations is needed. We suggest measurement of GFR via an exogenous filtration marker in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials (ungraded). Conclusions: Based on the results of this SR, we suggest use of contemporary methods for estimation of GFR (CKD-EPICr-Cys and CKD-EPICr-Cr) and avoidance of older and less accurate formulae such as Cockcroft-Gault.

e24003 Background: Cancer patients undergoing chemotherapy suffer from a variable degree of cancer therapy–related cardiac dysfunction and heart failure (HF). It is known that sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF independent of diabetes mellitus and left ventricular ejection fraction; our study aims to investigate the potential benefits of SGLT2 inhibitory therapy specifically in cancer patients undergoing chemotherapy. Methods: We performed an electronic search on PubMed, Embase, and Cochrane, from the inception of databases till January 29, 2024, to identify all the articles that compared the use of SGLT2 inhibitors in adult (≥18 years) with type 2 diabetes mellitus and exposure to cardiotoxic antineoplastic therapy, subsequently diagnosed with cardiomyopathy, heart failure, or LVEF < 40%. The data was extracted and pooled using a random effects model to calculate the odds ratio (OR) with a respective 95% confidence interval (CI). R software (v.4.3) was used for all statistical analyses. Results: Our search identified three observational studies with a total of 3,164 patients (SGLT2- inhibitor group: 1,550; Control group: 1,614). We found that the use of SGLT2 inhibitors was associated with a lower risk of all-cause mortality (OR: 0.25 [0.20, 0.31]; I2 = 16%; p < 0.001), hospitalizations from heart failure (OR: 0.25 [0.10, 0.62]; I2 = 0%; p = 0.003), and acute exacerbation of heart failure (OR: 0.35 [0.27, 0.47]; I2 = 0%; p < 0.001). Conclusions: Our findings suggest a favorable association between the use of SGLT2 inhibitors and reduced mortality, as well as improved cardiac clinical outcomes in cancer patients undergoing chemotherapy. However, further validation through large-scale studies and randomized controlled trials across diverse malignancies is warranted to establish the efficacy of these drugs. [Table: see text]