Citations

Abstract Newer approaches to control alloreactivity may produce similar transplant outcomes using HLA-mismatched donors vs HLA-matched unrelated donors (MUD). However, prospective comparisons are lacking. BMT CTN 1702 used a donor search prognosis score to assign patients to an 8/8 HLA MUD or the center’s preference of haploidentical related donors (HAPLO), mismatched unrelated donors (MMUD), or umbilical cord blood (UCB). Outcomes of MUD were compared to HAPLO, MMUD, and UCB transplantation after adjusting for covariates. Patients (n = 1179 [93% adults]) underwent transplantation with MUD (n = 772), HAPLO (n = 254), MMUD (n = 112), and UCB (n = 41) at a median of 3.7, 3.4, 3.9, and 3.8 months from enrollment. Posttransplant cyclophosphamide (PTCy) was used in 23.9%, 83.9%, 65.2%, and 0% of MUD, HAPLO, MMUD, and UCB. In multivariate analyses, compared to MUD, survival was lower for UCB (hazard ratio [HR], 2.65; P< .001) but not statistically different for HAPLO and MMUD (HRs, 1.08 and 1.18, respectively). Relapse risk was not significantly different by donor, but treatment-related mortality (HR, 3.31; P< .001) and disease-free survival (HR, 1.99; P = .002) were inferior for UCB but not different for HAPLO and MMUD than MUD. In patients who received PTCy, HAPLO and MMUD were associated with increased grade 3 or 4 acute graft-versus-host disease (GVHD; HR, 2.39 [P = .017] and 2.53 [P = .038], respectively) and chronic GVHD (HR, 1.71 for both; P = .028 and .080) than MUD, but other outcomes were not different. HAPLO or MMUD may be used to expedite transplantation when finding MUD is unlikely. This study was registered at www.clinicaltrials.gov as NCT03904134.

ABSTRACT Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA ( n = 35) or alloHSCT ( n = 31). Baseline characteristics such as genetics, co‐morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow‐up from therapy initiation was 18 months (95% CI: 11–26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real‐world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05–0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant‐eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score‐based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

8057 Background: The NCI Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) study tested resected stage II-IIIB(N2) NSCLC for targetable EGFR and ALK alterations and PD-L1 expression to screen patients for biomarker-driven adjuvant therapy trials (NCT02194738). Local lab results were requested when available for comparison to central lab results. Methods: We identified patients with both central and local PD-L1 results in the ALCHEMIST adjuvant immunotherapy study screening population. Discrepancies in tumor proportion score (TPS) between central and local PD-L1 were defined using prespecified cut-points (granular: <1%, 1-<5%, 5-<10%, 10-<20%, 20-<30%, 30-<40%, 40-<50%, 50-60%, 60-<70%, 70-<80%, 80-<90%, 90-<100%; clinical: <1%, 1-<50%, 50-100%). Large discrepancies were defined as ≥ 50 percentage point differences; for these cases, local PD-L1 and hematoxylin & eosin-stained slides were requested. These and all central slides were digitally scanned at 40X. Three expert pathologists reviewed the scanned slides in a blinded fashion. Differences between patient or tumor characteristics were assessed by Chi-square and Wilcoxon rank sum tests. Percent agreement was computed within and between the reviewers. Results: Central and local PD-L1 results were available for 497 patients. 177 cases (36%) had discrepancies that placed patients in different clinical TPS categories (<1%, 1-<50%, 50-100%). Among these, 43 cases had large TPS discrepancies; 14 had available local testing slides. 46 of the 320 cases without discrepancy were randomly selected as controls. No patient or tumor characteristics were associated with discrepancy, including tumor location, histology, grade or cancer stage (p > 0.05). Pairwise comparisons of TPS according to three pathologists re-reading the same scanned PD-L1 slides showed similar levels of disagreement in clinical TPS category whether there was initial discrepancy between central and local results (24%, 34%, and 23%; mean 27%) or not (33%, 30%, and 20%; mean 28%). Among the 14 cases with large initial discrepancies and local slides available, there was agreement in clinical TPS category when the anonymized central and local scanned slides were re-read by the pathologists in 54%, 38%, and 43% of cases, despite 100% non-agreement in initial reads. There were higher rates of agreement when the tested slides both originated from the same (100%) versus different (35%) blocks, when the same (48%) versus different (40%) PD-L1 antibodies were used, and when the cases were of non-squamous (52%) versus squamous (14%) cell carcinoma. Conclusions: There are substantial differences in PD-L1 TPS read by pathologists that can result in placement of patients in different categories commonly used for clinical management. These differences have clear implications in clinical trials and routine patient care.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found on the ASCO Publications website .

Abstract Background Several bispecific antibodies (BsAbs), including mosunetuzumab, glofitamab, and epcoritamab, are approved for non-Hodgkin lymphoma (NHL). However, real-world patient-centered data evaluating treatment-related time burden and preferences are lacking. Methods We conducted an online survey of 120 patients with relapsed/refractory follicular lymphoma (FL; N = 60) and diffuse large B-cell lymphoma (DLBCL; N = 60) receiving BsAbs. Participants reported all-cause healthcare visits and time spent on cancer-related healthcare resource utilization over the past 30 days, including travel, treatment administration, recovery, and impact on daily activities. Participants also evaluated two hypothetical treatment profiles to assess preference for fixed-duration versus treat-to-progression therapy. Results Participants with FL reported a mean of 2.5 healthcare visits in the past 30 days, with significantly fewer visits for mosunetuzumab versus epcoritamab (1.7 vs 3.3, respectively; P &lt; .01). In DLBCL, the mean was 2.6 visits, with fewer visits for glofitamab versus epcoritamab (2.2 vs 3.0; P =.01). Although epcoritamab visits were shorter in FL, more frequent visits and longer recovery time resulted in significantly lower monthly time burden with mosunetuzumab versus epcoritamab (31.2 vs 61.9 hours; P &lt; .05). Similarly, monthly time burden was also lower with glofitamab than epcoritamab in DLBCL (43.0 vs 87.7 hours; P &lt; .05). Most participants reported little to moderate impact on daily activities. Across treatment groups, ≥92% preferred a hypothetical fixed-duration regimen over a treat-to-progression therapy. Conclusion Our real-world data, including novel aspects of time toxicity, demonstrate clinically meaningful differences in time burden associated with BsAbs and emphasize the importance of incorporating patient convenience and preference into shared decision-making in NHL.

Abstract Rationale American Indians and Alaska Native (AI/AN) people have the highest prevalence of tobacco use of any US racial or ethnic minoritized group, though this varies regionally. Smoking, and smoking-related cancers including lung cancer are more common in AI/AN people than non-Hispanic whites in the Pacific Northwest. Lung cancer screening (LCS) is effective but broadly under-utilized in AI/AN eligible adults. This study’s objective was to evaluate a AI/AN community co-designed patient navigation intervention to bridge community healthcare settings to a LDCT-capable LCS program. Methods We conducted a single-arm pilot study of the patient navigation intervention, grounded in community-based participatory research principles. The intervention was formalized in a living handbook, co-created with input from patients and providers at an AI/AN Urban Indian Organization and primary care clinic, Seattle Indian Health Board. Two community health workers served as navigators to deliver culturally sensitive support, link to shared decision-making with a nurse practitioner at the academic LCS program, coordinate transportation, interface with insurance and provide other barrier-directed activities. Patients eligible for LCS (n = 44) were recruited from the AI/AN clinic setting through on-site outreach. Enrolled participants completed pre-navigation surveys which assessed baseline knowledge, attitudes, experiences and barriers. Those who engaged with the central program completed an additional post-navigation survey (n = 15). Electronic health records were reviewed for all navigation and LCS-related data. Results Between July 2023 - November 2024, 44 participants were enrolled in the study. The median age of the participants was 65 (IQR 58-70), 66% reported current smoking, and 76% reported an annual household income &lt;$30,000. All participants reported at least one barrier that delayed care in the past 12 months. On review, two participants were up-to-date on LCS prior to enrollment. Within 6 months, 13 participants completed a shared decision-making appointment and 11 went forward with LDCT. On post-intervention surveys, barriers most commonly addressed were: scheduling (100%), transportation (80%), explaining LCS (80%) and cost/insurance (73%). Participants reported high acceptability, measured by Acceptability of Intervention Measure (AIM median 5.0, IQR 5-5) and patient satisfaction measured by Patient Navigation Satisfaction Measured-Instrument (PNS-I median 45, IQR 42-45). Conclusion A culturally tailored patient navigation program for LCS was feasible and highly acceptable among urban AI/AN adults. Navigation addressed multiple barriers and successfully connected some patient participants from a community clinic to tertiary screening centers for shared decision-making and/or screening. These findings support the effectiveness of academic-community partnered navigation to increase LCS uptake in AI/AN clinic settings. This abstract is funded by: ATS/ALA/Chest Foundation: Respiratory Health Equity Research Award (Triplette)

Abstract Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with median survival remaining approximately 12–15 months despite aggressive multimodal therapy. Therapeutic resistance and tumor recurrence are driven in part by limited drug penetration across the blood–brain barrier (BBB) and the persistence of brain cancer stem cells (BCSCs), highlighting the need for brain-penetrant therapeutic platforms capable of achieving sustained intratumoral delivery. Here, we developed a dendrimer-based nanotherapeutic by conjugating metformin to a fourth-generation hydroxyl-terminated polyamidoamine dendrimer (P4-MET) to enhance intracranial bioavailability and therapeutic efficacy in GBM. P4-MET exhibited favorable pharmacokinetic properties, including prolonged retention within the tumor microenvironment, and demonstrated enhanced cytotoxicity against GBM cell lines relative to free metformin (f-MET). Mechanistical studies with transcriptomic profiling by RNA sequencing revealed distinct treatment-associated molecular signatures, identifying BOLA2B as the most significantly differentially expressed gene between treatment groups. Specifically, BOLA2B expression was markedly elevated in f-MET–treated cells but not so following P4-MET treatment. Given the established association of BOLA2B with mTORC1 signaling and GPX4-mediated ferroptosis resistance, these findings suggest that P4-MET may, at least in part, enhance therapeutic efficacy by modulating ferroptosis-associated pathways. In orthotopic GBM models, combination treatment with P4-MET and radiotherapy (RT) significantly prolonged overall survival and increased tumor cell death compared with either monotherapy alone, consistent with a synergistic radiosensitizing effect. Importantly, P4-MET demonstrated minimal systemic toxicity, supporting its favorable therapeutic index and translational potential. Collectively, these findings establish P4-MET as a brain-penetrant nanomedicine platform that improves metformin delivery, modulates ferroptosis-related signaling networks, and potentiates radiotherapeutic response in GBM. This study highlights the potential of dendrimer-enabled metabolic nanotherapies to overcome therapeutic resistance in malignant brain tumors.