Bispecific Antibody Research Articles

Easy as ABC: Managing Toxicities of Antibody-Drug Conjugates, Bispecific Antibodies, and CAR T-Cell Therapies.

Antibody-drug conjugates (ADCs), bispecific antibodies that engage T cells (BsAbs), and chimeric antigen receptor (CAR) T cells are widely used standard-of-care therapies that have revolutionized the treatment of lymphoid and plasma cell malignancies. With recent regulatory approvals, these therapies are poised to also revolutionize the treatment of common solid tumors and become a part of the everyday lexicon, the ABCs, of the practicing oncologist. Drawing from experience in hematology, we review the early, late, and rare toxicities of ADCs, BsAbs, and CAR T cells and provide general principles for their management.

Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell surface markers.

Targeted mRNA delivery with bispecific antibodies that tether LNPs to cell surface markers.

Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances.

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. Additionally, bsAbs targeting tumor growth factors or receptor tyrosine kinases offer solutions for overcoming drug resistance in solid tumors. Although bsAbs have shown remarkable success in hematologic malignancies, their expansion into solid tumors faces key challenges, including tumor heterogeneity, limited tumor penetration, and the risk of on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, and careful patient selection to maximize therapeutic benefit while mitigating adverse effects. The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in development. Combination strategies with chemotherapy, targeted agents, and immune CPIs could represent a promising strategy to further expand their potential. As research progresses, bsAbs are expected to play a role in reshaping the future of precision oncology, offering more effective and tailored treatment options.

Comparative analysis of adverse event profiles for CAR-T cell therapies and bispecific antibodies in lymphoma.

e19019 Background: CAR-T cell therapies and bispecific antibodies (BsAbs) emerged as transformative treatment options for relapsed or refractory lymphomas. Despite their efficacy, these therapies come with distinct safety profiles. CAR-T therapies modify the patient's T-cells to target tumor cells, while BsAbs engage both T-cells and tumor cells. This study compares the adverse event (AE) profiles of CAR-T and BsAb therapies in lymphoma treatment. Methods: A retrospective analysis was conducted using the FAERS database to assess AE reports associated with CAR-T therapies (Breyanzi, Kymriah, Yescarta, and Tecartus) and BsAbs (Epcoritamab, Glofitamab, Odronextamab, Mosunetuzumab, and Plamotamab). AEs were categorized by System Organ Classes (SOCs) using MedDRA terminology, and the frequency of events was calculated for each drug. Results: A total of 114,398 reports were analyzed: Yescarta (44,620), Kymriah (35,135), Tecartus (15,043), Epcoritamab (9,927), Glofitamab (4,373), Breyanzi (2,929), Mosunetuzumab (2,344), Odronextamab (22), and Plamotamab (5). For CAR-T therapies, the most frequently reported AEs were nervous system AEs (15.33%), General AEs (11.23%), and immune system AEs (9.59%). In contrast, BsAbs had higher incidences of AEs related to Infections (11.96%), General AEs (11.80%), and Immune system AEs (8.28%). CAR-T therapies showed an increased incidence of nervous system and psychiatric disorders, while BsAbs were more commonly associated with infection-related AEs. Notably, Immune system disorders were prevalent across both therapeutic modalities. The results are summarized in the table below. Conclusions: This analysis highlights key differences in the safety profiles of CAR-T and BsAb therapies for lymphoma. CAR-T therapies were associated with a higher incidence of neurological and psychiatric AEs, while BsAbs demonstrated a greater risk of infections. These findings may offer valuable guidance for clinicians in therapy selection and underscore the importance of vigilant monitoring, particularly for neurological toxicities in CAR-T treatments and infection-related risks with BsAbs. Further research is recommended to better understand these trends and inform improved management strategies for both therapeutic options. AE* Breyanzi % Epcoritamab % Glofitamab % Kymriah % Mosunetuzumab % Odronextamab % Plamotamab % Tecartus % Yescarta % Nerv 15 5 4 10 9 - - 15 16 Genrl 11 12 17 11 15 64 20 13 12 Immun 10 8 10 7 7 - 40 9 10 Infec 6 12 9 6 10 14 20 6 5 Resp 6 8 8 5 11 5 20 5 4 Blood 6 8 8 10 6 - - 5 6 Inv 4 5 6 13 4 9 - 4 5 Musc 2 2 2 3 2 5 20 2 2 Neopl 3 5 5 8 6 - - 4 3 Vasc 4 4 4 4 3 9 20 4 4 Card 3 3 2 2 3 - - 3 3 Metab 3 3 2 2 2 - - 2 3 Skin 2 2 2 2 4 - - 2 2 Surg 1 1 0 0 1 - - 1 1 * Nerv: Nervous system;Card: Cardiac; Genrl: General disorders; Immun: Immune system; Infec: Infections; Inv: Investigations; Metab: Metabolism; Musc: Musculoskeletal; Neopl: Neoplasms;Resp: Respiratory; Surg: Surgical and medical procedures; Vasc: Vascular.

Removal of homodimer species with MabSelect VH3 during the purification of an asymmetric bispecific antibody.

Removal of homodimer species with MabSelect VH3 during the purification of an asymmetric bispecific antibody.

Differential patterns of cell surface marker expression in clinically relevant subgroups of non-small cell lung cancer.

e20553 Background: Antibody-drug conjugates (ADC) and bispecific antibodies have an increasing role in solid tumors including thoracic malignancies. In the present work, we examine untargeted proteomic data for non-small cell lung cancer (NSCLC) from clinical proteomic tumor analysis consortium (CPTAC) datasets to determine patterns of protein expression for cell surface targets of ADCs and bispecific antibodies that have entered clinical trials for NSCLC. Methods: We compare quantified levels of protein expression in tumors and normal adjacent tissue to identify proteins that are up-regulated in tumor tissues. Criteria for up-regulation were defined as Log 2 (fold-change) >1 (tumor/normal), with Bonferroni-adjusted p-value from Wilcox rank-sum test <0.01. Results: We report that targets including MET, MUC1, NECTIN4, and SLC34A2 (NaPi2b) are up-regulated in EGFR-mutant lung adenocarcinoma relative to adjacent lung tissue, and that CD38 and NECTIN4 are up-regulated for KRAS-mutant lung adenocarcinoma relative to adjacent tissue. We also report up-regulation of CD276 (B7H3), CD38, NECTIN4, PTK7, and TPBG (5T4) in squamous cell carcinoma relative to adjacent tissue. Conclusions: Of these suggested targets, only MET has been successfully exploited with therapeutic success in EGFR-mutant NSCLC (Amivantimab: EGFRxMET bispecific antibody). Agents directed at the other suggested targets have yet to advance beyond early phase clinical trials for NSCLC. Our results showing over-expression of particular cell surface targets in specific tumor subsets suggests to us that these agents in early phase trials may ultimately be most effective in specific clinically-relevant subsets of NSCLC patients.

How I Investigate Measurable Residual Disease in B-Cell Precursor Acute Lymphoblastic Leukemia After Therapy With Bi-Specific Monoclonal Antibodies and 19CAR-T Cells.

Measurable residual disease (MRD) in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) following anti-CD19 targeted therapies requires specific strategies to identify residual blast cells due to loss or reduced CD19 expression that makes it inconsistent as a primitive marker for B-cell gating. Due to the increased access of BCP-ALL patients to therapies with CD3/CD19 bispecific T-cell engagers (BiTe) and CD19-targeted chimeric antigen receptor T-Cell (CAR-T), it is essential that flow cytometry laboratories are prepared to evaluate therapeutic responses. Here, validated strategies for MRD detection in the context of anti-CD19 therapies are described, accessible to flow cytometry laboratories according to their different facilities. The paper includes an 8-color flow cytometry (FC) strategy for BCP-ALL MRD based on alternative gating without the use of additional markers (Euroflow protocol), as well as other strategies using alternative markers to CD19, comprising 2 protocols using 8 colors, one using 10 colors and another 14 colors/15 markers. Different strategies are needed to detect MRD without using CD19 for B-cell population gating after CD19-targeted therapies. However, it is essential that validated protocols are used according to the available resources to ensure reliable results for clinical decision-making.

Longitudinal tissue analysis and correlation of microenvironmental changes with combined immunotherapy and targeted therapy response in metastatic breast cancer.

1022 Background: The ability to interrogate changes within the tumor microenvironment before, during and following therapeutic intervention could yield important understanding of treatment response and causes for disease progression.Here we conducted a multicenter phase II clinical trial (NCT04521179) examining the effect of a novel CTLA-4/PD-L1 bispecific (KN046) antibody in combination with a a novel anti-HER2 bispecific (KN026) antibody in treatment resistant metastatic breast cancer. Our on-going trial demonstrated that in advanced HER2-positive breast cancer (HER2+ BC) patients, who have progressed after prior anti-HER2 combinational therapies, the objective response rate (ORR) of this chemo-free therapy of KN026 in combination of KN046 was about 47.2% ( 95% CI: 30.4-64.5). To explore the underlying mechanism of this regimen, we collected tumor specimens from patients before and after receiving this combinational treatment for emerging multi-modal molecular analyses ("Multi-omics") to provide an in-depth description of the tumor immune microenvironment and its correlation with treatment response. Methods: We performed matched pre- and on-treatment investigative biopsies on index tumors and performed single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) analysis. Results: We performed comprehensive scRNA-seq on tumor biopsies obtained from a total of 17 patients that evaluable for overall response. Among them, 13 patients had two biopsies taken, and four patients had one biopsy collected either before or during treatment. Single-cell RNA and T cell receptor sequencing from 334,183 cells from site-matched tumors reveal significant temporal shift of various immune cell populations and phenotypes within the tumor microenvironment associated with treatment responses. In-depth analysis of subpopulations revealed that CD8 + T cells are activated in responsive patients during treatment, and T REG cells, one of CD4 + T cell subtypes, are activated in non-responsive patients after therapy. Moreover, we also found that combined-therapy activates cDCs and induces an inflammation shift in Mϕs of responsive patients. Conclusions: We identified that regulatory T cells are activated while effector T cells, natural killer cells, and dendritic cells were significantly depleted in non-responding tumors. The immune response in responsive patients was effectively enhanced, whereas in nonresponsive patients, it was significantly diminished. And higher baseline levels of Mϕs were associated with therapeutic resistance. These results support that longitudinal analysis of tumor microenvironment to generate multi-omics data that can lead to rich insight disease process and to provide clinical value in evaluating treatment responses. Clinical trial information: NCT04521179 .

Risk of pulmonary toxicities in patients with EGFR-mutant non-small cell lung cancer (NSCLC) treated with amivantamab: A systematic review and meta-analysis of phase 3 randomized controlled trials.

e24035 Background: Amivantamab is a novel bispecific antibody that inhibits tumor growth by targeting both the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) receptors. Its accelerated approval by the FDA in mid 2021 for the treatment of EGFR-mutant non-small cell lung cancer (NSCLC), was considered an important advancement in the field of lung cancer management. However, as with any other new therapy, its introduction has also brought up concerns about possible new adverse events (AEs). This meta-analysis aims to explore the incidence of pulmonary toxicities in patients with EGFR-mutant NSCLC treated with amivantamab. Methods: A comprehensive literature search was conducted using MEDLINE and EMBASE databases from inception through December 31, 2024. Phase III randomized controlled trials (RCTs) utilizing amivantamab in EGFR-mutant NSCLC and reporting pulmonary AEs were included. We used the Mantel-Haenszel method to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: The analysis included 1,791 patients from three phase III RCTs (MARIPOSA n = 849, MARIPOSA-2 n = 636, PAPILLON n = 306). MARIPOSA tested amivantamab-lazertinib vs osimertinib vs lazertinib, while MARIPOSA-2 involved amivantamab-lazertinib-chemotherapy vs chemotherapy vs amivantamab-chemotherapy, and PAPILLON tested amivantamab-chemotherapy vs chemotherapy. Randomization ratios were 2:2:1, 2:2:1, and 1:1, respectively. The overall incidence of both interstitial lung disease (ILD) and pneumonitis was not statistically different between the amivantamab group and control group. However, when compared solely to chemotherapy by excluding MARIPOSA, the amivantamab cohort was noted to have a statistically significant higher incidence of both ILD and pneumonitis, with rates of 2.38% vs 0% (RR, 10.46; 95% CI: 1.37-79.89; P = 0.02) and 2.20% vs 0% (RR, 9.88; 95% CI: 1.29-75.68; P = 0.03), respectively. No statistically significant differences were noted between the two treatment arms in terms of incidence of pneumonia, any-grade or high-grade Covid-19 infections. Conclusions: This study revealed a higher risk of ILD and pneumonitis in patients with EGFR-mutant NSCLC treated with amivantamab combination regimens compared to chemotherapy alone. However, amivantamab has shown a similar safety profile to the standard treatment in terms of respiratory infections incidence. Prompt identification and providing the proper management and supportive care are crucial in managing those pulmonary toxicities, and ultimately, optimizing the patients’ quality of life.

Efficacy and safety from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma: Analyses at an extended median follow-up.

7528 Background: Talquetamab (Tal) is the first and only approved anti-GPRC5D bispecific antibody (BsAb) for relapsed/refractory multiple myeloma (RRMM). In previous results from the phase 1/2 MonumenTAL-1 study (CCO Jan 2024; median follow-up [mFU] 20–30 mo), Tal elicited deep, durable responses with low discontinuation rates. We report efficacy and ongoing safety from MonumenTAL-1 at an extended mFU of 30–38 mo, the longest mFU for any anti-GPRC5D agent. Methods: Patients (pts) were intolerant to or progressed on established therapies (phase 1, NCT03399799) or had ≥3 prior lines of therapy (LOT), including ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb (phase 2, NCT04634552). Pts received recommended phase 2 doses (RP2D) of SC Tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step-up doses. Results: As of Sept 2024, mFU was 38.2, 31.2, and 30.3 mo in the QW (n=143), Q2W (n=154), and prior T-cell redirection (TCR; n=78, received either RP2D) cohorts, respectively. Across cohorts, overall response rate (ORR; 67–74%) was unchanged vs previous results. Median duration of response (mDOR) and median progression-free survival (mPFS) continued to demonstrate superior outcomes in the Q2W vs QW cohort (mDOR 17.5 vs 9.5 mo; mPFS 11.2 vs 7.5 mo). In the prior TCR cohort, mDOR was reached with longer mFU (19.2 mo), and mPFS was 7.7 mo. In the QW, Q2W, and prior TCR cohorts, median overall survival (OS) was 34.0 mo, not reached, and 28.3 mo (36-mo OS rates: 49%, 61%, and 45%), respectively (Q2W data not mature). In pts with <4 vs ≥4 prior LOT, ORR was higher (85% vs 72%), but responses were less durable (mDOR 6.8 vs 10.8 mo) in the QW cohort, whereas ORR was similar (71% vs 69%), but responses were more durable (mDOR 20.7 vs 16.8 mo) in the Q2W cohort. As previously reported, most common adverse events (AE) were CRS and GPRC5D-associated (oral and dermatologic) AEs, and most common grade 3/4 AEs were cytopenias. No new discontinuations occurred due to oral or dermatologic GPRC5D-associated AEs and no new discontinuations occurred due to weight loss. In QW, Q2W, and prior TCR cohorts, respectively, any-grade infections occurred in 61%, 71%, and 78% of pts; grade 3/4 infections (23%, 21%, 26%) were mostly limited to early treatment cycles. A new safety signal, ataxia/balance disorders, was recently identified in association with Tal and had low prevalence in MonumenTAL-1. Dose reduction and discontinuation rates due to AEs remained low. No pts died due to Tal-related AEs. Conclusions: At an extended mFU, high ORRs elicited by Tal were durable and led to promising 36-mo OS rates (45–61%). The safety profile was consistent with previous results and continued to show lower risk of high-grade infections relative to approved anti-BCMA BsAbs, potentially contributing to the OS benefit seen in pts receiving Tal. Clinical trial information: NCT03399799 / NCT04634552 .

Long-term efficacy and safety of etentamig, a B-cell maturation antigen (BCMA) bispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM).

7527 Background: Etentamig (etenta) is a differentiated BCMA x CD3 bispecific T-cell engager composed of high avidity bivalent BCMA-binding domains, low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS), and silenced Fc tail for extended half-life enabling convenient dosing. We present long term results from 2 ongoing Ph 1 studies evaluating efficacy and safety of etenta in patients (pts) with RRMM. Methods: Data were from a Ph 1 multicenter, open-label, dose escalation/expansion (NCT03933735) trial and Arm A of a Ph 1b, open label (NCT05650632) trial of etenta; both enrolled pts ≥18 years with RRMM, ≥3 prior lines of therapy (LoT), and triple-class exposed. Pts received 60 mg Q4W or 40 mg Q3W, both regimens with similar dose intensity, in the Ph 1 trial; pts from Arm A of the Ph 1b trial received a step-up dose (SUD) on day 1 and full dose of 60 mg Q4W on day 4. This pooled analysis assessed long-term efficacy, safety, and tolerability. Tumor response was assessed per IMWG 2016 criteria. Results: Of 146 pts with RRMM who received etenta, 87 (60%) were male, median age (range) was 68 (40–87) years, median prior LoT were 4 (3–23), and median duration of follow-up was 13 (1–48) months (mo). ORR was achieved in 96 (66%) pts and ≥VGPR in 79 (54%) pts. Response rates across subgroups are reported in the Table. Median duration of response was not reached (NR) (NR–NR) among responders; Kaplan-Meier (KM) estimate at 12 mo was 71% (58.5%–80.5%). Median PFS (mPFS) was NR (8.7–NR) mo; KM estimate at 12 mo was 55% (44.9%–63.1%). Any grade and G3/4 treatment emergent adverse events (TEAEs) occurred in 145 (99%) pts and 116 (79%) pts. Most common G3/4 TEAEs (≥15%) were neutropenia (38%), anemia (23%), lymphopenia (25%), and thrombocytopenia (16%). Infections G3/G4 were reported in 32 (22%) pts; most common infections G3/G4 (≥5%) were pneumonia (12%) and sepsis (5%). TEAEs leading to etenta discontinuation were reported in 13 (9%) pts. Deaths from TEAEs were reported in 13 (9%) pts; 10 were not attributed to etenta treatment. In Arm A of Ph 1 study where 60mg Q4W was administered with SUD and modified dex as premedication, CRS incidence was 30% (4% G2; No ≥G3 events) with median time to CRS onset of 22.3 (5.5–29.6) hours; and median time to CRS resolution of 20.7 (1.8–131.7) hours. Conclusions: Etenta with SUD demonstrated a low CRS incidence, durable response, and tolerability in pts with heavily pretreated RRMM. Efficacy across all subgroups was comparable and maintained, suggesting therapeutic benefits among a broad population and supporting further exploration in the ongoing Ph 3 Cervino study. Subgroup ORR, n (%) ≥VGPR, n (%) mPFS, months (range) Age ≥75years 26 (72) 23 (63.9) NR (7.5–NR) Race: Black 15 (63) 13 (54.2) 13.7 (5.0–NR) High cytogenetic risk 21 (55) 18 (47.4) 7.4 (2.8–NR) 3 prior LoT 29 (64.4) 23 (51.1) 13.5 (5.6–NR) ≥4 prior LoT 67 (67) 56 (56) NR (8.3–NR)

Amivantamab for recurrent/metastatic adenoid cystic carcinoma: A multicenter, single-arm, phase 2 clinical trial.

6101 Background: Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer with heterogenous clinical behavior. ACC typically presents with locoregional disease and is treated with curative intent surgery and adjuvant radiation, but many patients develop locally recurrent/metastatic (R/M) disease even years later. Two recognized molecular subtypes exist: ACC 1 (37%), characterized by MYC amplification and NOTCH -activating mutations and a poor prognosis, and ACC 2 (63%), which demonstrates P63 expression and upregulated EGFR and MET and a better prognosis. There is no standard treatment for R/M ACC, but multi-targeted tyrosine kinase inhibitors are a mainstay of treatment despite their limited efficacy. Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET, causing immune-directed destruction of cancer cells. Since MET expression renders EGFR inhibitors ineffective, we hypothesized that amivantamab would overcome resistance especially in the ACC 2 subtype. This multicenter, single arm, Phase 2 clinical trial (NCT05074940) evaluated the efficacy of amivantamab in patients with R/M ACC supported by Janssen Pharmaceuticals. Methods: Eligible patients were ≥18 years of age with R/M ACC and had progressive disease (PD) within 6 months of enrollment, ECOG ≤1, with adequate organ and marrow function. Patients received amivantamab 1050 mg or 1400 mg (≥80kg) IV weekly for 4 weeks then Q2 weeks until PD or unacceptable toxicity. The primary end point was overall response rate (ORR) assessed by RECIST 1.1. Among 18 treated patients the lower limit of a one-sided 90% exact binomial CI would be >14% if ≥5 patients respond. Adverse events (AEs) were assessed by CTCAE v5. Secondary end points included progression- free survival (PFS) and overall survival (OS). Key exploratory end points were P63 and MYC expression. Results: We enrolled 21 patients with 17 evaluable for response at time of submission. Most were male (14, 67%) non-Hispanic (20, 95%), and White (19, 90%) with a median age of 61 (range, 36-76) years. The majority received prior treatment. The best ORR was 6% (1 partial response), while 9 (53%) had stable disease (SD) and 7 (41%) PD. Median duration of SD was 5.4 months. The most common treatment-related AEs (TRAEs) were acneiform rash (17, 81%), infusion related reaction (16, 76%), and fatigue (15,71%). Grade 3 TRAEs occurred in 3 patients (14%) including acneiform rash, oral mucositis, and elevated alkaline phosphatase with no Grade ≥4 TRAEs. Median PFS and OS were 4.8 (95% CI, 1.84-7.64) and 10.4 months (95% CI, 5.48-NR), respectively. There was no correlation between tumor P63 or MYC levels and clinical benefit (PR+SD). Conclusions: While amivantamab did not achieve the target ORR, the safety profile was manageable and clinical benefit was observed in 59% of patients. Clinical trial information: NCT05074940 .

Real world safety outcomes of an outpatient lymphoma bispecific antibody program: A single center experience from Johns Hopkins.

e19018 Background: Bispecific Antibodies (BsAb) have demonstrated efficacy in the treatment of patients with hematologic malignancies through leveraging of T cell activity in targeting of malignant cells. Despite lacking the curative potential of CAR-T, limited toxicities and off the shelf availability make BsAbs a compelling treatment option for lymphoma. At the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (JHSKCCC) a unique inpatient/outpatient program (IPOP) is a hybrid nursing unit that allows for deployment of intensive therapies in an outpatient setting nested in the hospital. This outpatient clinic is located adjacent to the hospital ward, allowing for daily appointments-ranging from 15 minutes to 12 hours-7 days a week. Patients are required to reside within a one-hour drive and have a 24-hour caregiver during ramp up dosing days. This infrastructure is bolstered by an adjacent oncology urgent care center, where supportive therapies for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can be initiated outside of IPOP hours. Methods: In this retrospective electronic medical record (EMR) analysis of 28 patients at the JHSKCCC IPOP treated with the CD20/CD3 BsA therapies epcoritimab or mosunetuzumab from 1/2023 to 11/2024, safety outcomes including CRS and ICANS incidence and management are analyzed. Results: A total of 6 patients were treated with mosunetuzumab, of whom 2 developed grade 1 CRS. Both cases presented with fever within 24 hours after D15 dosing, and both resolved with supportive care. There were no cases of ICANS in this population. A total of 22 patients were treated with epcoritamab, of whom 6 developed grade 1 CRS, 6 developed grade 2 CRS, and 1 developed grade 4 CRS (vs. acute respiratory distress syndrome [ARDS] ). Among these patients, 5/6 of grade 1 cases, 5/6 of grade 2 cases, and 1/1 of grade 4 cases occurred following D15 dosing. In patients who developed grade 1 CRS, median onset was D17, and all cases were treated with supportive care only. In patients who developed grade 2 CRS: 1 received tocilizumab alone, 2 received tocilizumab plus dexamethasone, 1 received dexamethasone alone, and 2 were treated at outside hospitals with limited records. In the singular patient with grade 4 CRS, he was admitted to an outside hospital with grade 4 CRS vs ARDS from COVID-19 infection on D41. Conclusions: Review of IPOP patient safety data resulted in the following initiatives targeting common sites of workflow breakdown: 1) Standardized BsAb toxicity management algorithms, 2) A BsAb toxicity management order set in the EMR including a PRN Tocilizumab dose, and 3) patient education resources for toxicity recognition after D15. Through optimal education of patients and providers paired with bolstered EMR support during transitional care, we hope to maximize patient quality of life and access to efficacious care.

Multi-virus specific T cells to enhance the activity of bispecific antibodies in lymphoma.

7004 Background: Although Bispecific Antibodies (BsAbs) have the advantage of an “off the shelf” immune approach, their clinical activity relies on the patients’ native T-cell population that is impaired by prior chemotherapy and tumor-induced T cell exhaustion. T-cell dysfunction within the TME is one potential mechanism of BsAb resistance (Falchi, L. et. al. Blood), while continuous exposure to bispecific molecules also induces T-cell exhaustion (Phillipp, N. et. al. Blood). A higher frequency of regulatory T cells and increased markers of T cell exhaustion were seen in BsAb non-responders (Cortes-Selva, D. et. al. Blood). Banks of multi-virus specific T cells (MVSTs) have safely controlled viral infections in allogeneic hematopoietic stem-cell transplantation recipients (Tzannou, et. al JCO). Expanded MVSTs have a differentiated phenotype, exhibit immediate effector functions (cytotoxicity and cytokine secretion) and have not produced severe graft versus host disease in hundreds of recipients. We hypothesized that MVSTs would enhance the antitumor activity of BsAbs. Methods: To compare the anti-tumor activity of PBMCs and MVSTs, we cocultured GFP-labeled CD20+ BJAB lymphoma cells alone or with healthy donor PBMCs or MVST at a 1:1 ratio, in the presence or absence of CD3xCD20 BsAb. We evaluated T-cell activation using CD69 and CD25 antibodies using quantitative flow cytometry and tumor cell killing by assessing tumor survival at 24 and 48 hours. Results: While the addition of both MVSTs and PBMCs alone reduced tumor cell numbers, PBMCs + BsAbs reduced tumor cells to less than 50% of the cultures at 24 hours but the subsequent increase tumor cell numbers indicated lack of effective control. By contrast, MVSTs reduced the frequency of tumor cells from 42.5% at 24 hours and less than 2% by 48 hours. The number of T-cells in PBMCs decreased by 0.88-fold after 48-hours, while MVSTs increased by 2.16-fold in the presence of 1ng/ml BsAb. The number of T cells expressing CD25 increased 6.25-fold with PBMCs and 456.68-fold with MVST in the presence of BsAb. Conclusions: We have demonstrated that in combination with BsAb, MVSTs exhibit more rapid effector function and expansion than similarly cultured PBMCs, suggesting they could enhance tumor response depth. Despite using healthy donor PBMCs, which showed a 6-fold increase in activated T cells with BsAb, MVSTs induced 456-fold increase. This significant boost in T cell activation highlights MVSTs’ potential to overcome endogenous T cell exhaustion and enhance BsAb therapy. Tumor cell and T cell numbers after co-culture with PBMC or MVST +/- BsAb. Tumor cell numbers CD3+ T-cell numbers CD25+ Activated T-cells 24 hours 48 hours 48 hours 48 hours BJAB Alone 104,345 101,992 + PBMC 104,632 57,094 30,458 5,058 + PBMC + BsAb 1ng 17,350 37,621 26,665 31,621 BJAB Alone 51,633 69,183 + MVST 52,815 19,858 86,545 419 + MVST + BsAb 1ng 28,259 1,584 186,737 191,348

Incidence of venous thromboembolism (VTE) events in patients with EGFR-mutant non-small cell lung cancer (NSCLC) treated with amivantamab: A systematic review and combined meta-analysis of phase 3 randomized controlled trials.

12042 Background: Amivantamab is a bispecific antibody that was granted accelerated approval by the FDA in May 2021 for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In addition, it also targets the mesenchymal-epithelial transition (MET) pathway which is involved in cancer cell proliferation. While amivantamab approval is considered a significant advancement in the EGFR-mutant lung cancer management, its introduction has raised concerns about potential new adverse events. This study aims to evaluate the incidence of venous thromboembolism (VTE) events in patients with EGFR-mutant NSCLC receiving amivantamab. Methods: We conducted a comprehensive literature search using MEDLINE and EMBASE databases from inception through December 31, 2024. Phase III randomized controlled trials (RCTs) utilizing amivantamab in EGFR-mutant NSCLC and reporting VTE adverse events were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was employed. Results: A total of 1,791 patients from three phase III RCTs (MARIPOSA n = 849, MARIPOSA-2 n = 636, PAPILLON n = 308) were included in the analysis. MARIPOSA tested amivantamab-lazertinib vs osimertinib vs lazertinib, while MARIPOSA-2 involved amivantamab-lazertinib-chemotherapy vs chemotherapy vs amivantamab-chemotherapy, and PAPILLON tested amivantamab-chemotherapy vs chemotherapy. Randomization ratios were 2:2:1, 2:2:1, and 1:1, respectively. The incidence of any-grade VTE was higher in the amivantamab group compared to the control group, with a rate of 25.90% vs 7.26% (RR, 3.69; 95% CI: 2.74-4.98; P < 0.00001). VTE as a serious adverse event was reported higher in the amivantamab arm compared to the control arm, 5.69% vs 2.42% (RR, 2.36; 95% CI: 1.31-4.27; P = 0.004). There was no statistically significant difference between the two treatment groups in terms of incidence of high-grade VTE. A subgroup analysis based on the type of VTE was performed. Incidence of both pulmonary embolism (PE) and deep vein thrombosis (DVT) was higher in the amivantamab cohort compared to the control cohort, with a rate of 9.94% vs 3.75% (RR, 2.62; 95% CI: 1.50-4.58; P = 0.0007) and 7.97% vs 1.81% (RR, 5.0; 95% CI: 2.90-8.62; P < 0.00001), respectively. Conclusions: This study showed increased risk of VTE events in patients with EGFR-mutant NSCLC treated with amivantamab-containing regimens compared to the standard arm. These findings highlight the importance of close monitoring for those events in order to early detect and provide the appropriate management. Further studies are needed to better understand this association between amivantamab and VTE.

The clinical trials landscape in follicular lymphoma: A systematic review.

e23016 Background: Follicular lymphoma (FL) is an incurable B-cell lymphoma, with advances in therapy leading to a median overall survival (OS) exceeding fifteen years. However, prolonged survival presents challenges in clinical trial design, particularly in endpoints that meaningfully capture OS. Notably, progression-free survival (PFS), a commonly used surrogate, has shown only a weak association with OS in FL. To ensure clinical trials address both longevity and well-being, it is crucial to incorporate endpoints that reflect patients' ability to live longer, healthier lives. This systematic review evaluates ongoing randomized trials in FL, focusing on the integration of QoL and survival endpoints. Methods: A systematic review was conducted on ongoing Phase III FL clinical trials registered on ClinicalTrials.gov. Key data extracted include primary and secondary endpoints and QoL measures. Trials were categorized based on investigational product, and treatment duration. Results: A total of 28 trials were identified, with PFS as the most common primary endpoint (79% of trials), followed by response rates, including ORR and CR (18%). Alternative surrogate survival endpoints, including progression-of-disease within 24 months (POD24), complete response at 30 months (CR30), and minimal residual disease (MRD) was included as an endpoint in 4%, 14%, and 7% of trials respectively. QoL measures were incorporated in 50% of trials. Trials were evenly distributed between first-line (50%) and relapsed/refractory (50%) treatment settings. The most frequently investigated therapeutic category was bispecific antibodies (32%), followed by monoclonal antibodies (21%) and chimeric antigen receptor (CAR) T-cell therapy (18%). Treatment duration was time-limited in 85.7% of trials, while 14.3% involved indefinite treatment plans. Conclusions: Current FL clinical trials exhibit variability in endpoint selection, with PFS frequently used as the primary endpoint despite its weak association with OS. Surrogate survival outcomes such as CR30, POD24, and MRD status remain of uncertain value in FL and continue to be explored. QoL measures are included in 50% of trials, highlighting opportunities for further improvement in addressing patient-centered outcomes. The emergence of CAR T-cell therapy and bispecific antibodies holds promise for further improving OS in FL, underscoring the need for ongoing research into validated surrogates and QoL to guide treatment decisions effectively. Summary of trial characteristics. Variable Trials, n (%) Treatment Status First-line 14 (50) Relapsed/Refractory 14 (50) Primary endpoint OS 1 (3.57) PFS 22 (78.6) Response rates 5 (17.9) Secondary endpoints POD24 1 (3.57) CR30 4 (14.3) MRD 2 (7.14) Quality of life data Collected 14 (50)

Real-world data on bispecific antibodies (BsAbs) administration in community oncology settings.

e13532 Background: BsAbs represent a transformative advancement in oncology, with 10 FDA-approved agents as of early 2025. Despite their potential, widespread adoption of BsAbs in community oncology settings has been limited due to risks of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infection, and logistical challenges. Consequently, real-world data on BsAb utilization outside academic centers remain sparse, with no significant publications to date. The American Oncology Network (AON), a large community oncology practice network, has implemented protocols to address these challenges. Starting in late 2022, AON developed standard operating procedures and conducted extensive educational outreach through pharmacy staff and physician leadership. Additionally, staff have engaged with partner hospitals to facilitate inpatient dosing and toxicity management. As of 1/1/2025, over 1100 doses of BsAbs have been administered in AON clinics, representing one of the largest real-world applications of BsAbs outside academic institutions. Methods: Using the Meaningful Insights Biotech Analysis (MiBA) platform, an AON-associated technology partner, and manual data extraction, we analyzed BsAb utilization and outcomes via our EMR database. Eligible patients received BsAb therapy between November 1, 2022, and November 1, 2024. Data collection included demographics, disease characteristics, doses, and other factors listed below. Results: Over 1100 doses of BsAbs were administered across AON clinics during the study period. Patient median age was 70, ECOG performance status 1. 81% of patients were White, and 16% African American. Patients with B-cell lymphoma, myeloma, and SCLC had received a median of 4, 2, and 4 prior lines of therapy, respectively. 16.39% of patients experienced any-grade CRS, 11.48% experienced ICANS. Only 1 patient required tocilizumab. For teclistimab, median PFS has not been reached at 300 days. Values to date are consistent with outcomes reported in clinical trials, suggesting similar efficacy in community settings. Conclusions: This study highlights the feasibility of administering BsAbs in appropriately resourced community oncology settings. AON's comprehensive approach to protocol development, staff training, and clinical oversight across the inpatient and outpatient spectrum has facilitated the safe and effective use of BsAbs at a scale previously limited to academic centers. These data underscore the potential for broader adoption of BsAbs in community practices and support the need for further real-world evidence to optimize their integration into routine oncology care. BsAbs administered and PFS. Drug Patient number Doses given 2023-24 Median PFS (days) Elranatamab 3 37 150 Epcoritamab 10 40 430 Tarlatamab 5 59 126 Mosunetuzumab 8 10 NR Amivantamab 37 375 NR Talquetamab 7 58 76 Teclistimab 14 332 NR NR, Not Reached.

Anti-tumor effectiveness of a novel bispecific antibody that blocks both PD-L1 and LAG-3.

Anti-tumor effectiveness of a novel bispecific antibody that blocks both PD-L1 and LAG-3.

First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial phase 1 results.

7505 Background: Bispecific antibodies (BsAbs) have begun to transform outcomes in MM. Emerging data suggest that targeting two MM antigens with T-cell redirection may overcome tumor heterogeneity and acquired resistance to further improve clinical outcomes. JNJ-5322 is a next-generation TsAb dually targeting BCMA and GPRC5D via T-cell redirection, comprising novel binding domains, including low affinity CD3, selected in vitro to enhance on-tumor effects and reduce off-tumor impact. We report first results from an ongoing phase 1 study of JNJ-5322 (NCT05652335). Methods: Dose escalation/expansion cohorts enrolled measurable RRMM pts previously exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody. Escalating fixed Q2W or Q4W SC doses (0.4–300 mg) were explored, including 100 mg Q4W, the putative recommended phase 2 dose (RP2D). Pts received 1 step-up dose (SUD) (5 mg) prior to receiving the 100 mg Q4W dose, allowing faster full dose initiation and attenuation of cytokine release syndrome (CRS) risk. Adverse events (AEs) were graded by CTCAE v5.0; CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Overall response rate (ORR) was assessed by IMWG criteria. Results: As of Jan 15, 2025, 126 pts received JNJ-5322 (36 at 100 mg Q4W); median follow-up (mFU) 8.2 mo. Median age 64 yrs; median 4 prior lines of therapy; 100% triple-class exposed (56% refractory); 31% high-risk cytogenetics; 23% had prior anti-BCMA/-GPRC5D therapy (77% naïve). The putative RP2D was identified as 100 mg Q4W. Overall, 99% of pts had ≥1 AE, most commonly CRS (59%; all grade [gr] 1 [45%]/2 [14%]; no gr ≥3), nail AEs (gr 1/2 56%), taste AEs (gr 1/2 56%), neutropenia (48%; gr 3/4 41%), and non-rash skin AEs (47%; gr 3/4 1%). Overall, 16% had weight decreases (no gr ≥3), 16% had rashes (no gr ≥3), 2% had ICANS (all gr 1), and 75% had infections (gr 3/4 28%). 5 pts had dose-limiting toxicities. 4 pts died due to AEs. In response-evaluable pts, ORR was 86% (75% ≥VGPR) at the RP2D (n=36), and 73% (66% ≥VGPR) overall (n=124). ORR was 100% (89% ≥VGPR) at the RP2D among pts naïve to anti-BCMA/-GPRC5D therapies (n=27), and all patients remain in response (mFU 8.5 mo). Median time to first response was 1.2 mo. Conclusions: In the largest data set for a next-generation dual antigen T-cell redirecting TsAb, the first clinical data for JNJ-5322 showed a 100% ORR at the putative RP2D in anti-BCMA/-GPRC5D naïve patients, with convenient Q4W dosing. Tolerability appeared improved, including lower incidence and severity of GPRC5D-associated AEs vs anti-GPRC5D BsAbs and manageable gr 3/4 infection rates. CRS was mostly gr 1 (no gr ≥3 CRS) using 1 SUD. First data with JNJ-5322 suggest a paradigm shift, offering ORRs similar to CAR-Ts but as an off-the-shelf therapy intended for outpatient dosing. Clinical trial information: NCT05652335 .

Exploring steroid prophylaxis to mitigate CRS: Enhancing access to bispecific antibodies in RRMM.

e19537 Background: Talquetamab, an FDA-approved bispecific antibody (bsAb) for relapsed/refractory multiple myeloma (RRMM), demonstrates an ORR >70% and a 24-month OS rate of 67%. However, CRS rates exceed 70%, with 29%, 44%, and 33% after step-up doses (SUDs) 1, 2, and 3, respectively. Guidelines recommend inpatient monitoring with 48-hour intervals between SUDs due to high CRS rates. Similarly, high CRS rates and need for close monitoring are observed with FDA-approved bsAbs for melanoma and lung cancer, necessitating generalizable strategies to increase bsAb uptake. Prophylactic tocilizumab (toci) reduces CRS rates, but its cost and availability restrict broad use. BsAbs like epcoritamab use post-SUD steroid prophylaxis to mitigate CRS. This study evaluates the role of prophylactic (CRSppx) steroids—dexamethasone (dex) administered between SUDs—in reducing CRS in patients (pts) receiving talquetamab (Tal). Methods: This single-center retrospective study included RRMM pts who completed SUD and received ≥1 treatment dose of Tal from 8/9/23 to 12/31/24. CRSppxwas defined as the group of pts who received dex between each SUD, in addition to standard pretreatment dex. Results: Of the 26 pts who received Tal, 13 received CRSppx. Median age was 65 in CRSppx vs. 70 in standard of care (SOC). High-risk cytogenetics were present in 54% (CRSppx) vs. 62% (SOC). R-ISS stages I, II, and III were 60%, 40%, and 0% (CRSppx) vs. 22%, 33%, and 44% (SOC). Extramedullary disease was present in 6 CRSppx vs. 3 SOC pts; CNS involvement was present in 2 CRSppx pts. Both groups had 1 pt with plasma cell leukemia. Median prior lines of therapy were 7 (CRSppx) vs. 8 (SOC); 85% were penta-refractory in both groups. Median CRSppx dose of dex was 8 mg (range 4 – 10). Any-grade CRS occurred in 4/13 (31%) CRSppx vs. 10/13 (77%) SOC pts; 96% were grade 1 and managed with dex. One CRSppx pt had grade 2 CRS requiring toci, while 2 SOC pts required toci due to persistent CRS despite dex use. No CRS recurrence was noted in CRSppx pts vs. in one SOC pt. One CRSppx pt had concerns for ICANS, though this was confounded by limited pt literacy. Median LOS was 8 days (CRSppx) vs. 9 days (SOC). Any-grade infections occurred in 1 CRSppx vs. 5 SOC pts. 30d-readmission rate was 2/13 (15%) in CRSppx (1 associated with CRS) vs. 3/13 (23%) in SOC. 11 CRSppx and all SOC pts were evaluable for response. At 5.5 months median follow-up, ORR was 91% (70% VGPR) in CRSppx vs. 70% (78% VGPR) in SOC. Disease progression occurred in 2 CRSppx vs. 7 SOC pts. Conclusions: Prophylactic steroids reduced CRS incidence while maintaining high response rates and low infection and readmission rates. This approach could facilitate safe outpatient bsAb administration, improving accessibility in resource-limited settings. Further research is needed to validate these findings, assess steroid-related side effects, and refine dosing. CRSppx has broad applicability with growing use of bsAbs across various tumor types.