CD3 Bispecific Antibody Research Articles

Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors.

A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies

Abstract T-cell activation is a multistep process requiring T-cell receptor engagement by peptide–MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell–mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell–mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti–programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti–programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen–targeted anti-CD3 (Signal 1) T-cell engagers.

Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Combination with Daratumumab and Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma: Safety and Efficacy Results from the Phase 1b Monumental-2 Study

Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Combination with Daratumumab and Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma: Safety and Efficacy Results from the Phase 1b Monumental-2 Study

Initial Results from a Phase 1 Study of TQB2934, a BCMA × CD3 Bispecific Antibody, As Monotherapy in Patients with Relapsed/Refractory Multiple

Initial Results from a Phase 1 Study of TQB2934, a BCMA × CD3 Bispecific Antibody, As Monotherapy in Patients with Relapsed/Refractory Multiple

Efficacy and Safety of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Japanese Patients with Relapsed/Refractory Multiple Myeloma from the Phase 1/2 Monumental-1 Study

Efficacy and Safety of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Japanese Patients with Relapsed/Refractory Multiple Myeloma from the Phase 1/2 Monumental-1 Study

Comparison of CAR T-cell and bispecific antibody as third-line or later-line treatments for multiple myeloma: a meta-analysis

BackgroundCAR-T-cell therapy and bispecific antibody have revolutionized the treatment landscape for multiple myeloma. However, there is currently a lack of studies comparing the efficacy and safety of these two approaches....

Abstract B010: A PD-L1 x CD3 bispecific antibody enhances the anti-tumor efficacy of regorafenib in pre-clinical colon cancer models

Abstract B010: A PD-L1 x CD3 bispecific antibody enhances the anti-tumor efficacy of regorafenib in pre-clinical colon cancer models

BCMA chimeric antigen receptor T cells therapy re-treatment of a patient with recurrent/refractory IgD multiple myeloma: A case report and literature review

Multiple myeloma (MM) is a malignant plasma cell disease that currently cannot be cured. Several new drugs have continuously been introduced in the recent years. New drugs targeting B-cell maturation antigen (BCMA) have greatly improved the efficacy and prognosis of MM compared with traditional treatments. This article reports the case of an IgD type relapsed and refractory MM patient with poor efficacy of BCMA×CD3 bispecific antibody. The patient achieved deep remission after receiving BCMA-targeted CAR-T cell therapy after initial seven lines of treatment. Literature review was also conducted to improve the clinical physicians' understanding of BCMA target therapy for relapsed and refractory MM patients.

Sequencing of cellular therapy and bispecific antibodies for the management of diffuse large B-cell lymphoma.

Historically, the management of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) following first-line chemoimmunotherapy has been second-line chemotherapy, followed by high-dose chemotherapy and consolidative autologous hematopoietic stem cell transplantation (HSCT), resulting in durable remissions in approximately 40% of patients. In 2017, chimeric antigen receptor (CAR) T-cell therapy changed the landscape of treatment for patients with R/R DLBCL, with complete response rates ranging from 40-58% and long-term disease-free survival of >40% in the highest risk subgroups, including patients who relapsed after autologous HSCT. Since that time further studies have demonstrated improved overall response rates and survival outcomes in patients with primary refractory or early-relapsed (relapse within 1 year) DLBCL treated with CAR T-cell therapy compared with autologous HSCT, advancing CAR T-cell therapy into the second-line setting. However, >50% of patients will relapse in the post-CAR T-cell setting. In the past 2 years, two CD20 x CD3 bispecific antibodies were approved by the Food and Drug Administration for the treatment of R/R DLBCL after two or more lines of systemic therapy. These bispecific antibodies have demonstrated overall response rates exceeding 50% and durable remissions at >2 years of follow-up. Additionally, a notable treatment advantage of bispecific antibodies is their ability to be administered in the community setting, making treatment more accessible for patients. The development and advancement of these novel therapies raise questions regarding the ongoing role of HSCT in the management of R/R DLBCL and the best sequence of cellular and bispecific therapies to optimize patients' outcomes.

Evaluation of Drug-Drug Interaction Potential of Talquetamab, a T-Cell-Redirecting GPRC5D×CD3 Bispecific Antibody, as a Result of Cytokine Release Syndrome in Patients with Relapsed/Refractory Multiple Myeloma in MonumenTAL-1, Using a Physiologically Based Pharmacokinetic Model.

Cytokine release syndrome, commonly associated with T-cell immunotherapies, was observed with talquetamab, a T-cell-redirecting bispecific antibody, in the phase I/II MonumenTAL-1 study, leading to elevated interleukin (IL)-6, which can suppress cytochrome P450 (CYP) enzyme activity. We aimed to evaluate the potential impact of elevated IL-6 on the exposure of co-administered CYP450 substrates for two scenarios: (1) the observed median IL-6 profile and (2) a profile with the highest IL-6 maximum concentration following talquetamab treatment. A physiologically based pharmacokinetic model was developed based on the literature and simulations performed using observed IL-6 profiles from patients in MonumenTAL-1 who received the subcutaneous recommended phase 2 doses (RP2Ds) of talquetamab: 0.4 mg/kg weekly (QW) and 0.8 mg/kg every other week (Q2W). Median IL-6 maximum concentration was 18.4 and 7.1 pg/mL, and maximum IL-6 maximum concentration was 213 and 3503 pg/mL for talquetamab QW and Q2W RP2Ds, respectively. For the median IL-6 profile, no interaction between IL-6 and studied CYP substrates was predicted at either RP2D. The maximum IL-6 profile predicted weak-to-moderate impact on exposure of CYP2C19, CYP3A4, and CYP3A5 substrates and minimal impact on exposure of CYP1A2 substrates at both RP2Ds. Impact on exposure of CYP2C9 substrates was predicted as minimal at QW and minimal-to-weak at Q2W RP2Ds. Time to return to 20% difference from baseline enzymatic activity was predicted as 7 and 9 days after start of cycle 1 for QW and Q2W RP2Ds, respectively. These modeling results suggest that IL-6 release due to talquetamab-induced cytokine release syndrome has limited impact on potential drug-drug interactions, with the highest likelihood of impact occurring from initiation of talquetamab step-up dosing up to 7 (QW) or 9 (Q2W) days after first treatment dose in cycle 1 and during and after cytokine release syndrome. Multiple myeloma can be treated with immunotherapies such as the bispecific antibody, talquetamab, which binds the novel antigen G protein-coupled receptor family C group 5 member D on multiple myeloma cells and CD3 on T cells and induces T-cell-mediated lysis of multiple myeloma cells. Following talquetamab treatment, many patients experience cytokine release syndrome, an inflammatory immune response where levels of proinflammatory cytokines, including interleukin (IL)-6, are increased. Interleukin-6 can suppress the activity of important enzymes in the body (cytochrome [CYP] P450s) that are involved in drug clearance. This study used a physiologically based pharmacokinetic computer model to investigate the potential impact of increased IL-6 levels on CYP450 enzymes to determine subsequent impact on drugs that are metabolized by CYP450 enzymes. The results showed no predicted interaction between median levels of IL-6 observed in patients and CYP substrates (such as caffeine and omeprazole) with talquetamab. In a simulation that assessed higher (maximum) IL-6 levels observed in patients, the predicted impact of IL-6 was minimal to weak for most of the CYP substrates assessed. The effect on CYP450 enzymatic activity was highest from initiation of talquetamab step-up dosing up to 7-9 days after the first treatment dose of talquetamab. These results suggest that, in this treatment time period, elevated IL-6 levels due to talquetamab-induced cytokine release syndrome have limited impact on drugs that are CYP substrates that may be used in conjunction with talquetamab, but that the concentration and toxicity of these drugs should be monitored and the dose of CYP substrate adjusted as required.

1371P An anti-EpCAM x CD3 bispecific antibody, M701, for the treatment of malignant pleural effusion in NSCLC patients: Intermediate results of a prospective multicenter phase Ib trial

1371P An anti-EpCAM x CD3 bispecific antibody, M701, for the treatment of malignant pleural effusion in NSCLC patients: Intermediate results of a prospective multicenter phase Ib trial

Long-Term Efficacy and Safety Results From the Phase 1/2 MonumenTAL-1 Study of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)

Long-Term Efficacy and Safety Results From the Phase 1/2 MonumenTAL-1 Study of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)

Talquetamab (Tal), a GPRC5D×CD3 Bispecific Antibody (BsAb), in Combination With Pomalidomide (Pom) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM): Efficacy and Safety Results From the Phase 1b MonumenTAL-2 Study

Talquetamab (Tal), a GPRC5D×CD3 Bispecific Antibody (BsAb), in Combination With Pomalidomide (Pom) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM): Efficacy and Safety Results From the Phase 1b MonumenTAL-2 Study

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

BackgroundJNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.MethodsAdult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).ResultsOverall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.ConclusionJNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels.Trial registration number ClinicalTrials.gov (No. NCT04991740).

Safety and efficacy of odronextamab in patients with relapsed or refractory follicular lymphoma

Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma after two or more lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in cycle 1 to help mitigate the risk of cytokine release syndrome, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate by independent central review. Among 128 patients evaluated, 95% completed cycle 1, and 85% completed four or more cycles. At 20.1months' efficacy follow-up, objective response rate was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events occurred in 16% of patients. The most common treatment-emergent adverse events were cytokine release syndrome [56%; grade ≥31.7% (1/60) with 0.7/4/20 mg step-up], neutropenia (39%), and pyrexia (38%). Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R follicular lymphoma.

Talquetamab Versus Real-World Physician's Choice Treatment: Comparative Effectiveness in Patients With Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

BackgroundTalquetamab, a first-in-class GPRC5D×CD3 bispecific antibody, is approved for treatment of triple-class exposed (TCE) patients with relapsed/refractory multiple myeloma (RRMM) based on MonumenTAL-1 results. We evaluated the comparative effectiveness of talquetamab in MonumenTAL-1 versus real-world physician's choice (RW) treatment. Materials and MethodsAn external control arm for MonumenTAL-1 was created from eligible patients in the Flatiron Health database who satisfied key MonumenTAL-1 eligibility criteria (n = 629 with 1169 eligible lines of therapy). Patient-level data from MonumenTAL-1 were included for patients who received subcutaneous talquetamab 0.4 mg/kg QW (n = 143) and 0.8 mg/kg Q2W (n = 145). After adjusting for baseline covariate imbalances, comparative effectiveness was assessed for progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). ResultsBaseline covariates were comparable across cohorts after adjustment. Talquetamab 0.4 mg/kg QW and 0.8 mg/kg Q2W cohorts, respectively, showed significant improvement in PFS (HR, 0.55 [95% CI, 0.44-0.69; P<0.0001; median, 7.5 vs. 4.0 months] and 0.40 [95% CI, 0.31-0.53; P<0.0001; median, 14.2 vs. 4.0 months]), TTNT (HR, 0.59 [95% CI, 0.47-0.74; P<0.0001; median, 9.1 vs. 5.1 months] and 0.45 [95% CI, 0.35-0.59; P<0.0001; median, 13.3 vs. 5.1 months]), and OS (HR, 0.56 [95% CI, 0.40-0.78; P=0.0007; median, NR vs. 16.5 months] and 0.48 [95% CI, 0.33-0.70; P=0.0002; median NR vs. 15.9 months]) versus RW treatment. ConclusionBoth talquetamab schedules demonstrated superior effectiveness over RW treatment for all outcomes assessed. These data suggest talquetamab as an effective novel immunotherapy option in patients with TCE RRMM. MicroabstractTalquetamab has been evaluated in the single-arm MonumenTAL-1 trial in patients with relapsed/refractory multiple myeloma. Effectiveness of talquetamab was assessed against outcomes of real-world treatments using indirect treatment comparison methodology. Talquetamab led to better outcomes compared to standard treatments, suggesting that novel immunotherapies such as talquetamab may be a superior treatment option versus previous standard regimens.

IL-15/IL-15Rα-Fc-Fusion Protein XmAb24306 Potentiates Activity of CD3 Bispecific Antibodies through Enhancing T-Cell Expansion.

An insufficient quantity of functional T cells is a likely factor limiting the clinical activity of T-cell bispecific antibodies, especially in solid tumor indications. We hypothesized that XmAb24306 (efbalropendekin alfa), a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein, may potentiate the activity of T-cell dependent (TDB) antibodies. The activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in the upregulation of the IL-2/15Rβ (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to IL-15. XmAb24306 enhanced T-cell bispecific antibody-induced CD8+ and CD4+ T-cell proliferation and expansion. In vitro combination of XmAb24306 with cevostamab or anti-HER2/CD3 TDB resulted in significant enhancement of tumor cell killing, which was reversed when T-cell numbers were normalized, suggesting that T-cell expansion is the main mechanism of the observed benefit. Pretreatment of immunocompetent mice with a mouse-reactive surrogate of XmAb24306 (mIL-15-Fc) resulted in a significant increase of T cells in the blood, spleen, and tumors and converted transient anti-HER2/CD3 TDB responses to complete durable responses. In summary, our results support the hypothesis that the number of tumor-infiltrating T cells is rate limiting for the activity of solid tumor-targeting TDBs. Upregulation of CD122 by TDB treatment and the observed synergy with XmAb24306 and T-cell bispecific antibodies support clinical evaluation of this novel immunotherapy combination.

Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma.

We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

Phase 3 trial of odronextamab plus lenalidomide versus rituximab plus lenalidomide in relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL; OLYMPIA-5).

TPS7094 Background: FL and MZL are indolent B-cell non-Hodgkin lymphomas (B-NHLs) that are treated in a similar way in the R/R setting. Despite the efficacy of rituximab–lenalidomide (R2) in patients (pts) with R/R FL, and MZL to a lesser extent, a notable proportion fail to achieve an optimal, durable response. Odronextamab is an off-the-shelf, CD20×CD3 bispecific antibody. In the Phase (Ph) 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a generally manageable safety profile across R/R B-NHL subtypes, including FL and MZL (Bannerji, et al. Lancet Haematol 2022). In the Ph 2 ELM-2 study, odronextamab elicited an objective response rate of 80% and complete response (CR) rate of 73% in pts with heavily pretreated R/R FL (Villasboas, et al. ASH 2023). The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. These positive data support the evaluation of odronextamab in R/R FL and MZL in earlier lines of therapy. Combining odronextamab with lenalidomide has the potential to improve efficacy in the R/R setting compared with R2. Methods: OLYMPIA-5 (NCT06149286) is a Ph 3, open-label, randomized study of odronextamab plus lenalidomide versus R2 in pts with R/R FL and MZL. The study consists of Part 1 (safety run-in) followed by Part 2 (randomization). In Part 1, odronextamab and lenalidomide will be administered for 12×28-day cycles or until relapse, progressive disease, withdrawal of consent, or unacceptable toxicity. Odronextamab IV infusion will be administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C1 Day 22. In Part 2, pts will be randomized 1:1 to receive 12 cycles of odronextamab plus lenalidomide, or R2 for the first 5 cycles followed by lenalidomide monotherapy for C6–12 per standard schedule (Leonard, et al. J Clin Oncol 2019). Key inclusion criteria: aged ≥18 years; histologically confirmed FL Grade 1–3a or MZL (nodal, splenic, or extra nodal) that is refractory or relapsed after ≥2 cycles of prior systemic therapy that included ≥1 anti-CD20 antibody; measurable disease; ECOG PS 0–2; and adequate organ function. Pts with central nervous system (CNS) lymphoma, history of or current relevant CNS pathology, histological evidence of transformation to high-grade or diffuse large B-cell lymphoma, and prior use of lenalidomide or any CD20×CD3 bispecific antibody within the past 6 months are excluded. The Part 2 primary endpoint is progression-free survival as assessed by independent central review. Key secondary endpoints are CR, best overall response, and overall survival. Minimal residual disease (by ctDNA) analysis is an exploratory endpoint. The trial is currently recruiting and is expected to enroll approximately 24–48 pts in Part 1 and 422 pts in Part 2 (352 R/R FL; 70 R/R MZL) at ~200 global sites. Clinical trial information: NCT06149286 .

Safety and preliminary efficacy results of IBI389, an anti-CLDN18.2/CD3 bispecific antibody, in patients with solid tumors and gastric or gastro-esophageal tumors: A phase 1 dose escalation and expansion study.

2519 Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .