Across Cancer Types, Trispecific Antibodies Show Promise in Early Result

When the FDA granted fullantibody blinatumomab (Blincyto) in 2017 for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children, it opened the door to further exploration and novel drug development.¹Prior to this, the agent had received approval in 2014 for the treatment of patients with Philadelphia chromosome–negative relapsed or refractory B-cell precursor ALL.² Now, next-generation antibodies are undergoing evaluation with modest success. Several abstracts evaluating trispecific antibodies across cancer settings were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. Notably, agents were evaluated in multiple myeloma, neuroendocrine carcinoma, and small cell lung cancer.

JNJ-5322

The trispecific antibody JNJ-5322 (JNJ-79635322) showed a manageable safety profile and responses similar to chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/ refractory multiple myeloma at the recommended phase 2 dose (RP2D).3 Findings from a first-in-human phase 1 trial (NCT05652335) defined the RP2D as 100 mg subcutaneously every 4 weeks, preceded by a 5-mg step-up dose. Among patients who were B-cell maturation antigen (BCMA)/GPRC5D naïve (n = 27), the overall response rate (ORR) was 100%, with a 70.4% complete response (CR) and a 96.3% very good partial response (VGPR) or better rate.

“JNJ-5322 binds more efficiently to myeloma cells that express both targets compared with bispecific antibodies…and this translates into higher potency in preclinical studies,” Niels W. van de Donk, MD, PhD, of the Department of Hematology at Amsterdam University Medical Center, Vrije Universiteit Amsterdam, the Netherlands, said in his presentation. “Importantly, JNJ-5322 also eliminates tumor cells with only BCMA expression or only GPRC5D expression. This is very relevant because myeloma is a very heterogeneous disease when it comes to antigen expression, and it’s also very important in order to prevent antigen escape.” Additionally, the novel CD3 binding domain contributes to a manageable cytokine release syndrome (CRS) profile with only 1 step-up dose.

This study, which enrolled 147 patients, was designed with a dose escalation and dose optimization to identify the RP2D, as well as different administration schedules. The primary objectives were to identify the RP2D; safety, including dose-limiting toxicities (DLTs); and a preliminary efficacy assessment. The RP2D was determined based on safety, pharmacokinetic, and efficacy end points; however, the maximum tolerated dose was not reached.

Participants needed to have relapsed/refractory multiple myeloma and be triple-class exposed to a proteasome inhibitor, immunomodulatory drug, and a CD38-based therapy. Patients also needed an ECOG performance status of 0 or 1 and measurable disease.

Of the 147 patients enrolled, 36 were treated with the RP2D. For the total population, there was a 9.3-month median follow-up, and for those receiving the RP2D, there was an 11.6-month median follow-up. In the RP2D group, 9 (25%) patients were previously exposed to a BCMA- or GPRC5D-targeted therapy, and 27 (75%) patients were BCMA/GPRC5D naive. There were 19 patients (52.8%) whose disease was refractory to a proteasome inhibitor, and 100% were refractory to an immunomodulatory drug and a CD38-based therapy. Two patients had penta-drug refractory disease.

The most common hematologic treatment-emergent AEs (TEAEs) for all patients and patients receiving RP2D were lymphocytopenia and neutropenia. Van de Donk noted that thrombocytopenia and anemia were rare. The most common nonhematologic TEAEs were any-grade infections at 80.6% and 33.3% grade 3/4 infections in the RP2D group. In this population, there was 1 DLT of neutropenia and 1 grade 5 TEAE of pneumonia. There were 4 DLTs and grade 5 TEAEs each among the other doses on the trial. The DLTs were maculopapular rash, palmar-plantar erythrodysesthesia syndrome, pneumonia, and respiratory failure; the grade 5 TEAEs were drug-related adenoviral encephalitis, embolic stroke, multiple organ dysfunction syndrome, and pulmonary hemorrhage.

“Twenty-six patients were treated with 100 mg of JNJ-5322 without prophylactic tocilizumab [Actemra]. In this patient population, the frequency of CRS was 69%, with the majority of cases being grade 1, only a few grade 2 cases, and no grade 3 or higher CRS events. In the cohort of patients that received prophylactic tocilizumab, we see a substantial reduction in CRS risk to only 20%, and these cases were all grade 1. All patients recovered from CRS with the appropriate supportive care measures,” van de Donk explained.

Overall, prophylactic tocilizumab decreased CRS incidence and severity for these patients. In the RP2D group, no patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS). Infections, which were the most common TEAE, included grade 3/4 pneumonia in 11.1% of patients given the RP2D, and upper respiratory tract infection and urinarytract infection both in 2.8% of patients. Hypogammaglobulinemia was seen in 50.0% of the RP2D group, which was a contributing factor in the infections, and 47.2% of those patients received 1 or more doses of intravenous immunoglobulin supplementation. Two patients died due to infections in the setting of hypogammaglobulinemia.

The most common oral TEAE related to GPRC5D was taste-related events, 58.3% any grade in the RP2D group. Less frequent oral TEAEs included dry mouth, dysphagia, stomatitis, and decreased appetite.

“It’s important to mention that the frequency and also the severity of these oral AEs are lower than what is typically seen with talquetamab [Talvey]. Also, the duration of the taste abnormalities is, in my experience, shorter than what you see with talquetamab,” van de Donk said.

In the RP2D cohort, 6% had grade 1/2 weight loss, and 12% of the total population experienced grade 1/2 weight loss. There were no grade 3 or higher events of this type. In the patients previously exposed to BCMA/GPRC5D who received 50 to 300 mg of JNJ-5322 (n = 20), the ORR was 55.0%, and the stringent CR rate and the CR rate were both 15.0%. In the BCMA/GPRC5D-naive groups, those who received JNJ-5322 at 50 mg (n = 21) had a 66.7% ORR, and the RP2D and 300-mg (n = 8) groups had 100% ORR.

This RP2D group had a stringent CR rate of 55.6%, CR rate of 14.8%, VGPR rate of 25.9%, and partial response rate of 3.7%. The progression-free survival rate at 1 year in the BCMA/GPRC5D-naive RP2D group was 95.0%, and across all dose levels, it was 74.1%. In the RP2D-naive group, there was 1 discontinuation in which a patient died of pneumonia with a VGPR, but there have been no patients with progression or other discontinuations in this group to date.

TRIgnite-1 Study

Findings from the dose escalation portion of the phase 1 TRIgnite-1 study (NCT05862012) revealed no DLTs, a mild safety profile, mild CRS, and low rate of infection in heavily pretreated patients with relapsed/refractory multiple myeloma who were treated with ISB 2001.⁴ ISB 2001 is a trispecific T-cell engager targeting CD38 and BCMA on myeloma cells while engaging T cells via CD3. The dual high affinity binding to myeloma cells enhances cytotoxicity at low antigen expression.

“The low affinity to CD3 minimizes off-tumor T cell-mediated cytotoxicity and T-cell exhaustion,” Hang Quach, MBBS, MD, FRACP, FRCPA, professor of hematology at the University of Melbourne, Australia, explained during a presentation of the data.

As of January 13, 2025, 24 patients were treated with ISB 2001 across 8 dose levels (5 mg/kg to 1800 mg/kg) with a median follow-up of 6 months (range, 2–12). Quach noted deep and durable responses from dose level 3 at active doses greater than 50 μg/kg with an ORR of 79% and a 30% or better complete response rate.

Patients had a median of 6 prior lines of therapy. Approximately 50% of patients were triple class refractory. More than 70% of patients were penta-drug exposed, with 46% of patients considered to be quad refractory, having been treated with prior BCMA-targeted therapies, including chimeric antigen receptor T cells, T-cell engagers, and antibody-drug conjugates.

Grade 3 or higher hematological toxicities occurred in 60% of patients; treatment-related grade 3 or higher neutropenia, thrombocytopenia, and anemia occurred in 29%, 14%, and 6% of patients, respectively.

Other treatment nonhematologic AEs occurred in 91% of patients at grade 3 or higher, 20% with no DLTs. Treatment-­ related grade 3 or higher infections occurred in 11% of patients. CRS was reported in 69% of patients. Most cases were grade 1 (57%), with only 4 patients having grade 2, mostly confined to the first administration dose. Median time to and duration of CRS was 2 days for each, with some patients requiring tocilizumab.

“Responses were durable, with some patients responding beyond 12 months,”

Quach said. Responses deepened over time, particularly in 6 out of 8 evaluable patients (75%), achieving minimal residual disease negativity.

Patients were a median age of 65 years (range, 47-82); 35% were women, and 77% were White. Patients underwent a median of 6 lines of prior lines of therapy (range, 3–11). In addition, 34% had extramedullary disease at screening, 40% had high-risk cytogenetic profile, and the majority (74%) had an ECOG performance status of 0.

“Importantly, robust activity was seen across key subgroups who were difficult to treat,” Quach said. “With a median half-life of 17 days, that supports a less frequent dosing. Dose expansion in part 2 is ongoing to establish the recommended phase 2 dose and optimal dosing schedule.”

Alveltamig (ZG006)

In an open-label phase 2 dose ­ optimization trial (NCT06440057), 17 patients with neuroendocrine carcinoma (NEC) were randomly assigned to receive either 10 mg (n = 8) or 30 mg (n = 9) of alveltamig (ZG006), a trispecific T-cell engager targeting CD3/DLL3/DLL3.⁵ The primary end point was ORR, according to RECIST1.1. Alveltamig binds to DLL3 on tumor cells and CD3 on T cells, eliciting T-cell specific killing of DLL3-expressing tumor cells in small cell lung cancer (SCLC) or NEC.

Overall, the ORR was 33.3%, and the disease control rate (DCR) was 66.7%. Duration of response and progression-free survival have not matured. All patients had received 1 or more prior lines of treatment, and the majority (76.5%) had received 2 or more lines. Ten (58.8%) of 17 had received a prior anti–PD-L1 treatment. The primary tumor sites included colorectum and cervix (24.0% each), esophagus (18.0%), and stomach and gallbladder (12.0% each).

Fifteen (88.2%) patients experienced treatment-related AEs (TRAEs), with the

3 most common being pyrexia (70.6%), CRS (58.3%), and increased aspartate aminotransferase levels (35.3%). Four (23.5%) patients experienced grade ¾ TRAEs, including decreased neutrophil and platelet counts, asthenia, and hypertension. No patients experienced TRAEs leading to treatment discontinuation or death. Two (11.8%) patients reported serious TRAEs. The safety profile between the 2 dosage groups was similar, with no significant differences, investigators reported.

With these limited data, the investigators reported that the agent exhibited an antitumor activity trend in previously treated patients with NEC.

During another ASCO 2025 presentation, investigators in a phase 1/2 trial (NCT06283719) reviewed tolerability, safety, and efficacy findings for alveltamig in patients with SCLC or NEC.⁶ In this trial, 47 patients were enrolled (43 with SCLC and 4 with NEC) and received 1or more doses of the agent every 2 weeks.Patients were randomly assigned to 1 of 8 doses: 0.1 mg (n = 4), 0.3 mg (n = 3), 1.0 mg (n = 3), 3.0 mg (n = 3), 10.0 mg (n = 5), 30.0 mg (n = 14), 60.0 mg (n = 12), or 100.0 mg (n = 3) ina standard 3+3 design.⁶

All patients reported TRAEs, and 38.3% experienced TRAEs of grade 3 or higher. The most common TRAEs were CRS, anemia, leukocytopenia, and pyrexia. Most were grade 1 or 2, the investigators reported. They noted that CRS most often occurred after the first 2 doses, and patients usually recovered within 2 days. One patient experienced grade 1 ICANS, and 1 patient in the 100 mg group experienced DLT events, which were a grade 3 CRS and a grade 4 pneumonia.

Across the 10-mg, 30-mg, and 60-mg doses, the confirmed ORRs were 75.0 (95% CI, 19.4%–99.4%), 53.8% (95% CI, 25.1%–80.8%), and 58.3% (95% CI, 27.7%–84.8%), respectively. In addition, the DCR was 75% (95% CI, 19.4%–99.4%), 76.9% (95% CI, 46.2%–95.0%), and 83.3% (95% CI, 51.6%–97.9%), respectively.

The investigators concluded that the agent was generally well tolerated, with most TRAEs including CRS being grade 1 or 2. Overall, the agent exhibited promising antitumor activity across several dose levels. Further, phase 2 dose optimization studies have been initiated to determine the efficacy and safety of the agent in patients with SCLC and NEC.

REFERENCES:

1. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. FDA. News release. Updated July 12, 2017. Accessed June 13, 2025. https://tinyurl.com/whmwpv56

2. Przepiorka D, Ko CW, Deisseroth A, et al. FDA approval: blinatumomab. Clin Cancer Res. 2015;21(18):4035-4039. doi:10.1158/1078-0432.CCR-15-0612

3. van de Donk NW, Vega G, Perrot A, et al. 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. J Clin Oncol. 2025;43(suppl 16):7505. doi:10.1200/JCO.2025.43.16_suppl.7505

4. Lichtman EI, Khot A, Augustson B, et al. Phase 1, first-in-human study of ISB 2001: a BCMAxCD38xCD3-targeting trispecific antibody for patients with relapsed/refractory multiple myeloma (RRMM)—dose escalation (DE) results. J Clin Oncol. 2025;43(suppl 16):7514. doi:10.1200/JCO.2025.43.16_suppl.7514

5. Xu J, Hu H, Lu M, et al. A phase 2 dose expansion study of ZG006, a trispecific T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with advanced neuroendocrine carcinoma. J Clin Oncol. 2025;43(suppl 16):e163341. doi:10.1200/JCO.2025.43.16_suppl.e16341

6. Ai X, Zhang YY, Zhang T, et al. A phase 2 dose expansion study of ZG006, a trispecific T cell engager targeting CD3/DLL3/DLL3, as monotherapy in patients with advanced small cell lung cancer. J Clin Oncol. 2025;43(suppl 16):8007. doi:10.1200/JCO.2025.43.16_suppl.8007