From:  Bispecific antibodies in the treatment of epithelial ovarian, endometrial, and cervical cancer: an overview of current applications, challenges, and emerging opportunities

 Summary of main clinical trials investigating bsAbs in ovarian cancer.

Drug nameTargetSettingPhasenEfficacyTEAEs/TRAEs/irAEs G ≥ 3* (in at least 5% of pts) and any grade CRS/IRR/ICANS**
(%)
ICE mechanism
Ubamatamab (REGN4018) [85]MUC16 × CD3PROC
1–3 lines		178ORR: 14.3% (95% CI: 5.4–28.5)
DCR: 57.1% (95% CI: 41–72.3)

TEAEs G ≥ 3

  • anemia 24.4%

  • neutropenia 7.7%

  • pain 23.1%

Any grade

  • CRS 74.4%

  • ICANS 1.3%

  • IRR NR

Ubamatamab (REGN4018) + cemiplimab [86]MUC16 × CD3 + antibody anti-PD-1PROC
1–3 lines		135ORR: 18.2% (95% CI: 5–40)

TEAEs G ≥ 3

  • anemia 23%

  • pain 20%

  • neutropenia 9%

  • fatigue 9%

  • hypo-phosphataemia 6%

irAEs G ≥ 3

  • no events ≥ 5%

Any grade

  • CRS 68.6%

  • ICANS 3%

  • IRR NR

REGN5668 + cemiplimab [87]MUC16 × CD28 + antibody anti-PD-1PROC
≥ 1 line		128ORR: 4%

TRAEs/irAEs G ≥ 3

  • no events ≥ 5%

Any grade

  • CRS 10.7%

  • IRR 7.1%

  • ICANS NR

Catumaxomab [88]EpCAM × CD3PROC
≥ 3 lines		232mPuFI: 29.5 days (95% CI: 15–53)
mOS: 111 days (95% CI: 66–140)

TRAEs G ≥ 3

  • vomiting 13%

  • nausea 13%

  • fatigue 13%

  • ALP increased 9%

  • pain 6%

  • dehydration 6%

Any grade

  • CRS NR

  • IRR/ICANS NR

ABBV-428 [89]Mesothelin × CD40PROC
1–3 lines		159 (all pts)
14 (ovarian cancer)		ORR: 0

TRAEs G ≥ 3

  • pericardial effusion 5%

  • colitis 5%

Any grade

  • IRR 12%

  • CRS 0%

  • ICANS NR

JNJ-78306358 [90]HLA-G × CD3PSOC
PROC
> 2 lines		139 (all pts)
10 (ovarian cancer)		ORR: 0

TEAEs G ≥ 3

  • pain 10.3%

  • anemia 5.1%

  • lymphopenia 5.1%

  • neutropenia 5.1%

  • pneumonia 5.1%

  • pulmonary embolism 5.1%

  • ALT increased 5.1%

  • hypertension 5.1%

Any grade

  • CRS 48.7%

  • IRR/ICANS NR

Brenetafust +/– Gem or NP or PLD [91]Gp100 × CD3PROC
≤ 4 lines		147 (all pts)
Monotherapy: 37
Combination-therapy: 16

Monotherapy:

  • DCR: 58%

  • mPFS: 3.3 mths (95% CI: 2.1–4.0)

Combination-therapy:

  • DCR: 69%

  • mPFS: NA

TRAEs G ≥ 3

  • monotherapy

    • no events ≥ 5%

  • any grade

    • CRS 57%

    • IRR/ICANS NR

TRAEs G ≥ 3

  • combination-therapy

    • fatigue 6%

    • ALT/AST increased 19%/13%

  • any grade

    • CRS 75%

    • IRR/ICANS NR

ICI mechanism
Vudalimab (XmAb20717) [92]PD-1 × CTLA-4PROC1110 (all pts)
20 (ovarian cancer)		ORR:
13% (all pts)
5% (ovarian cancer)

irAEs G ≥ 3

  • rash 16.4%

  • AST/ALT increased 9.1%

  • hyper-glycemia 4.5%

Any grade

  • IRR/CRS/ICANS NR

Cadonilimab (AK104) + platinum + taxane [93]PD-1 × CTLA-4PSOC
Neoadjuvant setting		227R0 resection rate: 76.2%
ORR: 91.6%

TRAEs G ≥ 3

  • NA

  • 12.5% type not specified

irAEs G ≥ 3

  • no events ≥ 5%

Any grade

  • IRR/CRS/ICANS NR

Tebotelimab (MGD013) +/– margetuximab [94]PD-1 × LAG-3> 1 prior line1277 (all pts)
Monotherapy: 40 (ovarian cancer)
Combination: 7 (ovarian cancer)		Monotherapy: ORR 11% (4/36; 95% CI: 3–26)
Combination: ORR 19% [all pts HER2+ regardless PD-L1 (14/72; 95% CI: 11–30)]

TRAEs G ≥ 3

  • monotherapy

    • no events ≥ 5%

irAEs G ≥ 3

  • no events ≥ 5%

  • all grade

    • IRR 7.4%

    • CRS/ICANS NR

Combination:

TRAEs G ≥ 3

  • AST increased 5%

irAEs G ≥ 3

  • no events ≥ 5%

  • any grade

    • IRR 7.1%

    • CRS/ICANS NR

Ivonescimab (AK112/SMT112) [95]PD-1 × VEGFPROC
≥ 3 lines		151 (all pts)
19 (ovarian cancer)		ORR: 26.3%

TRAEs G ≥ 3

  • hypertension 13.7%

  • ALT increased 5.2%

irAEs G ≥ 3

  • no events ≥ 5%

  • any grade

    • IRR 7.8%

    • CRS/ICANS NR

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The Table provides a comprehensive overview of the main clinical trials evaluating bsAbs in ovarian cancer. Only studies with available clinical data in ovarian cancer are reported, with a focus on target specificity, study phase, treatment combinations, and preliminary efficacy or safety outcomes when available. *: Some trials reported treatment-related adverse events (TRAEs), other treatment-emergent adverse events (TEAEs), and immune-related adverse events (irAEs). Only grades ≥ 3 observed in more than 5% of patients are included in this Table; **: adverse events of special interest (AESIs), including cytokine release syndrome (CRS), infusion-related reaction (IRR), and immune effector cell-associated neurotoxicity syndrome (ICANS), are listed in the Table regardless of grade and even if occurring in less than 5% of patients. bsAbs: bispecific antibodies; n: number; G: grade; pts: patients; ICE: immune cell engager; MUC16: mucin 16; PROC: platinum-resistant ovarian cancer; ORR: objective response rate; CI: confidence interval; DCR: disease control rate; NR: not reported; PD-1: programmed cell death protein 1; EpCAM: epithelial cell adhesion molecule; mPuFI: median puncture-free interval; mOS: median overall survival; ALP: alkaline phosphatase; HLA-G: human leukocyte antigen-G; PSOC: platinum sensitive ovarian cancer; ALT: alanine aminotransferase; Gem: gemcitabine; NP: nab-paclitaxel; PLD: pegylated liposomal doxorubicin; mPFS: median progression-free survival; mths: months; NA: not available; AST: aspartate aminotransferase; ICI: immune checkpoint inhibitor; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; LAG-3: lymphocyte activation gene 3; HER2: human epidermal growth factor receptor 2; PD-L1: programmed death-ligand 1; VEGF: vascular endothelial growth factor.