Dear Colleagues,

Bispecific antibodies have emerged as a transformative immunotherapeutic platform in solid tumor oncology. By engaging two antigens or immune pathways within a single molecular construct, these agents offer a powerful strategy to redirect immune effector function, enhance tumor selectivity or modulate complementary oncogenic and immunologic axes. Yet, their clinical trajectory reveals a critical gap between preclinical promise and real-world efficacy. With 681 active clinical trials evaluating 183 distinct molecules—a number that has doubled since 2019—the field has achieved remarkable momentum.1 However, medical oncologists must recognize that this enthusiasm requires calibration: a 2023 meta-analysis demonstrated no significant improvement in overall survival (OS), progression-free survival (PFS) or objective response rates (ORR) with bispecific antibodies compared to conventional therapies across most solid tumors.2

Current clinical landscape

The therapeutic pipeline is currently dominated by immune checkpoint combinations, particularly PD-1/CTLA-4 (216 trials) and PD-1/VEGF (56 trials).1 When combined with chemotherapy, these agents demonstrate meaningful clinical benefit: meta-analysis of 2,495 patients showed improved PFS (HR: 0.52), OS (HR: 0.67) and ORR (HR: 0.31) compared to chemotherapy alone, with the greatest survival advantage observed in female and Asian patients, those under 65 years and patients receiving IgG-like bispecifics.3 FDA approvals have provided proof-of-concept in molecularly defined contexts: amivantamab for EGFR-mutant and exon 20 insertion non-small cell lung cancer (NSCLC), zanidatamab for HER2-positive (IHC 3+) biliary tract cancer, zenocutuzumab for NRG1 fusion-positive NSCLC and pancreatic adenocarcinoma and tebentafusp for HLA-A02:01-positive uveal melanoma. These approvals underscore that precision approaches targeting defined molecular populations offer the most viable clinical path forward.4

Toxicity management

Cytokine release syndrome remains the most frequent toxicity of bispecific antibodies, with incidence ranging from 17.5% to 82% depending on the agent and tumor type.5 Neutropenia emerged as the most common hematologic complication with an OR of 14.32 reported in 2021, followed by thrombocytopenia and anemia.6,7 Tumor lysis syndrome shows a concerning rising trend (OR: 58.58 in 2021).6 Agent-specific toxicities require individualized management: talquetamab causes dysgeusia and skin and nail changes, tebentafusp is commonly associated with rash and elevated liver enzymes, while tarlatamab induces dysgeusia.8

The Biomarker imperative

Only 38% of trials incorporate biomarker-driven patient selection—a critical missed opportunity in a field whose most compelling approvals have occurred in molecularly defined populations.1 Among oncogene-targeted bispecifics, HER2-positive alterations, PD-L1 expression and EGFR mutations are the most studied biomarkers, represented in 35, 33 and 26 trials, respectively.1

Strategic path forward

During the next stage of development, the field must resist replicating existing immunotherapy paradigms and pursue genuinely novel target combinations. Bispecific antibodies targeting PD-L1 and TGF-β represent innovative approaches to convert “cold” tumors into immune-inflamed phenotypes, with early efficacy signals observed in NSCLC and biliary tract cancers.1 For practicing oncologists, the clinical message is clear: bispecific antibodies hold transformative potential in molecularly selected populations with appropriate toxicity monitoring, but their broad application across unselected solid tumor patients remains premature.

Sincerely,

Prof. Dr Marcus Vetter
Chief Physician
Head of Center Oncology & Hematology
Cantonal Hospital Baselland (KSBL)
Liestal, Switzerland
marcus.vetter@ksbl.ch

Disclosures

Conflict of interest

Marcus Vetter received honoraria for consultancy from GSK, Roche, Novartis, Exact Sciences, Pfizer, Stemline, AbbVie and ASC Oncology. These funding entities did not play a role in the development of the manuscript and did not influence its content in any way.

Funding

The author has declared that no financial support was received from any organization for the submitted work.

Author contributions

The author has created and approved the final manuscript.