Over the past two decades, antibody drug conjugates have been tested in clinical trials and approved for use in patients. Researchers recently performed a comprehensive analysis of multiple scientific databases to outline the potential toxicities associated with these medications. Their findings “Treatment-related adverse events of antibody drug conjugates in clinical trials: a systematic review and meta-analysis” are published in Cancer.

“Antibody–drug conjugates (ADCs) have complex molecular structures and have been tested in numerous clinical trials. Therefore, understanding the mechanisms of their toxicity when applied in medical practice is of high importance,” write the investigators.

“In a systematic review and meta-analysis of data gathered from different scientific databases (PubMed, Embase, Cochrane, and Web of Science) between January 1, 2000, and June 7, 2022, the authors applied a random-effects model with logit transformation and evaluated the heterogeneity between studies using I2 statistics. The primary outcome was the incidence and 95% confidence interval (CI) for all-grade and grade ≥3 treatment-related adverse events and differences between different drugs, molecular structures, and cancer types.

“In total, 2511 records were identified that included 169 clinical trials involving 22,492 patients. The overall incidence of treatment-related adverse events was 91.2% (95% CI, 90.7%–91.7%; I2 = 95.9%) for all-grade adverse events and 46.1% (95% CI, 45.2%–47.0%; I2 = 96.3%) for grade ≥3 adverse events. The most common all-grade adverse events were lymphopenia (53.0%; 95% CI, 48.7%–57.3%), nausea (44.1%; 95% CI, 43.2%–44.9%), neutropenia (43.7%; 95% CI, 42.6%–44.9%), blurred vision (40.5%; 95% CI, 37.4%–43.6%), and peripheral neuropathy (39.6%; 95% CI, 38.2%–41.1%); and the most common grade ≥3 adverse events were neutropenia (31.2%; 95% CI, 30.2%–32.3%), hypoesthesia (23.3%; 95% CI, 10.6%–35.9%), thrombocytopenia (22.6%; 95% CI, 21.3%–23.9%), febrile neutropenia (21.2%; 95% CI, 19.3%–23.1%), and lymphopenia (21.0%; 95% CI, 18.2%–23.7%).”

A complex structure

An ADC has a complex structure comprised of an antibody that targets a protein expressed on cancer cells, a toxic compound to kill the targeted cells (also called a payload or warhead), and a linker to join the two. The clinical efficacy and toxicity of ADCs are affected by each component.

In 2000, gemtuzumab ozogamicin was the first ADC approved by the FDA, and more than a dozen ADCs have been approved worldwide to date. To investigate the side effects associated with different ADCs, a team led by Hong Zhu, PhD, of Xiangya Hospital, Central South University, in China, conducted a systematic review and meta-analysis of published clinical trials of ADCs that reported treatment-related toxicities.

The incidence of treatment-related adverse events was 91.2% for all events and 46.1% for serious adverse events (grade 3 or higher). The most common adverse events overall were lymphopenia (too few white blood cells), nausea, neutropenia (too few neutrophils), vision blurriness, and peripheral neuropathy. The most common serious adverse events were neutropenia, hypoesthesia (insensitivity), thrombocytopenia (too few blood platelets), neutropenia with fever, and lymphopenia. Certain ADCs were linked with higher average incidences of adverse events.

“Different ADCs appear to affect various treatment-related adverse events and provide comprehensive data on treatment-related adverse events for ADCs. The current results provide an important reference for clinicians and patients on how to care for toxicities from ADCs in clinical practice,” said Zhu.