Dr Jhaveri on the Association Between ADCs and Ocular Toxicities in Breast Cancer

“Overall, there are certain toxicities that we see with certain ADCs due to on-target, off-target mechanisms.”

Komal Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program, clinical director of Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center, discussed ocular toxicities associated with antibody-drug conjugates (ADCs) commonly used to treat patients with breast cancer.

ADCs deliver a specific payload in a targeted manner, thereby minimizing systemic adverse effects (AEs) and achieving a better toxicity profile than would be possible otherwise, Jhaveri began. The ADC construct is essential because it allows oncologists to offer cytotoxic agents that could not be administered as naked payloads or via the naked antibody, she said. However, despite the conceptual benefits of this targeted delivery, there remains room for improvement in optimizing the ADC platform, she emphasized. Efforts must focus on refining aspects like better linker technologies and improving the technology related to how the payload is delivered to the target, she continued. The overarching goal of these technological advancements is the minimization of off-target toxicities, she summarized.

One category of AEs that has been frequently observed with certain ADCs, particularly TROP-2–directed agents such as datopotamab deruxtecan-dlnk (Datroway) and sacituzumab govitecan-hziy (Trodelvy), is ocular toxicities, according to Jhaveri. Fortunately, ocular AEs are typically low grade and do not often lead to severe clinical complications, she stated. High-grade AEs, such as severe grade 3 keratitis or permanent blindness, are rare, she noted. Rather, symptoms like dry eyes are typically observed, she reported.

These ocular AEs may be related to both on-target and off-target mechanisms, Jhaveri clarified. The potential on-target toxicities are believed to stem from the expression of TROP-2 in the cells of the eye, she explained. In contrast, the off-target toxicities are related to the payload itself and how it is cleaved, leading to a bystander effect that can subsequently affect surrounding tissues, she said.

Ocular toxicities are also seen with sacituzumab tirumotecan, which is an investigational TROP-2–directed ADC currently in late-phase development, Jhaveri stated. Although exciting data for sacituzumab tirumotecan were presented at the 2025 ESMO Congress, the molecule is not yet approved by the FDA, she contextualized.