The Potential of Trastuzumab Deruxtecan as a Tissue Agnostic Drug

Abstract

Background: Many modern anticancer drugs are designed to target specific molecular alterations harbored by the cancer. If a specific drug is able to target these alterations, regardless of the organ or tissue in which the cancer originates, it will often be characterized as a tissue- or tumor agnostic drug. According to the Food and Drug Administration (FDA), a tissue-agnostic drug refers to a drug that targets a specific molecular alteration across multiple cancer types, as defined by organ, tissue, or tumor type. Summary: Over the last 6 years, the FDA has approved seven tissue-agnostic drugs, and more are anticipated in the future. One promising candidate for a tissue-agnostic classification is the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). Currently, T-DXd is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive and HER2-low breast cancer, HER2-positive gastric or gastroesophageal junction adenocarcinoma, and non-small cell lung cancer with activating HER2 mutations. Ongoing clinical research is exploring the potential of T-DXd in various solid tumors that harbor specific HER2 molecular alterations, and encouraging results, including the interim data from the DESTINY-PanTumor02 trial, have been published, which suggest a tissue-agnostic potential. Key Messages: Published phase I data as well as the interim results from the phase II DESTINY-PanTumor02 trial indicates that patients with different HER2-positive advanced solid tumors may benefit from treatment with T-DXd. Based on the currently available data, it seems likely that T-DXd possesses pantumor activity. However, different clinical trials are ongoing, and it will be necessary to see the results from these trials before drawing a final conclusion. When discussing tissue-agnostic potential, it is important to add that for most of the patients enrolled in the DESTINY-PanTumor02 and other trials, few treatment alternatives seem to exist, and T-DXd might be able to cover an unmet medical need.

Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies

“… 97 Trastuzumab deruxtecan (DS‐8201; T‐DXd) is a novel humanized HER2‐directed ADC with a high DAR (8:1) that was approved by the US FDA in 2019. 98 The structure of T‐DXd includes an anti‐HER2 IgG1 antibody (trastuzumab), a stable tetrapeptide‐based cleavable linker, and the exatecan derivative MAAA‐1181a (DXd), a DNA topoisomerase I inhibitor with 10‐fold higher inhibitory potency than irinotecan. T‐DXd has shown antitumor activity not only on HER2‐positive tumor cells but also on neighboring tumor cells with or without HER2 expression through a bystander effect.…”

“…T‐DXd has shown antitumor activity not only on HER2‐positive tumor cells but also on neighboring tumor cells with or without HER2 expression through a bystander effect. 98 The efficacy of TDM1 and T‐DXd has been demonstrated in randomized trials as first‐line, second‐line, or later treatment for solid cancer. Disitamab vedotin (RC48) is composed of: (1) hertuzumab, a new generation anti‐HER2 humanized monoclonal antibody with high specificity and affinity for HER2; (2) a maleimide–cysteine–valine–citrulline–para‐aminobenzyloxycarbonyl linker that releases the cytotoxic payload; and (3) a cytotoxic payload, MMAE, which inhibits microtubule polymerization in actively dividing cells.…”

The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results

“…As noted above, the efficacy of HER2-targeted therapy has been thought to vary between tumors of different primary origin, but the results demonstrating efficacy in such a wide range of areas has raised expectations for the tumor-agnostic effects of T-DXd [49]. In 2023, the DESTINY-PanTumor02 study was initiated as a phase II trial of T-DXd enrolling HER2-positive (IHC 2+ or IHC 3+) solid tumors for which HER2-targeted therapies had rarely or never been evaluated, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other tumors [50].…”