Discussion
GI toxicities, colorectal, gastric, and esophageal carcinomas, GI cancers, toxicity, nausea and vomiting, Serious hepatic toxicities, all-grade
MALIGNANCIES, DNA DAMAGE, SOLID TUMOR
ADCs are becoming increasingly prominent for the treatment of hematologic and solid tumor malignancies, with eleven ADCs approved globally, six of which, including the human epidermal growth factor receptor 2-directed ADC Enhertu, were approved since 2019 [Overall, TAK-164 had a manageable safety profile with no hepatic toxicity observed up to the dose level of 0.064 mg/kg every 3 weeks. Across all dose levels being evaluated, almost a third of patients reported grade ≥ 3 TEAEs related to TAK-164, but only 3 patients discontinued treatment due to TAK-164-related TEAEs, whilst 2 patients required a dose reduction and 5 patients had to delay their TAK-164 dose. The most frequently reported all-grade TEAEs related to TAK-164 included GI toxicities (nausea and vomiting, both occurring in 22.6% of patients). These are commonly reported in patients with GI cancers and were consistent with the TAK-164 mode of action, and with the TEAEs observed in TAK-264 clinical trials [Serious hepatic toxicities were reported at dose levels above the RP2D; these were unexpected since GCC expression has not been observed in hepatocytes, with the exception of a single study in rats where GCC was shown to be expressed in regenerating hepatocytes [Based on the promising preclinical data in a GCC-expressing human HEK293 cell line and a mouse xenograft model [Collection of biopsies throughout the trial, particularly post-treatment, was challenging; only two pairs of pre-treatment and on-treatment biopsies were collected at the 0.064 mg/kg and the 0.19 mg/kg dose levels. The patient samples from the 0.19 mg/kg dose level showed robust target engagement consistent with those seen in preclinical models. At the 0.064 mg/kg dose level, the baseline sample had high levels of γH2AX, most likely due to smoking status, highlighting a limitation of the DNA damage marker as it captures any instance of DNA damage and not necessarily TAK-164-induced DNA damage. The varied GCC expression across the patient cohort was in line with previously published GCC expression data in colorectal, gastric, and esophageal carcinomas [In conclusion, intravenously administered TAK-164 up to 0.064 mg/kg had a manageable safety profile in patients with various GCC-positive GI cancers. Given the hepatic toxicity signal at higher TAK-164 doses and insufficient clinical benefit observed, further evaluation of single-agent TAK-164 is not warranted in this setting. ADCs are a rapidly evolving class of drugs; considering the existing preclinical evidence for the anti-tumor effect of targeting GCC, future development and investigation of novel anti-GCC ADCs, as single agents or in combination with existing therapy regimens, may lead to clinically effective anticancer treatments.