DISCUSSION
urothelial cancer, tumor, cancers, pembrolizumab, UBC, breast and gastric cancers, tumors, PD‐L1
TUMOR, CANCERS, BREAST CANCER, RECRUITMENT, SECONDARY, PANCREATIC CANCER, TUMORS, CHOLANGIOCARCINOMA
In this phase II study of non‐breast tumor types, HER2‐positivity was detected via gene‐protein assay in 24.3% of patients with UBC, 1.5% with pancreatic cancer, and 8.2% with cholangiocarcinoma. The relatively low prevalence of HER2‐positivity resulted in poor accrual and premature termination of the study. Although centralized HER2 testing may help identify these individuals, the recruitment of such patients is likely to be prohibitively slow if HER2‐positivity rates are as low as those encountered, especially in pancreatic cancer. For biomarker‐driven clinical studies to succeed, we recommend that HER2 testing become part of the standard diagnostic work‐up of non‐breast cancers. Moreover, novel antibody‐drug conjugates like trastuzumab deruxtecan and trastuzumab duocarmazine have resulted in clinically meaningful responses in patients with tumors expressing low HER2 levels,For each of the three cancers studied in KAMELEON, no meaningful differences were observed regarding the proportion of patients with IHC 3+ tumors exhibiting heterogeneous vs. homogenous HER2 staining. Among patients with metastatic UBC, the HER2 staining pattern did not appear to influence the response to T‐DM1, but the number of responders was too small to make a reliable comparison (The concordance between HER2 IHC score and the gene‐protein assay and between ISH and the gene‐protein assay has been estimated at 93% and 96%, respectively.In contrast to guidelines developed for breast and gastric cancers that also consider Due to early termination, KAMELEON was unable to address its primary and secondary objectives fully. Per the original study design, an objective response (CR or PR) in at least four of 27 patients per cohort would have been regarded as evidence of promising efficacy. Five of 13 patients with previously treated HER2‐positive metastatic UBC‐administered single‐agent T‐DM1 exhibited a PR, resulting in an ORR of 38.5%. However, the treatment of metastatic UBC has evolved since KAMELEON was initially planned. PD‐1 or PD‐L1 checkpoint inhibitors (pembrolizumab or atezolizumab), enfortumab vedotin, and erdafitinib were granted accelerated approval by the United States Food and Drug Administration for this indication. For the pancreatic cancer/cholangiocarcinoma cohort, it was not possible to conclude the presence/absence of an efficacy signal due to the small number of enrolled patients (Several early‐phase studies exploring HER2‐targeted therapies in non‐breast tumors, as well as a T‐DM1 combination therapy in breast cancer, may have implications for the treatment of the tumor types studied in KAMELEON. In a phase I study, trastuzumab deruxtecan led to an almost 80% reduction in tumor size in a patient with cholangiocarcinoma.In conclusion, KAMELEON provided preliminary insight into the prevalence of HER2‐positivity, as well as the patterns of HER2 expression, in patients with locally advanced or metastatic non‐breast tumors. The efficacy of single‐agent T‐DM1 observed in patients with advanced UBC is encouraging and suggests that HER2 may represent a viable treatment target for these patients. This is supported by data from a phase I study of trastuzumab duocarmazine, where four of 16 patients with HER2‐expressing urothelial cancer achieved PR.