Phase II study (KAMELEON) of single‐agent T‐DM1 in patients with HER2‐positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma

Abstract

The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer.We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors.In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types.

Antibody–drug conjugates in urothelial carcinoma: scientometric analysis and clinical trials analysis

“…In preclinical models, T-DM1 demonstrated robust anti-tumor efficacy in bladder cancer cells overexpressing HER-2 ( 109 ). The KAMELEON, a Phase II study, aims to evaluate the optimal tumor response subsequent to T-DM1 administration in patients manifesting HER2-overexpressed solid neoplasms ( 110 ). However, due to insufficient patient enrollment, the study was prematurely terminated and primary endpoints were not achieved.…”

Expression of HER2 in high-grade urothelial carcinoma based on Chinese expert consensus and the clinical effects of disitamab vedotin-tislelizumab combination therapy in the treatment of advanced patients

“…Trastuzumab emtansine (TDM1), an ADC comprising the anti-HER2 antibody rastuzumab, has received FDA approval for treating HER2-positive bladder cancer patients who have previously undergone paclitaxel/rastuzumab therapy. In the phase II KAMELEON study (NCT02999672), patients with advanced urothelial bladder cancer positive for HER2 were included ( de Vries et al, 2023 ). Following a median follow-up duration of 7.39 months (4.11–10.02) and a median exposure duration of 7.14 weeks for the metastatic UBC cohort, an overall response rate (90% CI) of 38.5% (16.57%–64.52%) to TDM1 was achieved.…”

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

“…Among these patients, five exhibited a partial response for an ORR of 38.5%, which would have cleared the ORR threshold of four of 27 patients in the initial design. 87 …”