Trastuzumab Deruxtecan FDA Approval and Future Directions for HER2-Positive Bladder Cancer

Vadim Koshkin, MD, of University of California, San Francisco, and Amanda Nizam, MD, of Cleveland Clinic, discuss the trastuzumab deruxtecan FDA approval and the DESTINY-PanTumor02 clinical trial, focusing on its impact on HER2-targeted therapy for metastatic urothelial carcinoma (UC).

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Dr. Nizam: Can you describe the DESTINY-PanTumor02 clinical trial and specifically which patients were included in the UC cohort?

Dr. Koshkin: DESTINY-PanTumor02 was an open-label, phase 2 study that evaluated trastuzumab deruxtecan across various solid tumor cohorts. Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) combining the trastuzumab antibody, which targets HER2, with a topoisomerase payload. This study investigated trastuzumab deruxtecan in HER2-expressing solid tumors. Patients needed to have tumors with HER2 immunohistochemistry (IHC) expression of 2+ or 3+ to qualify, and these were treatment-refractory patients with metastatic disease. The study enrolled nearly 300 patients, specifically 267 across 7 different tumor cohorts, including endometrial, cervical, ovarian, biliary tract, pancreatic, other rare tumors, and a bladder cohort.

The primary endpoint of the study was the objective response rate (ORR). Trastuzumab deruxtecan is already established in treating breast cancer, gastric cancer, and HER2-mutant lung cancer, and this study aimed to explore its efficacy in other HER2-expressing cancers. The overall ORR across all cohorts was 37%, with higher response rates in patients with IHC 3+ tumors. Specifically, 75 patients had IHC 3+ tumors, accounting for about 30% of the population, with a 61% response rate.

Focusing on the UC cohort, there were 41 patients. Investigator-assessed responses were observed in 39% of these patients, with higher responses in those with IHC 3+ tumors, showing a 56% response rate. Updated results for confirmed ORR based on independent central review, which informed the FDA approval, indicated a 37% response rate for the 27 IHC 3+ UC patients. This data led to the FDA approval of trastuzumab deruxtecan for IHC 3+ patients only.

To conclude, the rate of grade 3 and higher adverse events in the overall population was about 40%, with common adverse events including cytopenias and drug-related ILD or pneumonitis, which occurred in about 10% of patients. There were three deaths due to ILD, none in the UC cohort, but it remains an important side effect to monitor.

Dr. Nizam: We often see issues with HER2 testing in breast and gastric cancers. Can you describe how HER2 testing was performed in the DESTINY-PanTumor02 trial and the challenges anticipated with HER2 testing in UC since it is not standardized yet?

Dr. Koshkin: HER2 staining is more established and standardized in breast and gastric cancers, with many labs performing it reflexively. We have not reached that point in bladder cancer yet, but with this approval, it is an important next step. In this study, most patients’ HER2 IHC status was assessed centrally, though some were assessed locally. The central assessment used the HER2 HercepTest from Dako, scored according to ASCO and College of American Pathology guidelines for gastric cancer, as HER2 staining patterns differ among tumor types. Bladder cancer resembles gastric tumors more than breast tumors in staining patterns, influencing this decision.

Dr. Nizam: I know you have been involved in trials for HER2-directed agents in UC. Can you describe the prevalence of HER2 expression in UC?

Dr. Koshkin: This is becoming more relevant with ongoing trials and the recent approval. Initial literature reviews and retrospective studies show that high HER2 expression (IHC 3+ or 2+ and FISH positive) is seen in about 15% of advanced bladder cancer tumors. However, some degree of HER2 expression (IHC 1+ or 2+ and FISH negative) is present in 33-40% of tumors. Combining these, around 50-60% of advanced bladder cancer patients have some HER2 expression, which could benefit from HER2-targeting therapies. Emerging trial data show activity even in low-expression patients.

Dr. Nizam: There are ongoing trials with disitamab vedotin and trastuzumab deruxtecan in combination with other therapies in the frontline setting for UC. How does the recent FDA approval of trastuzumab deruxtecan in the treatment-refractory setting impact the current treatment landscape and these ongoing frontline trials?

Dr. Koshkin: This approval adds another targeted therapy for metastatic UC, the third ADC approved after enfortumab vedotin and sacituzumab govitecan. Unlike these, trastuzumab deruxtecan is for a subset of patients with IHC 3+ tumors, less than 15% of advanced UC patients, and is available only in later-line therapy. While it may not affect a large number of patients, it paves the way for additional HER2-targeted therapies and sets a precedent for HER2 testing in bladder cancer. Ongoing trials, such as those for disitamab vedotin, which targets HER2 differently from trastuzumab, are exploring its use as monotherapy and in combination with pembrolizumab in frontline settings. Robust data from global trials and earlier studies in China suggest potential new treatment options for metastatic urothelial cancer, with trastuzumab deruxtecan’s approval being the first step.

Dr. Nizam: I agree. If disitamab vedotin and pembrolizumab are approved for frontline use, that will not preclude this since it uses a different payload. The more options, the better.

Dr. Koshkin: Exactly. We do not fully understand resistance mechanisms in ADCs yet—whether it is due to target downregulation or payload resistance. We need more data, but this opens up new clinical and research questions.

Dr. Nizam: So the key takeaway is that this is an exciting new option for patients with IHC 3+ HER2 expression in treatment-refractory metastatic UC. Clinicians and researchers should start testing for HER2 upfront when sending next-generation sequencing for other targetable mutations, hopefully standardizing it soon.

Dr. Koshkin: Absolutely. Building a good relationship with your pathologist is crucial to ensure HER2 testing is done, moving us forward in treating advanced UC. You summarized it well; this is a significant first step, and we hope to test more patients for HER2 status.