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HER2 ADCs in Advanced Bladder Cancer
From Testing to Treatment: Expert Perspectives on HER2-Targeted ADCs in Advanced Bladder Cancer

Released: April 09, 2026

Shilpa Gupta
Shilpa Gupta, MD
Vadim S. Koshkin
Vadim S. Koshkin, MD
Daniel P. Petrylak
Daniel P. Petrylak, MD
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Key Takeaways
  • HER2 testing by IHC is recommended at the time of diagnosis of advanced urothelial carcinoma, preferably using the most recent biopsy sample.
  • T-DXd is an FDA-approved, guideline-recommended option for HER2 IHC 3+ advanced urothelial carcinoma after prior therapy.
  • Disitamab vedotin, another emerging HER2-targeted ADC, has shown impressive efficacy as monotherapy in the treatment-refractory setting, and in a phase III trial in combination with an anti–PD-1 agent in the frontline setting.

Advanced urothelial carcinoma (UC), most commonly originating in the bladder, has historically been a difficult disease to treat beyond platinum-based chemotherapy, with limited options after progression on first-line therapy. The treatment landscape has shifted dramatically with the approval of enfortumab vedotin (EV) plus pembrolizumab as standard first-line therapy and the emergence of antibody–drug conjugates (ADCs) targeting HER2 for patients with HER2-expressing tumors. HER2 (encoded by the ERBB2 gene) is a cell-surface receptor overexpressed (immunohistochemistry [IHC] 3+) in approximately 13% of advanced urothelial tumors, and more than 50% of advanced UC tumors express some detectable level of HER2, making it a meaningful and actionable target. For oncologists and urologists managing this disease, understanding when and how to test for HER2, which agents are approved, and how to manage their associated toxicities is essential. In this commentary, Daniel P. Petrylak, MD, Vadim S. Koshkin, MD, and Shilpa Gupta, MD, address common questions healthcare professionals (HCPs) face as HER2-directed therapies become increasingly incorporated into the treatment paradigm, as discussed at a recent live symposium.

Which patients are you testing for HER2, and what approach do you recommend?

Daniel P. Petrylak, MD:
HER2 testing should ideally happen when metastatic disease is first identified, not after progression. If a patient experiences failure on EV plus pembrolizumab and then tissue is sent for HER2 testing, a delay is introduced at exactly the moment when they should be moved to the next line of treatment. HCPs should be thinking about HER2 status as part of the initial workup for metastatic disease, so the information is in hand when needed.

For the testing method, IHC on the most recent tumor biopsy is preferred, as it can help determine patient eligibility for trastuzumab deruxtecan (T-DXd). HER2 protein expression is scored from 0 to 3+ based on membranous localization and completeness. IHC 3+ is the threshold for T-DXd eligibility based on the DESTINY-PanTumor02 trial. Next-generation sequencing (NGS) panels such as FoundationOne CDx or Guardant360 CDx provide complementary information on ERBB2 amplification, but it is important to recognize that ERBB2 amplification and HER2 protein expression do not always correlate. Some IHC 3+ tumors are not ERBB2-amplified, and vice versa. For decisions regarding eligibility of patients for T-DXd in the current treatment landscape, IHC expression is most important.

One practical challenge worth highlighting is intratumoral heterogeneity: within the same specimen, different regions may be scored differently (ie, IHC 1+, 2+, and 3+). This is why pathologist experience matters. An experienced pathologist familiar with HER2 scoring is essential for accurate interpretation. When possible, testing a biopsy from a metastatic lesion is preferable to archival primary tissue.

How are you using T-DXd in your practice for patients with HER2-positive bladder cancer?

Vadim S. Koshkin, MD:
T-DXd received FDA approval for HER2-positive (IHC 3+) unresectable or metastatic solid tumors, including UC, after prior systemic therapy and no satisfactory alternatives based on data from the phase II DESTINY-PanTumor02 trial. In this study, patients with HER2 IHC 3+ urothelial cancer achieved a confirmed objective response rate (ORR) of 56.3%. This result is particularly significant given the heavily pretreated nature of the cohort, which had a median of 2.0 prior lines of systemic therapy. Of note, 100% of the UC cohort had received prior platinum-based chemotherapy, and the majority had progressed on prior immunotherapy. Of consequence, NCCN guidelines now recommend T-DXd as a subsequent-line option for patients with HER2-positive (IHC 3+) advanced UC.

In everyday clinical practice, I typically use T-DXd in the third-line setting or later for patients with IHC 3+ disease who have progressed on EV plus pembrolizumab and platinum-based chemotherapy. This sequencing reflects current evidence and the fact that most patients receive EV plus pembrolizumab in the first-line setting. I tend to use T-DXd before taxane-based chemotherapy in this population, given the response data mentioned above.

What are your thoughts about disitamab vedotin and how it might affect practice?

Vadim S. Koshkin, MD:
Disitamab vedotin (DV) is a HER2-targeted ADC that carries the MMAE chemotherapy payload, the same payload found in EV. This ADC is currently approved in China but not yet by the FDA. That said, the clinical data are compelling enough that it is worth discussing now.

The pivotal data come from the phase III RC48-C016 trial, which randomized patients with previously untreated advanced HER2-expressing metastatic UC to DV plus toripalimab (an anti–PD-1 agent) or platinum-based chemotherapy. The combination resulted in an ORR of 76% vs 50% with chemotherapy, with a disease control rate exceeding 90%. Furthermore, the combination demonstrated significant improvements in both progression-free survival (HR: 0.36; P <.001) and overall survival (OS) (HR: 0.54; P <.001), with a median OS of 31.5 months vs approximately 17 months with chemotherapy. These numbers are strikingly similar to the EV plus pembrolizumab data from the phase III EV-302 trial in the first-line setting.

For the regulatory path, the phase II RC48G001 study is evaluating DV monotherapy in patients with HER2-expressing locally advanced or metastatic UC who are refractory to prior therapy (including platinum-containing chemotherapy; Cohorts A and B) and DV plus pembrolizumab in patients who have not received prior systemic treatment (Cohort C). In Cohort C, after a safety run-in phase that included 20 patients, the confirmed ORR was 75%. The trial is currently enrolling, and patients in this cohort are randomized to DV plus pembrolizumab or DV monotherapy. In addition, the global SGNDV-001 phase III trial, which has completed enrollment, is comparing DV plus pembrolizumab to platinum-based chemotherapy in patients with previously untreated HER2-positive (IHC 1+ or greater) disease, and results are anticipated in the next couple of years.

The important implication is that DV combinations may eventually extend HER2-directed treatment to patients with lower HER2 expression (IHC 1+ and 2+), which would encompass more than half of patients with advanced UC. How these treatments fit alongside EV plus pembrolizumab as a potential competing first-line standard, particularly in patients with HER2-expressing tumors, will be one of the pivotal questions in this disease space over the next several years.

What has been your experience with the adverse events associated with these HER2-targeted ADCs?

Shilpa Gupta, MD:
Both T-DXd and DV have manageable toxicity profiles, but each has a defining safety concern that HCPs need to anticipate proactively rather than reactively.

For T-DXd, the most important toxicity is interstitial lung disease (ILD) or pneumonitis, which carries a boxed warning due to the risk of fatal outcomes. In DESTINY-PanTumor02, any-grade ILD occurred in approximately 10% of patients, with grade 3 or higher events (including fatal cases) reported in approximately 1.5% of patients. I think that the “5 S’s” framework is a helpful way to remember the approach:

  • Screen patients
  • Scan for ILD with radiologic scans
  • Synergy, which includes multidisciplinary management
  • Suspend treatment if ILD is suspected
  • Steroids

Do not continue T-DXd through respiratory symptoms, hoping they will resolve. Grade 2 or higher ILD requires permanent discontinuation and prompt initiation of corticosteroids. Other T-DXd toxicities include cytopenias, particularly neutropenia, for which G-CSF support and dose modifications should be considered. Nausea is common, and antiemetics should be given prophylactically. Cardiac toxicity (left ventricular ejection fraction decrease) is notably less common with T-DXd than with HER2-directed agents like trastuzumab, occurring in approximately 4.6% of patients pooled from clinical trials. The recommended starting dose is 5.4 mg/kg every 3 weeks, with defined dosage modifications before discontinuation.

For DV, the primary concern is peripheral neuropathy, a class effect of the MMAE payload shared with EV. Grade 1 peripheral sensory neuropathy occurred in almost 33% of patients and grade 2 or higher in approximately 36% across the RC48 trials. Because grade 2 neuropathy is already functionally disabling (affecting fine motor tasks like buttoning a shirt or maintaining grip), HCPs should not wait for grade 3 before acting. Hold DV at grade 2 neuropathy, resume at a reduced dose once symptoms resolve to grade 1 or less, and permanently discontinue for recurrent grade 3 or grade 4. A quick gait or grip assessment at each visit is worth the time it takes. An important note for sequencing: patients who have received prior EV may have cumulative neuropathy risk from MMAE exposure, which must factor into the decision to use DV subsequently.

Your Thoughts
Are you using HER2-targeted ADCs for your patients with advanced bladder cancer? What has your experience been? Have you gotten feedback from your patients on these agents? What other questions do you have related to the use of HER2 therapy for bladder cancer? Share your perspectives; insights from the community help all of us improve care for our patients.

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