(UroToday.com) The 2025 GU ASCO annual meeting featured a session on the ABCs of antibody drug conjugates and a presentation by Dr. Funda Meric-Bernstam discussing HER2 antibody drug conjugate therapy, a new frontier in bladder cancer. Dr. Meric-Bernstam started her presentation by highlighting that bladder cancer has a HER2 alteration incidence of 12.4%. Across all cancers, 2.7% are HER2 IHC 3+:
However, next generation sequencing is not a substitute for IHC testing in solid tumors. Most, but not all tumors, amplified on next generation sequencing overexpress IHC, however not all patients with HER2 expression/overexpression have HER2 amplification on next generation sequencing. To date, there is still an opportunity for improvement in IHC testing and reporting across all cancers.
Based on the DESTINY-Breast03 trial, trastuzumab deruxtecan has emerged as a powerful next generation antibody drug conjugate. In 2024, Dr. Meric-Bernstam and colleagues published primary results from the DESTINY-PanTumor02 phase II trial assessing trastuzumab deruxtecan in patients with HER2-expressing solid tumors.1 Investigator assessed objective response rates in all patients was 39.0% (95% CI 24.2-55.5) for bladder cancer (n = 41), with a median duration of response of 8.7 months (95% CI 4.2-11.8). In patients with centrally confirmed HER2 IHC, the investigator assessed objective response rate was 56.3% for bladder cancer (95% CI 29.9-80.2):
Among bladder cancer patients, the median progression free survival was 7.0 months (95% CI 4.2-9.7) and the median overall survival was 12.8 months (95% CI 11.2-15.1). On April 5, 2024, the FDA granted accelerated approval to treat adult patients with unresectable or metastatic HER2 positive (IHC 3+) cancer with trastuzumab deruxtecan. This recommendation was based on data from 192 patients from three trials that had IHC 3+ HER2 on testing at enrollment:
- DESTINY-PanTumor02: objective response rate of 51.4% (95% CI 41.7-61.0) and duration of response of 19.4 months (range: 10 – NE)
- DESTINY-Lung01: objective response rate of 52.9% (95% CI 27.8-77.0) and duration of response of 6.9 months (range: 4 – 11.7)
- DESTINY-CRC02: objective response rate of 46.9% (95% CI 34.5-59.8) and duration of response of 5.5 months (range: 1.3 – 9.7)
This represents the first tumor agnostic approval for HER2 and the first tumor agnostic approval for an antibody drug conjugate. Other HER2 antibody drug conjugates are also being evaluated, including trastuzumab emtansine and disitamab vedotin:
In 2024, Sheng and colleagues2 assessed the efficacy and safety of disitamab vedotin in two phase II trials of patients with HER2-positive locally advanced or metastatic urothelial carcinoma. Among 107 patients enrolled, the overall confirmed objective response rate was 50.5% (95% CI, 40.6 to 60.3). By the cutoff date of May 10, 2022, the median duration of response was 7.3 months (95% CI, 5.7 to 10.8), and the median progression free survival and overall survival were 5.9 months (95% CI, 4.3 to 7.2) and 14.2 months (95% CI, 9.7 to 18.8), respectively. As follows is the percent tumor change from baseline:
Based on this data, disitamab vedotin is now in phase III trials being tested as a first line therapy.
HER2 antibody drug conjugates vary significantly in adverse event profile, which is mainly driven by the payload:
- Interstitial lung disease/pneumonitis
- Peripheral neuropathy
- Cytopenia
- Eye toxicity
- Increase in liver function tests
- Cardiac toxicity
Dr. Meric-Bernstam notes that there are multiple anti-HER2 therapies are in development:
- Targeting HER2 signaling
- Monoclonal antibodies
- Trastuzumab, pertuzumab
- Emerging agents: zanidatamab
- Small molecule inhibitors
- Tucatinib, lapatinib, neratinib
- Selective: zongertinib, ZN-1041, IAM-H1
- Pan-HER: TAS2940, BAY 2927088
- Monoclonal antibodies
- Targeting HER2 for immune strategies:
- Bispecific engagers
- Vaccines
- CAR-Ts
- CAR NK cells
- CAR macrophages
- Targeting HER2 by antibody drug conjugates:
- Dual targets
- Other cytotoxic payloads
- Other payloads
HER2 small molecular inhibitors have variation of response by histology/variant. For a specific mutation, different drugs may have differential activity, and for an individual drug, activity may vary by mutation. There may be differences in adaptive responses by disease, influencing activity and combination partner choice.
Dr. Meric-Bernstam concluded her presentation by discussing HER2 antibody drug conjugate therapy, a new frontier in bladder cancer with the following take-home points:
- HER2 is amplified, expressed, and mutated in urothelial cancers: we need to do NGS + HER2 IHC
- Trastuzumab deruxtecan is already FDA approved for HER2 IHC 3+: we need to define the activity for lower expression and/or mutated HER2
- Novel antibody drug conjugates have different payloads and bispecifics
- Antibody drug conjugates include: (i) immunotherapy + other agents, (ii) antibody drug conjugate + antibody drug conjugate, (iii) other antibody drug conjugate + HER2 targeted therapy, and (iv) other novel combinations
- Sequencing therapy will be important to assess
- There is a potential for HER2 targeting as first line therapy
Presented by: Funda Meric-Bernstam, MD, University of Texas MD Anderson Cancer Center, Houston, TX
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025.
References:
- Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results form the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024 Jan 1;42(1):47-58.
- Sheng X, Wang L, He W, et al. Efficacy and Safety of Disitamab Vedotin in Patients with Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials. J Clin Oncol. 2024 Apr 20;42(12):1391-1402.