(UroToday.com) The 2025 GU ASCO annual meeting featured a session on the ABCs of antibody drug conjugates and a presentation by Dr. Terence Friedlander discussing novel drug combinations with antibody drug conjugates. One of the main reasons why we should pursue combination therapy in metastatic urothelial carcinoma is that there is attrition of patients across lines of therapy:
Thus, we should be giving our “best” therapies first. Combination therapies with antibody drug conjugates should:
- Overcome antibody drug conjugate resistance
- Have minimal overlapping toxicity
- Enhance target antigen expression/minimize downregulation
- Promote bystander effect
We should also be aiming for synergistic combinations. However, we need to balance three competing aims: (i) increasing anticancer effect, (ii) minimizing adverse events, and (iii) accounting for financial toxicity. Dr. Friedlander then highlighted each of the three promising partners for antibody drug conjugates to combine within metastatic urothelial carcinoma: immunotherapy, chemotherapy, targeted therapy/other modalities.
There is mechanistic rationale for combining antibody drug conjugates with immunotherapy:
MMAE antibody drug conjugates lead to immunogenic cell death. For example, brentuximab vedotin is associated with: (i) DAMPs: calreticulin, extracellular ATP, and HMGB1, (ii) ER stress, (iii) dendritic and T cell pro-inflammatory cytokines (INF-y, TNF-a), and (iv) T cell memory. Importantly, PD-1 immunotherapy enhances this effect, in particular with emerging data from enfortumab vedotin.
Another antibody drug conjugate disitamab vedotin (an anti-HER2 antibody drug conjugate with MMAE payload) has also been shown to potentially pair well with immunotherapy. Disitamab vedotin + toripalimab and disitamab + pembrolizumab combinations have both shown encouraging tumor response:
Dr. Friedlander notes that it is unclear if the payload is more important than the target antigen for antibody drug conjugate + immunotherapy combinations. Does immunogenic cell death occur for antibody drug conjugates with other payloads? At this point, it is unclear, with limited published mechanistic studies. Irinotecan is associated with Treg depletion, increased tumor-infiltrating CD8+ T cells, and tumor PD-L1 upregulation. Of note, sacituzumab govitecan + pembrolizumab likely has additive activity:
Recently, trastuzumab deruxtecan + nivolumab has been assessed in a phase Ib/II trial in HER2+ metastatic urothelial carcinoma with encouraging results [1]. Among 30 patients, the objective response rate was 36.7%, median duration of response was 13.1 months, median progression free survival was 6.9 months, median overall survival was 11 months, with a 23.5% rate of interstitial lung disease/pneumonitis. As follows is the best percentage change in the sum of tumor diameter from baseline with the combination of trastuzumab deruxtecan + nivolumab:
Dr. Friedlander provided the following table of selected ongoing trials of antibody drug conjugates + immunotherapy in metastatic urothelial carcinoma:
Dr. Friedlander then discussed chemotherapy in combination with antibody drug conjugates. Work from the UNITE initiative for enfortumab vedotin suggests that histology matters when considering antibody drug conjugates:
It is also important to select appropriate cytotoxic partners for approved antibody drug conjugates:
- Nectin-4: is decreased in basal/squamous and neuroendocrine-like urothelial carcinoma
- Trop-2: variable basal/squamous subtypes, decreased in neuroendocrine-like urothelial carcinoma
- HER2: is decreased in basal urothelial carcinoma
- EGFR: is increased in basal urothelial carcinoma
To date, there is little published data assessing antibody drug conjugates + platinum based chemotherapy. With regards to antibody drug conjugate + antibody drug conjugate, the dual antibody drug trial (DAD) is assessing enfortumab vedotin + sacituzumab govitecan as 3rd line treatment (post-platinum chemotherapy and post immunotherapy). Initial data was presented at ESMO 2023, noting that at the RP2D for enfortumab vedotin of 1.25 mg/kg and 8 mg/kg for sacituzumab govitecan, the objective response rate was 70% with durable responses. Whether there is a role for adding a PD-1 inhibitor will be assessed in the DAD-IO trial. The following table highlights selected active trials of antibody drug conjugate + antibody drug conjugate for metastatic urothelial carcinoma:
Importantly, Dr. Friedlander notes that the real world cost for antibody drug conjugate combination therapies will be very high:
Finally, Dr. Friedlander discussed antibody drug conjugates + targeted therapy/other modalities. In this space, there is a phase Ib trial of erdafitinib + enfortumab vedotin in metastatic urothelial carcinoma among patients with FGFR2/3 alterations. Additionally, enfortumab vedotin + cabozantinib is being assessed in a phase I/II trial. The phase II BLAD RAD01/GETUC-AFU V07 trial is assessing the utility of antibody drug conjugates + radiation therapy:
Dr. Friedlander concluded his presentation discussing novel drug combinations with antibody drug conjugates with the following take-home points:
- Antibody drug conjugate combinations have the potential to improve outcomes for patients by giving optimal therapies early
- Rational selection of partner therapies, better biomarkers, and appropriate patient selection can enhance efficacy, minimize toxicity, and inform cost and payor decisions
Presented by: Terence W. Friedlander, MD, University of California, San Francisco Medical Center, San Francisco, CA
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:
- Hamilton E, Galsky MD, Ochsenreither S, et al. Trastuzumab deruxtecan with nivolumab in HER2-expressing metastatic breast or urothelial cancer: Analysis of the phase Ib DS8201-A-U105 Study. Clin Cancer Res. 2024 Dec 16;30(24):5548-5558.