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2025 European Society for Medical Oncology (ESMO) Annual Congress

ESMO 2025: Discussant – Disitamab Vedotin plus Toripalimab Versus Chemotherapy in First-Line Locally Advanced or Metastatic Urothelial Carcinoma (la/mUC) with HER2-Expression

(UroToday.com) The 2025 European Society for Medical Oncology (ESMO) Annual Congress held in Berlin, Germany between October 17th and 21st, 2025 was host to a presidential symposium. Dr. Andrea Necchi discussed the RC48-C016 trial of disitamab vedotin + toripalimab (DV+T) versus chemotherapy as 1st line therapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) with HER-2 expression, previously presented by Dr. Jun Guo.

Dr. Necchi began by noting that only 5-10% of patients are diagnosed with de novo metastatic urothelial carcinoma, with 50% of patients with la/mUC progressing from earlier stages. To date, based on evidence from clinical trials, the longest median overall survival is observed with enfortumab vedotin + pembrolizumab (EV+P) at 31.5 months.1 In contrast to other trials in this space evaluating other systemic therapy regimens that included ‘all comers’ (e.g., gemcitabine + cisplatin +/- nivolumab, maintenance avelumab, M-VAC, gemcitabine + carboplatin),2,3 pre-screening for HER2 IHC expression was required for enrollment in to the RC48-C016 trial.

Dr. Necchi remarked that, in his opinion, HER2 is a suitable target for antibody-drug conjugates (ADCs) in urothelial cancers. 60-80% of tumors express HER2 in modern studies, and ~20% harbor ERBB2 molecular alterations. Additionally, these tumors tend to be positive for TROP2 expression and FGFR3 mutations/fusions, which reflect a predominant luminal subtype.

Numerous studies have evaluated HER2-targeted antibody-drug conjugates (ADCs) in urothelial cancer. The initial studies evaluated trastuzumab + paclitaxel + carboplatin as 1st line therapy for patients with HER2+ metastatic urothelial carcinoma.4 Trastuzumab deruxtecan was granted accelerated approval by the US FDA for HER2 3+ urothelial carcinoma and is being evaluated in ongoing global trials.5 Disitamab vedotin was initially conditionally approved in China for HER2+ advanced urothelial carcinoma in the ≥2nd line setting. It has secured US FDA breakthrough designation for the treatment of 2nd line la/mUC that express HER2. DV monotherapy has demonstrated an objective response rate (ORR) of 51% in 107 patients with HER2+ la/mUC, with median progression-free (PFS) and overall survivals (OS) of 5.9 and 14.2 months, respectively.6

The combination of DV+T has been evaluated in a small trial of 20 patients with HER-2 expressing mUC treated in the 1st line setting. The ORR was 75%, with a 35% complete response (CR) rate.7 In another trial evaluating DV+T in the ≥1st line mUC setting, this combination was associated with an ORR of 73%, with a median PFS and OS of 9.3 and 33.1 months, respectively.8

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The study design of RC48-C016 is illustrated below. The key inclusion criteria were as follows:

  • Treatment-naïve patients with unresectable la/mUC
  • IHC 1+, 2+, or 3+
  • Eligible for platinum-based chemotherapy
  • Excellent performance status

Eligible patients underwent 1:1 randomization to:

  • Disitamab vedotin + toripalimab (no set maximum cycles)
  • Gemcitabine + cisplatin/carboplatin (maximum: 6 cycles) 

The dual primary endpoints were:

  • PFS, by blinded independent central review (BICR)
  • OS

The study design of RC48-C016 is illustrated below. The key inclusion criteria were as follows:

Dr. Necchi made several key comments regarding the study design of this trial:

  • Patients were required to have central lab-confirmed HER2 IHC expression (1+/2+/3+)
  • All patients were required to have an excellent performance status (ECOG 0-1)
  • Avelumab is not approved in China as maintenance therapy following platinum-based chemotherapy
  • EV+P is approved by the National Medial Products Administration (NMPA) in China, but only a few patients can afford this regimen 

He remarked that this is ‘a very important study addressing the needs of a precise geographical area’.

He remarked that this is ‘a very important study addressing the needs of a precise geographical area’.

There were several key study population characteristics that were unique to this trial:

  • None of the patients had ECOG performance status 0-2
    • EV-302: 2.5–3.4% of patients
    • CheckMate-901: 0–0.7%
  • Nearly 50% of patients in RC48-C016 had upper tract disease
    • EV-302: 23.4–30.5%
    • CheckMate-901: 10.9–14.5%
  • Only 51-52% of patients had visceral metastases
    • EV-302: 71.6-–71.9%
  • 16.4% of la/mUC patients were pre-screening failures due to HER2 non-expression 

There were several key study population characteristics that were unique to this trial:

Dr. Necchi noted that the magnitudes of effect (i.e., HRs) for PFS were similar for HER-2 high-expressing (2+/3+) and low-expressing (1+) tumors (HRs: 0.34 and 0.42, respectively). Additionally, there were no appreciable differences in the magnitude of benefit for EV+P versus chemotherapy and DV+T versus chemotherapy, questioning the value of opting for biomarker-selected (i.e., HER2+) regimens, such as DV+T, particularly when 16% of patients will be ineligible for this treatment and EV+P is widely available with a similar relative benefit.

Dr. Necchi noted that the magnitudes of effect (i.e., HRs) for PFS were similar for HER-2 high-expressing (2+/3+) and low-expressing (1+) tumors (HRs: 0.34 and 0.42, respectively). Additionally, there were no appreciable differences in the magnitude of benefit for EV+P versus chemotherapy and DV+T versus chemotherapy, questioning the value of opting for biomarker-selected (i.e., HER2+) regimens, such as DV+T, particularly when 16% of patients will be ineligible for this treatment and EV+P is widely available with a similar relative benefit.

A similar pattern was observed for OS:

Dr. Necchi noted that the magnitudes of effect (i.e., HRs) for PFS were similar for HER-2 high-expressing (2+/3+) and low-expressing (1+) tumors (HRs: 0.34 and 0.42, respectively). Additionally, there were no appreciable differences in the magnitude of benefit for EV+P versus chemotherapy and DV+T versus chemotherapy, questioning the value of opting for biomarker-selected (i.e., HER2+) regimens, such as DV+T, particularly when 16% of patients will be ineligible for this treatment and EV+P is widely available with a similar relative benefit. OS 

Notably, only 4.5% of patients achieved a CR with DV+T, which pales in comparison to EV+P (30.4%) and nivolumab + gemcitabine + cisplatin (21.7%).

Notably, only 4.5% of patients achieved a CR with DV+T, which pales in comparison to EV+P (30.4%) and nivolumab + gemcitabine + cisplatin (21.7%). 

From a global perspective, there is a clear geographic polarization of trials testing anti-HER2 ADCs in urothelial carcinoma – particularly in North America and China.

From a global perspective, there is a clear geographic polarization of trials testing anti-HER2 ADCs in urothelial carcinoma – particularly in North America and China. 

The ongoing DV-001/C5731001 trial (NCT05911295) is evaluating DV + pembrolizumab versus platinum chemotherapy followed by maintenance avelumab in patients with HER2-expressing la/mUC. Do we need to await the results of this trial prior to accepting front line DV + IO therapy on a global stage? Will pembrolizumab be as effective as toripalimab?

The ongoing DV-001/C5731001 trial (NCT05911295) is evaluating DV + pembrolizumab versus platinum chemotherapy followed by maintenance avelumab in patients with HER2-expressing la/mUC. Do we need to await the results of this trial prior to accepting front line DV + IO therapy on a global stage? Will pembrolizumab be as effective as toripalimab? 

Dr. Necchi concluded his discussion of the RC48-C016 trial of disitamab vedotin + toripalimab in HER2-expressing locally advanced/metastatic urothelial carcinoma as follows:

  1. Treatment Efficacy:
    1. The combination of disitamab vedotin and toripalimab resulted in a statistically significant and clinically meaningful improvement in PFS and OS, versus chemotherapy, in patients with HER2+ locally advanced/metastatic urothelial carcinoma
    2. Disitamab vedotin + toripalimab is an additional therapeutic option for such patients
  2. Healthcare Resource Allocation and Patient Selection Strategies:
    1. There were more similarities than differences among the RC48-C016 and EV-302 trials
    2. Provided that enfortumab vedotin + pembrolizumab is available and reimbursable in a certain region, is it worth screening for HER2 expression?
      1. When? For whom? Is there any appreciable benefit for HER2 3+ vs HER2 low-expressing patients?
    3. More pronounced differences in therapeutic pathways are eagerly awaited using biomarker-based strategies
    4. The treatment landscape is rapidly evolving, and therapeutic attrition will impact access to novel therapies
  3. Geographical disparities in trials and drug approval allocation have become noteworthy in this disease space, representing an urgent call for more inclusive trials a=nd equitable access to novel therapies reflecting the standard-of-care. 

Presented by: Andrea Necchi, MD, Chief of Genitourinary Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Professor of Oncology, Vita-Salute San Raffaele University, Milan, Italy

Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center – Tucson, AZ, @rksayyid on X during the 2025 European Society for Medical Oncology (ESMO) Annual Congress, Berlin, Germany, October 17–21, 2025

References:

  1. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888.
  2. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020; 383(13):1218-1230.
  3. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine–cisplatin in advanced urothelial carcinoma. N Engl J Med. 2023;389(19):1778-1789.
  4. Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced HER2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007;25(16):2218-2224.
  5. Meric-Berstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumours: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58.
  6. 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;42(12):1391-1402.
  7. Galsky MD, et al. Preliminary efficacy and safety of disitamab vedotin with pembrolizumab in treatment-naïve HER2-expressing locally advanced or metastatic urothelial carcinoma: RC48G001 Cohort C. ESMO 2024;13–17 Sept, Barcelona. Oral presentation #1967MO.
  8. Zhou L, Yang KW, Zhang S, et al. Disitamab vedotin plus toripalimab in patients with locally advanced or metastatic urothelial carcinoma (RC48-C014): a phase Ib/II dose-escalation and dose-expansion study. Ann Oncol. 2025;36(3):331-339.