Editor’s Note: The combination of antibody–drug conjugates (ADCs) with immunotherapy has delivered major breakthroughs across several tumor types, including urothelial carcinoma. At the 2025 European Society for Medical Oncology (ESMO) Congress, results from a pivotal Phase III trial (LBA7) were presented showing that the HER2-targeted ADC disitamab vedotin, combined with the PD-1 inhibitor toripalimab, nearly doubled overall survival compared with chemotherapy as first-line treatment for patients with HER2-expressing locally advanced or metastatic urothelial carcinoma (la/mUC). This novel regimen, centered on an innovative ADC, may redefine first-line therapy—though several key questions remain. In the Phase III RC48-C016 trial, with a median follow-up of 18.2 months, patients receiving disitamab vedotin plus toripalimab (n = 243) achieved a median overall survival (OS)—a co-primary endpoint—of 31.5 months, compared with 16.9 months for those given chemotherapy (n = 241) (HR 0.54; 95% CI 0.41–0.73; P < 0.0001). The second co-primary endpoint, median progression-free survival (PFS), also improved markedly—13.1 months vs 6.5 months (HR 0.36; 95% CI 0.28–0.46; P < 0.0001). The objective response rate (ORR) was 76.1% in the combination group versus 50.2% with chemotherapy.
“These positive outcomes are consistent with those reported in the Phase III EV-302/KEYNOTE-A39 trial, where enfortumab vedotin combined with pembrolizumab produced similarly striking results,” noted Professor Andrea Necchi of the Vita-Salute San Raffaele University in Milan, Italy.
Grade ≥ 3 treatment-related adverse events (TRAE) occurred less frequently with disitamab vedotin plus toripalimab than with chemotherapy (55.1% vs 86.9%). Importantly, severe TRAEs in the combination arm included grade ≥ 3 peripheral neuropathy in 4.1% of patients—closely mirroring the EV-302/KEYNOTE-A39 safety profile.
As ADC–immunotherapy combinations continue to evolve, rapid and accurate biomarker testing will be essential—especially for patients with symptomatic or rapidly progressive disease, who may already have other approved first-line options.
“We must acknowledge certain limitations,” said Prof. Necchi. “First, RC48-C016 was conducted exclusively in a Chinese population, so further studies involving more diverse racial and ethnic cohorts across broader geographic regions are urgently needed. Second, given the fast-changing treatment landscape, platinum-based chemotherapy may already be outdated as a control arm. Patients are increasingly reluctant to enroll in trials that randomize them to chemotherapy alone.”
Variability in HER2 biomarker assessment also remains an important consideration. As treatment pathways for urothelial carcinoma become increasingly complex, determining optimal sequencing of therapies poses another challenge.
“We don’t yet know how the disitamab vedotin + toripalimab combination will perform in patients previously treated with an ADC or immune checkpoint inhibitor at earlier disease stages,” Prof. Necchi noted. “Because adjuvant immunotherapy is now a standard option in such cases, achieving additional benefit in pretreated patients may be more difficult than in the treatment-naïve setting.”
He further pointed out that earlier this year, Chinese investigators reported encouraging preliminary results from perioperative disitamab vedotin plus toripalimab therapy in muscle-invasive bladder cancer, suggesting the combination’s potential beyond metastatic disease.
Ongoing research may soon help fill these knowledge gaps. Globally, multiple trials are assessing ADC–immunotherapy combinations across different disease stages. In the first-line setting, a Phase III study comparing disitamab vedotin + pembrolizumab versus platinum chemotherapy followed by maintenance immunotherapy is now enrolling patients in multiple regions—a step expected to pave the way for broader regulatory approval of disitamab vedotin outside China.
“Ultimately, biomarker-driven patient selection remains essential,” Prof. Necchi concluded. “HER2 and NECTIN-4 are both enriched in luminal-type tumors, suggesting that the patient populations benefiting from disitamab vedotin and enfortumab vedotin may partially overlap. Developing diagnostic strategies for novel biomarkers and sequencing ADCs with non-cross-resistant payloads will be key to refining future treatment algorithms and expanding the pool of patients who can benefit from ADC–immunotherapy combinations.”
Professor Andrea Necchi Vita-Salute San Raffaele University, Milan, Italy
